CN101495490A - Compostions containing pufa and/or uridine and methods of use thereof - Google Patents

Compostions containing pufa and/or uridine and methods of use thereof Download PDF

Info

Publication number
CN101495490A
CN101495490A CNA2006800270080A CN200680027008A CN101495490A CN 101495490 A CN101495490 A CN 101495490A CN A2006800270080 A CNA2006800270080 A CN A2006800270080A CN 200680027008 A CN200680027008 A CN 200680027008A CN 101495490 A CN101495490 A CN 101495490A
Authority
CN
China
Prior art keywords
another embodiment
acid
administration
uridine
choline
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CNA2006800270080A
Other languages
Chinese (zh)
Other versions
CN101495490B (en
Inventor
R·J·武特曼
I·理查森
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Massachusetts Institute of Technology
Original Assignee
Massachusetts Institute of Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Massachusetts Institute of Technology filed Critical Massachusetts Institute of Technology
Priority claimed from PCT/US2006/019778 external-priority patent/WO2006127627A2/en
Publication of CN101495490A publication Critical patent/CN101495490A/en
Application granted granted Critical
Publication of CN101495490B publication Critical patent/CN101495490B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Landscapes

  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

This invention provides methods of increasing or enhancing the synthesis and levels of phospholipids, synapses, synaptic proteins, and synaptic membranes by a neural cell or brain cell; methods of treating a subject with a memory disorder, memory impairment, neurological disorder, or brain disease or disorder, comprising administering to the subject a composition comprising an omega-3 fatty acid, an omega-6 fatty acid, uridine, a metabolic precursor thereof, or a combination thereof.

Description

The compoistion and method of use that contains polyunsaturated fatty acid and/or uridine
Invention field
The invention provides the enhancing brain development; Improve or increase intelligence; Improve or strengthen neurocyte or the brain cell method to the synthetic and level of phosphatide, cynapse, synapsin and synaptic membrane, it comprises individual or its mother pregnant or lactation is contacted with the composition that comprises omega-fatty acid, ω-6 lipid acid and/or uridine, its metabolic precursor thereof or their combination.
Background of invention
The correct brain development and the factor of intellectual level are not fully defined.The therapy of paediatrics neurological disorder is badly in need of in this area.
Summary of the invention
The invention provides the enhancing brain development; Improve or increase intelligence; Improve or strengthen neurocyte or the brain cell method to the synthetic and level of phosphatide, cynapse, synapsin and synaptic membrane, it comprises individual or its mother pregnant or lactation is contacted with the composition that comprises omega-fatty acid, ω-6 lipid acid and/or uridine, its metabolic precursor thereof or their combination.
In one embodiment, the invention provides the method for the amount of the synaptic membrane that improves individual neurocyte or brain cell, it comprises the pharmaceutical composition that comprises omega-fatty acid or its metabolic precursor thereof to described individual administration, thereby improves the amount of the synaptic membrane of neurocyte or brain cell phosphatide.
In another embodiment, the invention provides the method for the amount of the synaptic membrane that improves individual neurocyte or brain cell, it comprises the pharmaceutical composition that comprises ω-6 lipid acid or its metabolic precursor thereof to described individual administration, thereby improves the amount of the synaptic membrane of neurocyte or brain cell.
In another embodiment, the invention provides the method for the amount of the synaptic membrane that improves individual neurocyte or brain cell, it comprises to described individual administration and comprises (a) omega-fatty acid or its metabolic precursor thereof; (b) pharmaceutical composition of uridine, its acyl derivative, uridine phosphoric acid or CDP-choline, thereby the amount of the synaptic membrane of raising neurocyte or brain cell.
In another embodiment, the invention provides the method for the amount of the synaptic membrane that improves individual neurocyte or brain cell, it comprises to described individual administration and comprises (a) ω-6 lipid acid or its metabolic precursor thereof; (b) pharmaceutical composition of uridine, its acyl derivative, uridine phosphoric acid or CDP-choline, thereby the amount of the synaptic membrane of raising neurocyte or brain cell.
In another embodiment, the invention provides the method for improving or strengthening individual intelligence, it comprises the pharmaceutical composition that comprises omega-fatty acid or its metabolic precursor thereof to described individual administration, thereby improves or strengthen individual intelligence.
In another embodiment, the invention provides the method for improving or strengthening individual intelligence, it comprises the pharmaceutical composition that comprises ω-6 lipid acid or its metabolic precursor thereof to described individual administration, thereby improves or strengthen individual intelligence.
In another embodiment, the invention provides the method for improving or strengthening individual intelligence, it comprises to described individual administration and comprises (a) omega-fatty acid or its metabolic precursor thereof; (b) pharmaceutical composition of uridine, its acyl derivative, uridine phosphoric acid or CDP-choline, thus improve or strengthen individual intelligence.
In another embodiment, the invention provides the method for improving or strengthening individual intelligence, it comprises to described individual administration and comprises (a) ω-6 lipid acid or its metabolic precursor thereof; (b) pharmaceutical composition of uridine, its acyl derivative, uridine phosphoric acid or CDP-choline, thus improve or strengthen individual intelligence.
In another embodiment, the invention provides the method for improving or strengthening offspring's intelligence, it comprises that the mother to described offspring comprises the pharmaceutical composition of omega-fatty acid or its metabolic precursor thereof in the pregnancy duration administration, thereby improves or strengthen offspring's intelligence.
In another embodiment, the invention provides the method for improving or strengthening offspring's intelligence, it comprises that the mother to described offspring comprises the pharmaceutical composition of ω-6 lipid acid or its metabolic precursor thereof in the pregnancy duration administration, thereby improves or strengthen offspring's intelligence.
In another embodiment, the invention provides the method for improving or strengthening offspring's intelligence, it comprises that the mother to described offspring comprises (a) omega-fatty acid or its metabolic precursor thereof in the pregnancy duration administration; (b) pharmaceutical composition of uridine, its acyl derivative, uridine phosphoric acid or CDP-choline, thus improve or strengthen offspring's intelligence.
In another embodiment, the invention provides the method for improving or strengthening offspring's intelligence, it comprises that the mother to described offspring comprises (a) ω-6 lipid acid or its metabolic precursor thereof in the pregnancy duration administration; (b) pharmaceutical composition of uridine, its acyl derivative, uridine phosphoric acid or CDP-choline, thus improve or strengthen offspring's intelligence.
In another embodiment, the invention provides the method for improving or strengthening offspring's intelligence, its mother who is included in described offspring is described offspring between lactation, comprises the pharmaceutical composition of omega-fatty acid or its metabolic precursor thereof to described mother's administration, thereby improves or strengthen offspring's intelligence.
In another embodiment, the invention provides the method for improving or strengthening offspring's intelligence, its mother who is included in described offspring is described offspring between lactation, comprises the pharmaceutical composition of ω-6 lipid acid or its metabolic precursor thereof to described mother's administration, thereby improves or strengthen offspring's intelligence.
In another embodiment, the invention provides the method for improving or strengthening offspring's intelligence, its mother who is included in described offspring is described offspring between lactation, comprises (a) omega-fatty acid or its metabolic precursor thereof to described mother's administration; (b) pharmaceutical composition of uridine, its acyl derivative, uridine phosphoric acid or CDP-choline, thus improve or strengthen offspring's intelligence.
In another embodiment, the invention provides the method for improving or strengthening offspring's intelligence, its mother who is included in described offspring is described offspring between lactation, comprises (a) ω-6 lipid acid or its metabolic precursor thereof to described mother's administration; (b) pharmaceutical composition of uridine, its acyl derivative, uridine phosphoric acid or CDP-choline, thus improve or strengthen offspring's intelligence.
In another embodiment, the invention provides the size of cynapse in the individual brain of raising or the method for number, it comprises the pharmaceutical composition that comprises omega-fatty acid or its metabolic precursor thereof to described individual administration, thereby improves the size or the number of cynapse in the individual brain.
In another embodiment, the invention provides the size of cynapse in the brain that improves individuality or the method for number, it comprises the pharmaceutical composition that comprises ω-6 lipid acid or its metabolic precursor thereof to described individual administration, thereby improves the size or the number of cynapse in the individual brain.
In another embodiment, the invention provides the size that improves cynapse in the individual brain or the method for number, it comprises to described individual administration and comprises (a) omega-fatty acid or its metabolic precursor thereof; (b) pharmaceutical composition of uridine, its acyl derivative, uridine phosphoric acid or CDP-choline, thus the size or the number of cynapse in the individual brain improved.
In another embodiment, the invention provides the size that improves cynapse in the individual brain or the method for number, it comprises to described individual administration and comprises (a) ω-6 lipid acid or its metabolic precursor thereof; (b) pharmaceutical composition of uridine, its acyl derivative, uridine phosphoric acid or CDP-choline, thus the size or the number of cynapse in the individual brain improved.
In another embodiment; the invention provides the method for improving or strengthening offspring's intelligence; it comprises that the mother to described offspring comprises the pharmaceutical composition of uridine, its acyl derivative, uridine phosphoric acid or CDP-choline in the pregnancy duration administration, thereby improves or strengthen offspring's intelligence.
In another embodiment; the invention provides the method for improving or strengthening offspring's intelligence; its mother who is included in described offspring is that described offspring is between lactation; comprise the pharmaceutical composition of uridine, its acyl derivative, uridine phosphoric acid to described mother's administration, thereby improve or strengthen offspring's intelligence.
In another embodiment, the invention provides and comprise (a) uridine, its acyl derivative, uridine phosphoric acid; (b) pharmaceutical composition of ω-6 lipid acid or its metabolic precursor thereof.
In another embodiment, arbitrary method and composition of the present invention includes the administration of omega-fatty acid and choline.In another embodiment, arbitrary method and composition of the present invention includes the administration of omega-fatty acid and choline salt.In another embodiment, arbitrary method and composition of the present invention includes the administration of ω-6 lipid acid and choline.In another embodiment, arbitrary method and composition of the present invention includes the administration of ω-6 lipid acid and choline salt.
In another embodiment, arbitrary method and composition of the present invention includes the administration of the composition that comprises omega-fatty acid, uridine and choline.In another embodiment, arbitrary method and composition of the present invention includes the administration of the composition that comprises omega-fatty acid, uridine and choline salt.In another embodiment, arbitrary method and composition of the present invention includes the administration of the composition that comprises ω-6 lipid acid, uridine and choline.In another embodiment, arbitrary method and composition of the present invention includes the administration of the composition that comprises ω-6 lipid acid, uridine and choline salt.
In another embodiment, arbitrary method and composition of the present invention includes the administration of ω-6 lipid acid and omega-fatty acid.In another embodiment, arbitrary method and composition of the present invention includes the administration of ω-6 lipid acid, omega-fatty acid and uridine.In another embodiment, arbitrary method and composition of the present invention includes the administration of ω-6 lipid acid, omega-fatty acid and choline.In another embodiment, arbitrary method and composition of the present invention includes the administration of ω-6 lipid acid, omega-fatty acid and choline salt.In another embodiment, arbitrary method and composition of the present invention includes the administration of ω-6 lipid acid, omega-fatty acid, uridine and choline.In another embodiment, arbitrary method and composition of the present invention includes the administration of ω-6 lipid acid, omega-fatty acid, uridine and choline salt.
The accompanying drawing summary
The phosphatide that Fig. 1: DHA improves in the PC12 cell is synthetic.PC12 cell and lipid acid overnight incubation are containing C then 14Cultivate in the substratum of the choline of mark.Diagram has been described with the per minute decays (dpm) of every microgram (μ g) DNA and mixed C in phosphatidylcholine 14Mark.DHA: docosahexenoic acid.OA: oleic acid.PA: palmitinic acid. *-p＜0.05。
Increase is a dose-dependently to Fig. 2: DHA to the phosphatide synthetic. *-p＜0.05。 **-p＜0.001。
Fig. 3: the phosphatide that the A. arachidonic acid improves in the SHSY-5Y cell is synthetic.DHA: docosahexenoic acid.AA: arachidonic acid.PA: palmitinic acid. *：p＜0.05。 **：p＜0.001。Increase is a dose-dependently to B.AA to the phosphatide synthetic.
Fig. 4: in whole animal research, the collaborative kephalin level that improves of DHA and UMP. *: be higher than to significance control group (one-way analysis of variance (one-way ANOVA)).A. every milligram (mg) proteinic phosphatide pmol number.Be higher than to the UMP+DHA significance contrast (p＜0.05) (one-way analysis of variance [F (3,28)=4.12; P=0.015]).Two-way analysis of variance (two-wayANOVA) also shows with control group to be compared, the influence of the significance,statistical of DHA [F (1,28)=8.78; P=0.006].B. the phosphatide pmol number of every μ gDNA.Be higher than to the UMP+DHA significance contrast (p=0.020) (one-way analysis of variance [F (3,28)=3.215; P=0.038]).
Fig. 5: DHA is to the influence of brain CDP-choline level (A) and CDP-thanomin level (B).The winding of 8 gerbil jirds is subjected to control diet or contains the diet of UMP, gives DHA (in 5% carrier of gum arabic solution) or only gives 5% gum arabic solution through gavage, continues 28 days.At the 29th day, gather brain and measure the CDP-choline.Data representation is mean value ± SEM.Use single factor or two-way analysis of variance, then Tukey check carrying out statistical analysis.A: when comparing with the value that control diet adds vehicle group, P＜0.05; B: when comparing with the value that the UMP diet adds vehicle group, P＜0.05.
Fig. 6: UMP diet and DHA are to the influence of brain NF-70 (A) and NF-M (B) level, and the diet of describing in gerbil jird acceptance pattern 5 legends continues 21 days (group on the left side) or 28 days (group on the right).At the 22nd day and the 29th day, gather brain and measure NF-70.Value is expressed as mean value ± SEM.Use one-way analysis of variance and Tukey check to carry out statistical analysis, A. compares with the value of control diet+vehicle group, *: P＜0.01; * *: P＜0.001; B). *P＜0.05; *P＜0.01.Cytoskeletal protein 'beta '-tubulin level is not observed significant difference between group.
Fig. 7: UMP diet and DHA are to the influence of brain PSD-95 and synapsin-1 level.A) gerbil jird or accept control diet and add 5% Sudan Gum-arabic by the gavage administration, the diet of perhaps accepting to contain UMP (0.5%) adds the DHA (300mg/kg) in the carrier of being dissolved in by the gavage administration, continues 7 days (group on the left side) or 21 days (group on the right).At ensuing one day, gather brain and measure PSD-95 (A) or synapsin-1 (B).A. value is expressed as mean value ± SEM.Use one-way analysis of variance, then Tukey check carrying out statistical analysis.When comparing with the value that control diet adds vehicle group, *: P＜0.01; * *: P＜0.001; B). *P＜0.05; *P＜0.01.
Fig. 8: dendritic spine density improves in the gerbil jird hippocampus that grows up.
Fig. 9: uridine and/or DHA are to the influence of study.
Figure 10: DHA is to phosphatide synthetic influence in the cultured rat hippocampal neurone.The longitudinal axis: 14CDPM/50 μ l sample.
Detailed Description Of The Invention
The invention provides the enhancing brain growth; Improve or increase intelligence; Improve or strengthen nerve cell or brain cell to the method for the synthetic and level of phosphatide, cynapse, synapsin and synaptic membrane, it comprises individual or its mother pregnant or lactation is contacted with the composition that comprises omega-fatty acid, ω-6 aliphatic acid, uridine or its metabolic precursor thereof or their combination.
In one embodiment, the invention provides the method for the phosphatide level that improves individual nerve cell, it comprises to described individual administration omega-fatty acid or its metabolic precursor thereof, thus the phosphatide level of the nerve cell of raising individuality. In another embodiment, the method to as if developmental brain or its nerve cell. In another embodiment, described to as if be not diagnosed as the adult who suffers from any cognition or neurological disorder. Every kind of possibility represents an embodiment independently of the present invention.
In another embodiment of method and composition of the present invention, omega-fatty acid, ω-6 aliphatic acid, uridine, choline, choline salt or its are combined in administered in pharmaceutical compositions.
In another embodiment, the invention provides the method for the phosphatide level that improves individual brain cell, it comprises described brain cell contact with omega-fatty acid or its metabolic precursor thereof, thus the phosphatide level of the brain cell of raising individuality. In another embodiment, the method to as if developmental brain or its nerve cell. In another embodiment, described to as if be not diagnosed as the adult who suffers from any cognition or neurological disorder. Every kind of possibility represents an embodiment independently of the present invention.
In another embodiment, the invention provides raising or enhancing nerve cell or brain cell to the synthetic method of phosphatide, it comprises to described individuality or brain cell administration omega-fatty acid or its metabolic precursor thereof, thereby improves or strengthen nerve cell or brain cell synthesizing phosphatide. In another embodiment, the method to as if developmental brain or its nerve cell. In another embodiment, described to as if be not diagnosed as the adult who suffers from any cognition or neurological disorder. Every kind of possibility represents an embodiment independently of the present invention.
Provide such as this paper, the result who provides among the embodiment 1 and 5 shows, it is synthetic that neuralward cell and brain cell administration DHA (DHA) (a kind of omega-fatty acid) have improved their phosphatide, as mixing by the mark choline that increase proves. The administration omega-fatty acid has improved the level (embodiment 2) of total phospholipids, phosphatid ylcholine and phosphatidyl-ethanolamine, shows that this effect is not limited to specific phosphatide. The PC12 cell shows the difference in functionality of neuronal cell and is often used as in the art the clone model of neuronal cell. The result who provides among the embodiment 12 shows that phosphatide is synthetic in the neuron in the ω-3 aliphatic acid raising Short-term Culture thing.
In another embodiment, the invention provides the method for the amount of the synaptic membrane that improves individual nerve cell or brain cell, it comprises to described individual administration omega-fatty acid or its metabolic precursor thereof, thus the amount of the synaptic membrane of the nerve cell of raising individuality or brain cell. In another embodiment, the method to as if developmental brain or its nerve cell. In another embodiment, described to as if be not diagnosed as the adult who suffers from any cognition or neurological disorder. Every kind of possibility represents an embodiment independently of the present invention.
The method of measuring the amount of synaptic membrane in the individual brain is well known in the art, such as being described in people (the Facilitation at single synapses probed with optical quantal analysis.Nat Neurosci.2002Jul such as Oertner TG; 5 (7): 657-64); People (the Neuronal activity regulates diffusion across the neck of dendritic spines. Science.2005Nov 4 such as Bloodgood BL; 310 (5749): 866-9); People (the Generalized five-dimensional dynamic and spectral factor analysis.Med Phys.2006 Apr such as El Fakhri G; 33 (4): 1016-24) with Pautler RG.Biological applications of manganese-enhanced magnetic resonance imaging.Methods Mol Med. 2006; 124:365-86). Every kind of method represents an embodiment independently of the present invention.
In another embodiment of method and composition of the present invention, the composition of administration improves nerve cell or brain cell the synthesizing phosphatide of described individuality. In another embodiment, omega-fatty acid improves nerve cell or brain cell the synthesizing phosphatide of described individuality. In another embodiment, ω-6 aliphatic acid improves nerve cell or brain cell the synthesizing phosphatide of described individuality. In another embodiment, uridine, its acyl derivative, uridine phosphoric acid or CDP-C improve nerve cell or brain cell the synthesizing phosphatide of described individuality. In another embodiment, choline improves nerve cell or brain cell the synthesizing phosphatide of described individuality. In another embodiment, choline salt improves nerve cell or brain cell the synthesizing phosphatide of described individuality. Every kind of possibility represents an embodiment independently of the present invention.
The phosphatide that improves by method and composition of the present invention is phosphatidic acid in another embodiment. Term " phosphatidic acid " in another embodiment with term " phosphatide " synonym. In another embodiment, described phosphatide is phosphatid ylcholine (" PC "; Embodiment 1). In another embodiment, described phosphatide is phosphatidyl-ethanolamine (" PE "; Embodiment 2). In another embodiment, described phosphatide is phosphatidylserine (" PS "). In another embodiment, described phosphatide is phosphatidylinositols (" PI "). In another embodiment, described phosphatide is sphingomyelins. In another embodiment, described phosphatide is phosphoglyceride. In another embodiment, described phosphatide is any other phosphatide known in the art. Every kind of possibility represents an embodiment independently of the present invention.
In another embodiment, the PI that greatly improves by method of the present invention is as the bank of one or more second messenger molecules. In another embodiment, described second messenger molecule is Isosorbide-5-Nitrae, 5-InsP3 (IP3). In another embodiment, described second messenger molecule is DG (DAG). In another embodiment, improve protein kinase C (PKC) signal transduction by method and composition of the present invention. In another embodiment, activate the downstream signal transduction pathway of IP3 by method and composition of the present invention. In another embodiment, improve the intracellular Ca2+ level by method and composition of the present invention. In another embodiment, activate the downstream signal transduction pathway of DAG by method and composition of the present invention. In another embodiment, activate the downstream signal transduction pathway of PKC by method and composition of the present invention. In another embodiment, the downstream signal transduction pathway by calcium in the method and composition active cell of the present invention.
In another embodiment, the sphingomyelins that improves by method and composition of the present invention is as the ceramide source. Every kind of possibility represents an embodiment independently of the present invention.
In another embodiment, the signal transduction by one of above approach improves the brain growth among the premature. Every kind of possibility represents an embodiment independently of the present invention.
In another embodiment, the DHA in the method and composition of the present invention and/or uridine are as a large amount of precursors of cell phosphatide. In another embodiment, uridine plays a role by the P2Y acceptor of activation from the UMP of uridine formation. In another embodiment, DHA plays a role by activating syntaxin-3. In another embodiment, use the combination of these mechanism.
In another embodiment, as by as indicated in the data of this paper, administration DHA and/or uridine effectively treat and/or prevent take cynapse formation or myelin and form impaired illness as feature. In another embodiment, described illness is to grow illness. In another embodiment, described illness is the paediatrics neurological disorder. Every kind of possibility represents an embodiment independently of the present invention.
Provide such as this paper, to its pyrimidine metabolic and human similar gerbil jird administration polyunsaturated fatty acid and/or the level (embodiment 7) of uridine raising neural process nerve fibril albumen NF-70 and NF-M, postsynaptic density albumen PSD-95 and vesicle protein syntaxin 1. Therefore, the administration polyunsaturated fatty acid improves the level of the synaptic membrane in brain cell and the nerve cell. In another embodiment, under condition used herein, method and composition of the present invention is also useful in improving the neuron signal transduction. In another embodiment, under condition used herein, method and composition of the present invention is also useful in strengthening nervous function. In another embodiment, under condition used herein, method and composition of the present invention is also in that to improve neural process useful in the outgrowth. Every kind of possibility represents an embodiment independently of the present invention.
The omega-fatty acid that uses in the method and composition of the present invention is omega-3 polyunsaturated fatty acids (PUFA) in another embodiment. In another embodiment, described omega-fatty acid is DHA (embodiment 1-2). DHA is a kind of ω-3, polyunsaturated 22-carbon fatty acid, is also referred to as DHA.
In another embodiment, described omega-fatty acid is alpha-linolenic acid (cis 9,12,15-oc-tadecatrienoic acid). In another embodiment, described omega-fatty acid is parinaric acid (6,9,12,15-parinaric acid). In another embodiment, described omega-fatty acid is eicosatrienoic acid (ETA; ETA). In another embodiment, described omega-fatty acid is eicosatetraenoic acid (8,11,14,17-eicosatetraenoic acid). In another embodiment, described ω-3 aliphatic acid is eicosapentaenoic acid (EPA; EPA). In another embodiment, described omega-fatty acid is that DHA (is also referred to as " EPA "; 5,7,9,11,14,17-DHA). In another embodiment, described omega-fatty acid is clupanodonic acid (DPA; DPA). In another embodiment, described ω-3 aliphatic acid is nisioic acid (6,9,12,15,18,21-nisioic acid). In another embodiment, described omega-fatty acid is any other omega-fatty acid known in the art. Every kind of ω-3 aliphatic acid represents an embodiment independently of the present invention.
In another embodiment, described omega-fatty acid is the anti-inflammatory polyunsaturated fatty acid. In another embodiment, described anti-inflammatory polyunsaturated fatty acid is eicosapentaenoic acid (EPA; EPA). In another embodiment, described anti-inflammatory polyunsaturated fatty acid is DHA. In another embodiment, described anti-inflammatory polyunsaturated fatty acid is any other anti-inflammatory polyunsaturated fatty acid known in the art. Every kind of possibility represents an embodiment independently of the present invention.
Provide such as this paper, DHA, EPA and AA improve cephalin level (embodiment 8). Therefore, effect as herein described is not that specific polyunsaturated fatty acid is distinctive, but may extend to ω-3 and omega 6 polyunsaturated fatty acid family under condition used herein.
In another embodiment, described omega-fatty acid is the metabolic precursor thereof of DHA. In another embodiment, described metabolic precursor thereof is EPA). In another embodiment, described metabolic precursor thereof is clupanodonic acid (DPA; DPA). Every kind of possibility represents an embodiment independently of the present invention.
In another embodiment, " metabolic precursor thereof " refers to improve the compound of fatty acid concentration in blood flow or the tissue. In another embodiment, " metabolic precursor thereof " refers to that by the tissue of described individuality or enzymes metabolism be the compound of aliphatic acid. In another embodiment, " metabolic precursor thereof " refers to by the target cell metabolism to be the compound of aliphatic acid. Every kind of possibility represents an embodiment independently of the present invention.
In another embodiment of method and composition of the present invention, the metabolic precursor thereof of omega-fatty acid is alpha-linolenic acid, and it is as the precursor of EPA (eicosapentaenoic acid) and DHA (DHA). In another embodiment, described metabolic precursor thereof is any other ω-3 aliphatic acid precursor known in the art. Every kind of omega-fatty acid precursor represents an embodiment independently of the present invention.
" polyunsaturated fatty acid " refers to omega-fatty acid in another embodiment. In another embodiment, this term refers to ω-6 aliphatic acid. In another embodiment, this term refers to have the aliphatic acid of two or more pairs key. In another embodiment, this term refers to have the aliphatic acid of two two keys. In another embodiment, this term refers to have the aliphatic acid of three two keys. In another embodiment, this term refers to have the aliphatic acid that surpasses three two keys. Every kind of possibility represents an embodiment independently of the present invention.
In another embodiment, the invention provides the method for the amount of the synaptic membrane that improves individual nerve cell or brain cell, it comprises to described individual administration ω-6 aliphatic acid or its metabolic precursor thereof, thus the amount of the synaptic membrane of the nerve cell of raising individuality or brain cell. In another embodiment, the method to as if developmental brain or its nerve cell. In another embodiment, described to as if be not diagnosed as the adult who suffers from any cognition or neurological disorder. Every kind of possibility represents an embodiment independently of the present invention.
In another embodiment, the invention provides the method for the phosphatide level that improves individual nerve cell or brain cell, it comprises to described individual administration ω-6 aliphatic acid or its metabolic precursor thereof, thereby improves individual nerve cell or the phosphatide level of brain cell. In another embodiment, the method to as if developmental brain or its nerve cell. In another embodiment, described to as if be not diagnosed as the adult who suffers from any cognition or neurological disorder. Every kind of possibility represents an embodiment independently of the present invention.
In another embodiment, the invention provides the method for the phosphatide level that improves brain cell, it comprises described brain cell is contacted with ω-6 aliphatic acid or its metabolic precursor thereof, thus the phosphatide level of raising brain cell. In another embodiment, the method to as if developmental brain or its nerve cell. In another embodiment, described to as if be not diagnosed as the adult who suffers from any cognition or neurological disorder. Every kind of possibility represents an embodiment independently of the present invention.
In another embodiment, the invention provides raising or enhancing neurocyte or brain cell synthetic method to phosphatide, it comprises to described individuality or brain cell administration ω-6 lipid acid or its metabolic precursor thereof, thereby improves or strengthen neurocyte or brain cell synthesizing phosphatide.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
Provide as this paper, the result who provides among the embodiment 3 shows, it is synthetic that neuralward cell and brain cell administration arachidonic acid (a kind of ω-6 lipid acid) improve their phosphatide, as mixing by the mark choline that increase proves thereafter.The SHSY-5Y cell is used as the model system of neuronal function from human nerve's blastoma.In another embodiment, the raising of phosphatide synthetic causes its level to raise.
In another embodiment, described ω-6 lipid acid is omega 6 polyunsaturated fatty acid (PUFA).In another embodiment, described ω-6 lipid acid is arachidonic acid (embodiment 3).Arachidonic acid is a kind of ω-6,20-carbon fatty acid, is also referred to as 5,8,11, the 14-eicosatetraenoic acid.In another embodiment, described ω-6 lipid acid is arachidonic metabolic precursor thereof.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, described ω-6 lipid acid is linolic acid (9,12 octadecadienoic acid).In another embodiment, described ω-6 lipid acid is conjugated linolic acid (CLA).In another embodiment, described ω-6 lipid acid is gamma-linolenic acid (6,9, the 12-punicic acid).In another embodiment, described ω-6 lipid acid is eicosadienoic acid (11, the 14-eicosadienoic acid).In another embodiment, described ω-6 lipid acid is height-gamma-linolenic acid (8,11, the 14-eicosatrienoic acid).In another embodiment, described ω-6 lipid acid is two dodecadienoic acids (13,16-two dodecadienoic acids).In another embodiment, described ω-6 lipid acid is docosatetratenoic acid (7,10,13, the 16-docosatetratenoic acid).In another embodiment, described ω-6 lipid acid is 4,7,10,13, the 16-clupanodonic acid.In another embodiment, described ω-6 lipid acid is dihomo-gamma-linolenic acid (DGLA).In another embodiment, described ω-6 lipid acid is any other ω-6 lipid acid known in the art.Every kind of ω-6 lipid acid is represented an embodiment independently of the present invention.
In another embodiment of method and composition of the present invention, the metabolic precursor thereof of ω-6 lipid acid is a linolic acid.In another embodiment, described metabolic precursor thereof is trans isooleic acid (TVA) (a kind of linolic acid source).In another embodiment, described metabolic precursor thereof is any other ω-6 lipid acid precursor known in the art.Every kind of ω-6 lipid acid precursor is represented an embodiment independently of the present invention.
In another embodiment, the invention provides a kind of pharmaceutical composition, it comprises (a) uridine, its acyl derivative, uridine phosphoric acid; (b) ω-6 lipid acid or its metabolic precursor thereof.
In another embodiment, the invention provides a kind of pharmaceutical composition, it comprises (a) uridine, its acyl derivative, uridine phosphoric acid; (b) omega-fatty acid or its metabolic precursor thereof.
In another embodiment, pharmaceutical composition of the present invention also comprises choline.In another embodiment, described pharmaceutical composition also comprises choline salt.In another embodiment, described pharmaceutical composition also comprises the metabolic precursor thereof of choline salt.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, ω-6 lipid acid that exists in the pharmaceutical composition of the present invention or its metabolic precursor thereof are any ω-6 lipid acid disclosed herein or metabolic precursor thereof.In another embodiment, the omega-fatty acid that exists in the pharmaceutical composition of the present invention or its metabolic precursor thereof are any omega-fatty acid disclosed herein or metabolic precursor thereof.In another embodiment, the uridine that exists in the pharmaceutical composition of the present invention, its acyl derivative or uridine phosphoric acid are any uridine disclosed herein, its acyl derivative or uridine phosphoric acid.In another embodiment, the choline that exists in the pharmaceutical composition of the present invention or its choline salt are any choline disclosed herein or choline salt.
In another embodiment, ω-6 lipid acid that exists in the pharmaceutical composition of the present invention or its metabolic precursor thereof can exist by any dosage disclosed herein.In another embodiment, the omega-fatty acid that exists in the pharmaceutical composition of the present invention or its metabolic precursor thereof can exist by any dosage disclosed herein.In another embodiment, the uridine that exists in the pharmaceutical composition of the present invention, its acyl derivative or uridine phosphoric acid can exist by any dosage disclosed herein.In another embodiment, the choline that exists in the pharmaceutical composition of the present invention or its choline salt can exist by any dosage disclosed herein.
Every kind of ω-6 lipid acid or its metabolic precursor thereof; Omega-fatty acid or its metabolic precursor thereof; Uridine, its acyl derivative or uridine phosphoric acid; Choline or its choline salt; And dosage is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method for the phosphatide level that improves individual neurocyte or brain cell, it comprises to described individual administration and comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline; (b) composition of omega-fatty acid or its metabolic precursor thereof, thus the individual neurocyte or the phosphatide level of brain cell improved.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
Provide as this paper, omega-fatty acid and ω-6 lipid acid improve the synthetic and phosphatide level of phosphatide synergistically with uridine (as UMP) separately.In another embodiment, described uridine phosphoric acid is uridylic acid (UMP) (UMP).
In another embodiment, the invention provides the method for the phosphatide level that improves brain cell, it comprises described brain cell and comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline; (b) composition of omega-fatty acid or its metabolic precursor thereof contact, thereby the phosphatide level of raising brain cell.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method for the phosphatide level that improves individual neurocyte or brain cell, it comprises to described individual administration and comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline; (b) composition of ω-6 lipid acid or its metabolic precursor thereof, thus the individual neurocyte or the phosphatide level of brain cell improved.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method for the phosphatide level that improves brain cell, it comprises described brain cell and comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline; (b) composition of ω-6 lipid acid or its metabolic precursor thereof contact, thereby the phosphatide level of raising brain cell.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides and improve or strengthen neurocyte or the brain cell synthetic method to phosphatide, it comprises to described individuality or brain cell administration and comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline; (b) composition of omega-fatty acid or its metabolic precursor thereof, thus improve or strengthen neurocyte or brain cell synthesizing phosphatide.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides and improve or strengthen neurocyte or the brain cell synthetic method to phosphatide, it comprises to described individuality or brain cell administration and comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline; (b) composition of ω-6 lipid acid or its metabolic precursor thereof, thus improve or strengthen neurocyte or brain cell synthesizing phosphatide.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method for the amount of the synaptic membrane that improves individual neurocyte or brain cell, it comprises to described individuality or brain cell administration and comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline; (b) composition of omega-fatty acid or its metabolic precursor thereof, thereby the amount of the synaptic membrane of the neurocyte of raising individuality or brain cell.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method for the amount of the synaptic membrane that improves individual neurocyte or brain cell, it comprises to described individuality or brain cell administration and comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline; (b) composition of ω-6 lipid acid or its metabolic precursor thereof, thereby the amount of the synaptic membrane of the neurocyte of raising individuality or brain cell.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment of method and composition of the present invention, stimulate the synthetic phosphatide level that improves in target brain cell or the target neurocyte of phosphatide.In another embodiment, competent phosphatide level is important in the many aspects of neural function as cynapse signal transduction, neurotransmitter function, spinous process branch with to aspects such as outgrowths, and it is in another embodiment, also very important aspect correct brain function.
In another embodiment, the invention provides the method that improves the brain PC level in the individuality, it comprises to described individual administration composition of the present invention, and wherein said composition improves synthetic to phosphatide of the neurocyte of described individuality or brain cell, thereby improves the brain PC level in the individuality.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method that improves the brain SM level in the individuality, it comprises to described individual administration composition of the present invention, and wherein said composition improves synthetic to phosphatide of the neurocyte of described individuality or brain cell, thereby improves the brain SM level in the individuality.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method that improves the brain PI level in the individuality, it comprises to described individual administration composition of the present invention, and wherein said composition improves synthetic to phosphatide of the neurocyte of described individuality or brain cell, thereby improves the brain PI level in the individuality.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method that improves the brain PE level in the individuality, it comprises to described individual administration composition of the present invention, and wherein said composition improves synthetic to phosphatide of the neurocyte of described individuality or brain cell, thereby improves the brain PE level in the individuality.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method that improves the brain PS level in the individuality, it comprises to described individual administration composition of the present invention, and wherein said composition improves synthetic to phosphatide of the neurocyte of described individuality or brain cell, thereby improves the brain PS level in the individuality.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method for improving the cognitive function in the individuality, it comprises to described individual administration composition of the present invention, and wherein said composition improves synthetic to phosphatide of the neurocyte of described individuality or brain cell, thereby improves the cognitive function in the individuality.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
Provide as this paper, DHA and UMP improve animal performance (embodiment 10) in memory test.Therefore, method and composition of the present invention is effective in improvement and hypermnesis and other cognitive functions.
Provide as this paper, administration polyunsaturated fatty acid and/or uridine improve the amount of kephalin level and synthetic, proteic level of spinous process neuroneme and synaptic membrane.Therefore, the compositions and methods of the invention improve and strengthen cognitive function, neural function, intelligence, cynapse transmission and neurotransmitter levels and activity.
In another embodiment, the invention provides the method for improving the neural function in the individuality, it comprises to described individual administration composition of the present invention, and wherein said composition improves synthetic to phosphatide of the neurocyte of described individuality or brain cell, thereby improves the neural function in the individuality.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the neural function that improves by method of the present invention is the cynapse transmission.In another embodiment, described cynapse transmission is adjacent with motor neuron.In another embodiment, described cynapse transmission is adjacent with relay cell.In another embodiment, described cynapse transmission is adjacent with Sensory neurone.A representative embodiment independently of the present invention is transmitted in every type cynapse.
In another embodiment, improvement or enhanced neural function are the functions of neurotransmitter.In one embodiment, improve or strengthen the function of neurotransmitter by improving the level generation of neurotransmitter in the cynapse.In another embodiment, improving or strengthen neurotransmitter function takes place by improving the release of neurotransmitter in cynapse.In another embodiment, improve or strengthen neurotransmitter function to take place and do not change the level or the release of neurotransmitter in the cynapse.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, " improvement " cognitive function or neural function or intelligence are meant and realize that it improves 10%.In another embodiment, this term is meant and realizes that it improves 20%.In another embodiment, this term is meant and realizes that it improves 30%.In another embodiment, this term is meant and realizes that it improves 40%.In another embodiment, this term is meant and realizes that it improves 50%.In another embodiment, this term is meant and realizes that it improves 60%.In another embodiment, this term is meant and realizes that it improves 70%.In another embodiment, this term is meant and realizes that it improves 80%.In another embodiment, this term is meant and realizes that it improves 90%.In another embodiment, this term is meant and realizes that it improves 100%.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, with begin treatment before function recently estimate the improvement of cognitive function or neural function or intelligence mutually.In another embodiment, recently estimate described improvement mutually with untreated individuality.In another embodiment, for example check to wait according to standardized standard and estimate described improvement.Every type cognitive activities is improved a representative embodiment independently of the present invention.
In another embodiment, estimate the improvement of cognitive function or neural function or intelligence by the linking number between the neurone in the described individual brain.In another embodiment, by in the described individual brain or the number of the capillary vessel in the specific region of described individual brain estimate described improvement.In another embodiment, estimate described improvement by nervous activity.In another embodiment, estimate described improvement by neural function.In another embodiment, estimate described improvement by linguistic function.In another embodiment, estimate described improvement by ability to exchange.In another embodiment, estimate described improvement by the level of measuring vagusstoff or other neurotransmitters or the brain chemical substance relevant with cognitive function.In another embodiment, estimate described improvement by the brain of the described individuality of PET (positron emission tomography) scanner (PET) scanning.In another embodiment, estimate described improvement by the brain of the described individuality of Magnetic resonance imaging (MRI) scanning.In another embodiment, estimate described improvement the (people such as Peila R, Stroke.32:2882-9,2001) by cognitive ability screening instrument (CASI).In another embodiment, estimate described improvement by test such as for example test disclosed herein (embodiment 13).In another embodiment, adopt slight mental status test (Mini-Mental test) (people such as Tsai L, The Mini-MentalState Test and computerized tomography.Am J Psychiatry.1979Apr; 136 (4A): 436-8).It is well known in the art estimating the additive method that recognizing ability improves, and for example is described in people (Schizophr Res.2004Oct 1 such as Antonova E; 70 (2-3): 117-45) and Cognitive Function Analysis (Greenwood Pub Group, 1998) in.Every kind of method is represented an embodiment independently of the present invention.
In another embodiment, the invention provides and improve individual brain or the amount of the middle neurotransmitter of central nervous system (CNS) or the method for level, described method comprises to described individual administration omega-fatty acid or its metabolic precursor thereof, wherein said omega-fatty acid or its metabolic precursor thereof improve the synthetic of phosphatide in described brain or the central nervous system, thereby improve the amount or the level of neurotransmitter in individual brain or the central nervous system.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the amount of neurotransmitter in individual brain of raising or the central nervous system or the method for level, described method comprises to described individual administration ω-6 lipid acid or its metabolic precursor thereof, wherein said ω-6 lipid acid or its metabolic precursor thereof improve the synthetic of phosphatide in described brain or the central nervous system, thereby improve the amount or the level of neurotransmitter in individual brain or the central nervous system.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the amount that improves neurotransmitter in individual brain or the central nervous system or the method for level, described method comprises to described individual administration and comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline; (b) composition of omega-fatty acid or its metabolic precursor thereof, phosphatide is synthetic in wherein said composition raising brain or the central nervous system, thereby improves the amount or the level of neurotransmitter in individual brain or the central nervous system.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the amount that improves neurotransmitter in individual brain or the central nervous system or the method for level, described method comprises to described individual administration and comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline; (b) composition of ω-6 lipid acid or its metabolic precursor thereof, phosphatide is synthetic in described composition raising brain or the central nervous system, thereby improves the amount or the level of neurotransmitter in individual brain or the central nervous system.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In one embodiment, its level or activity or release are vagusstoffs by the neurotransmitter of method affect of the present invention.In another embodiment, described neurotransmitter is a Dopamine HCL.In another embodiment, described neurotransmitter is a L-glutamic acid.In another embodiment, described neurotransmitter is a thrombotonin.In another embodiment, described neurotransmitter is serotonin (5-HT).In another embodiment, described neurotransmitter is GABA.In another embodiment, described neurotransmitter is any other neurotransmitter known in the art.Every type neurotransmitter is represented an embodiment independently of the present invention.
In another embodiment, the invention provides and improve or strengthen individual brain cell repeats to discharge the neurotransmitter of significant quantity in cynapse the method for ability, described method comprises to described individual administration omega-fatty acid or its metabolic precursor thereof, wherein said omega-fatty acid or its metabolic precursor thereof improve described brain cell synthetic to phosphatide, thereby improve or strengthen individual brain cell repeats to discharge the neurotransmitter of significant quantity in cynapse ability.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
Dendritic spine density rising (embodiment 9) in the animal of administration DHA and/or uridine is provided as this paper.Therefore, composition of the present invention improves the number and the size of cynapse in the brain and strengthens brain cell carries out signal transduction by neurotransmitter ability.
In another embodiment, the invention provides and improve or strengthen individual brain cell repeats to discharge the neurotransmitter of significant quantity in cynapse the method for ability, described method comprises to described individual administration ω-6 lipid acid or its metabolic precursor thereof, wherein said ω-6 lipid acid or its metabolic precursor thereof improve described brain cell synthetic to phosphatide, thereby improve or strengthen individual brain cell repeats to discharge the neurotransmitter of significant quantity in cynapse ability.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides and improve or strengthen individual brain cell repeats to discharge the neurotransmitter of significant quantity in cynapse the method for ability, described method comprises to described individual administration and comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline; (b) composition of omega-fatty acid or its metabolic precursor thereof, wherein said composition improve described brain cell synthetic to phosphatide, thereby improve or strengthen individual brain cell repeats to discharge the neurotransmitter of significant quantity in cynapse ability.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides and improve or strengthen individual brain cell repeats to discharge the neurotransmitter of significant quantity in cynapse the method for ability, described method comprises to described individual administration and comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline; (b) composition of ω-6 lipid acid or its metabolic precursor thereof, wherein said composition improve described brain cell synthetic to phosphatide, thereby improve or strengthen individual brain cell repeats to discharge the neurotransmitter of significant quantity in cynapse ability.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
Provide as this paper, administration polyunsaturated fatty acid and/or uridine improve the amount of kephalin level and synthetic, proteic level of spinous process neuroneme and synaptic membrane.Therefore, the compositions and methods of the invention improve and strengthen neurotransmitter release and amount.
In another embodiment, the invention provides the method for improving or strengthening individual intelligence, it comprises to described individual administration omega-fatty acid or its metabolic precursor thereof, neurocyte that wherein said omega-fatty acid or the raising of its metabolic precursor thereof are individual or brain cell are synthetic to phosphatide, thereby improve or strengthen the intelligence of individuality.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method for improving or strengthening individual intelligence, it comprises to described individual administration ω-6 lipid acid or its metabolic precursor thereof, wherein said ω-6 lipid acid or its metabolic precursor thereof improve synthetic to phosphatide of the neurocyte of described individuality or brain cell, thereby improve or strengthen individual intelligence.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method that improves the number of cynapse sour jujube in individual brain or its zone, it comprises to described individual administration composition of the present invention, wherein said composition improves synthetic to phosphatide of the neurocyte of described individuality or brain cell, thereby improves individual brain or the number of the cynapse sour jujube in its zone.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method for improving or strengthening individual intelligence, it comprises to described individual administration and comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline; (b) composition of omega-fatty acid or its metabolic precursor thereof, wherein said composition improve synthetic to phosphatide of the neurocyte of described individuality or brain cell, thereby improve or strengthen individual intelligence.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method for improving or strengthening individual intelligence, it comprises to described individual administration and comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline; (b) composition of ω-6 lipid acid or its metabolic precursor thereof, wherein said composition improve synthetic to phosphatide of the neurocyte of described individuality or brain cell, thereby improve or strengthen individual intelligence.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, be language intelligence by method and composition improvement of the present invention or enhanced intelligence.In another embodiment, described intelligence is musical intelligence.In another embodiment, described intelligence is space intelligence.In another embodiment, described intelligence is limb motion intelligence (bodily intelligence).In another embodiment, described intelligence is interpersonal intelligence.In another embodiment, described intelligence is introspection intelligence (intrapersonal intelligence).In another embodiment, described intelligence is interpersonal intelligence.In another embodiment, described intelligence is logical mathematics intelligence.In another embodiment, described intelligence is the intelligence of any other type known in the art.Every type intelligence is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method that promotes or strengthen the brain reparation, it comprises to described individual administration omega-fatty acid or its metabolic precursor thereof, thereby promotes or strengthen the brain reparation.In another embodiment, this method to as if developmental brain or its neurocyte.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method that promotes or strengthen the brain reparation, it comprises to described individual administration ω-6 lipid acid or its metabolic precursor thereof, thereby promotes or strengthen the brain reparation.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides and promote or strengthen the method that brain is repaired, it comprises to described individual administration and comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline; (b) composition of omega-fatty acid or its metabolic precursor thereof, thus promote or strengthen the brain reparation.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides and promote or strengthen the method that brain is repaired, it comprises to individual administration and comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline; (b) composition of ω-6 lipid acid or its metabolic precursor thereof, thus promote or strengthen the brain reparation.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the brain reparation after promotion or the enhancing apoplexy.In another embodiment, the brain reparation after promotion or the enhancing brain injury.In another embodiment, promote or strengthen the brain reparation that to carry out after any other incident, disease or the illness that brain repairs known in the art.Every kind of possibility representative another embodiment of the present invention.
In another embodiment, the invention provides the method for improving or strengthening offspring's intelligence, it comprises that mother to described offspring is in pregnancy duration administration omega-fatty acid or its metabolic precursor thereof, wherein said omega-fatty acid or its metabolic precursor thereof improve synthetic to phosphatide of described offspring's neurocyte or brain cell, thereby improve or strengthen offspring's intelligence.
When to mother's administration gestation or lactation, the compositions and methods of the invention cause effectively to described offspring's administration polyunsaturated fatty acid and/or uridine.Provide as this paper, administration polyunsaturated fatty acid and/or uridine improve the amount of kephalin level and synthetic, proteic level of spinous process neuroneme and synaptic membrane.Therefore, administration mother's composition for improved gestation of the present invention or lactation offspring's brain development and increase intelligence and cognitive function and intelligence.
Provide as this paper, the level of the cynapse sour jujube number that obtains among the offspring of the gestation of administration DHA and/or uridine and animal lactation increases (embodiment 9).In addition, the phosphatide level (embodiment 11) in mother's administration DHA gestation and lactation and/or uridine raising offspring.Therefore, when composition of the present invention during to mother's administration gestation and lactation, it influences the brain development among the offspring energetically.
This result of experiment also shows, the usefulness of method and composition of the present invention in the treatment paediatrics nervous system disease relevant with brain development.In another embodiment, method of the present invention or composition are used in the brain development of premature infant's moderate stimulation.In another embodiment, method of the present invention or composition are used for the treatment of A Sibogeer syndrome.In another embodiment, this is to liking rett's syndrome.In another embodiment, this is to liking tourette's syndrome.In another embodiment, this is to liking angelman syndrome.In another embodiment, this is to liking familial dysautonomia.In another embodiment, this is to liking dislexia.In another embodiment, this is to liking peripheral neuropathy.In another embodiment, this is to liking ataxia.In another embodiment, this is to liking TD.
In another embodiment, this is to liking ADHD.In another embodiment, think that ADHD causes by lacking Dopamine HCL.
In another embodiment, method and composition of the present invention is used for the treatment of brain injury.In another embodiment, described damage is by radiation-actuate.In another embodiment, described damage is owing to big cerebral anoxia perinatal period.In another embodiment, described damage is owing to cerebrum ischemia perinatal period.In another embodiment, described perinatal period, big cerebral anoxia and/or ischemic were secondary to maternal infuries.In another embodiment, method and composition of the present invention is used for the treatment of the brain paralysis that is caused by one of above illness.
In another embodiment, method and composition of the present invention is used for the treatment of mongolism or trisomy 21.
In another embodiment, method and composition of the present invention is used for the treatment of and is secondary to the growth of the underfed impaired brain of source of parents or grows.In another embodiment, it is bad that described impaired brain growth or growth are secondary to infant nutrition.In another embodiment, described impaired brain growth or growth are secondary to metabolic trouble.
In another embodiment, method and composition of the present invention is used for the treatment of autism.In another embodiment, method and composition of the present invention is used for the treatment of the syndrome relevant with autism.In another embodiment, described syndrome is autism (autish).In another embodiment, described syndrome is any other syndrome relevant with autism known in the art.
In another embodiment, method and composition of the present invention is used for the treatment of any other paediatrics nervous system disease known in the art.Every kind of disease is represented an embodiment independently of the present invention.
In another embodiment, the invention provides treatment and suffer from the method for the individuality of one of above-mentioned disease or illness, it comprises to described individual administration composition of the present invention, wherein said composition improves the amount of synaptic membrane in the neurocyte of described individuality or the brain cell, thereby treatment suffers from the individuality of one of above-mentioned disease or illness.
In another embodiment, the invention provides treatment and suffer from the method for the individuality of one of above-mentioned disease or illness, it comprises to described individual administration composition of the present invention, wherein said composition improves the size or the number of the brain cynapse of described individuality, thereby treatment suffers from the individuality of one of above-mentioned disease or illness.
In another embodiment, the invention provides treatment and suffer from the method for the individuality of one of above-mentioned disease or illness, it comprises to described individual administration composition of the present invention, wherein said composition improves the phosphatide level of the neurocyte or the brain cell of described individuality, thereby treatment suffers from the individuality of one of above-mentioned disease or illness.
In another embodiment, the invention provides treatment and suffer from the method for the individuality of one of above-mentioned disease or illness, it comprises to described individual administration composition of the present invention, wherein said composition improves the neurotransmitter levels of the neurocyte or the brain cell of described individuality, thereby treatment suffers from the individuality of one of above-mentioned disease or illness.
In another embodiment, the invention provides treatment and suffer from the method for the individuality of nervous system disease or illness, it comprises to described individual administration composition of the present invention, wherein said composition improves the amount of synaptic membrane in the neurocyte of described individuality or the brain cell, thereby treatment suffers from the individuality of nervous system disease or illness.
In another embodiment, the invention provides treatment and suffer from the method for the individuality of nervous system disease or illness, it comprises to described individual administration composition of the present invention, wherein said composition improves the size or the number of the brain cynapse of described individuality, thereby treatment suffers from the individuality of nervous system disease or illness.
In another embodiment, the invention provides treatment and suffer from the method for the individuality of nervous system disease or illness, it comprises to described individual administration composition of the present invention, wherein said composition improves the phosphatide level of the neurocyte or the brain cell of described individuality, thereby treatment suffers from the individuality of nervous system disease or illness.
In another embodiment, the invention provides treatment and suffer from the method for the individuality of nervous system disease or illness, it comprises to described individual administration composition of the present invention, wherein said composition improves the neurotransmitter levels of the neurocyte or the brain cell of described individuality, thereby treatment suffers from the individuality of nervous system disease or illness.
In another embodiment, nervous system disease or the illness by method and composition treatment of the present invention is to be the disease or the illness of feature with the synaptic membrane shortage.In another embodiment, the numerical abnormality of cynapse is low.In another embodiment, cynapse mean sizes is unusually little.In another embodiment, described disease or illness are feature with the shortage of presynaptic neuron in the given area of brain.In another embodiment, described disease or illness are feature with the presynaptic neuron shortage of carrying out given function in brain.In another embodiment, described disease or illness are feature with the shortage of postsynaptic neuron in the given area of brain.In another embodiment, described disease or illness are feature with the postsynaptic neuron shortage of carrying out given function in brain.In another embodiment, described neurotransmitter levels deficiency or acceptor lack relevant to the response of described neurotransmitter in the inappropriate release of described disease or illness and neurotransmitter or the cynapse.In another embodiment, described disease or illness are heredopathias.In another embodiment, described disease or illness are metabolic disease or endocrinopathy or nutritional trouble.
In another embodiment, described disease or illness are the outbreaks (seizures) relevant with maternal infuries.In another embodiment, described outbreak is secondary to cerebral anoxia.In another embodiment, described outbreak is secondary to ischemic.In another embodiment, described disease or illness are the results of the neuronal damage that caused by toxin.In another embodiment, described damage is caused by high fever.In another embodiment, described disease or illness are kernicterus.In another embodiment, described disease or illness are phenylketonurias.In another embodiment, described disease or illness are idiopathys.In another embodiment, described disease or illness are diel rhythm or somnopathy.In another embodiment, described disease or illness are the cognitive disorders that is secondary to infection or immunologic derangement.In another embodiment, described cognitive disorder is caused by cerebral tumor or its operative treatment or chemotherapy.In another embodiment, described disease or illness are the outbreak obstacles (seizure disturbance) that is secondary to infection.In another embodiment, described infection is a meningitis.In another embodiment, described infection is the infection of any other type known in the art.
Every kind of method, disease and illness are represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method for improving or strengthening offspring's intelligence, it comprises that mother to described offspring is in pregnancy duration administration ω-6 lipid acid or its metabolic precursor thereof, wherein said ω-6 lipid acid or its metabolic precursor thereof improve synthetic to phosphatide of described offspring's neurocyte or brain cell, thereby improve or strengthen offspring's intelligence.
In another embodiment, the invention provides the method for improving or strengthening offspring's intelligence, it comprises that the mother to described offspring comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline in the pregnancy duration administration; (b) composition of omega-fatty acid or its metabolic precursor thereof, wherein said composition improve synthetic to phosphatide of described offspring's neurocyte or brain cell, thereby improve or strengthen offspring's intelligence.
In another embodiment, the invention provides the method for improving or strengthening offspring's intelligence, it comprises that the mother to described offspring comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline in the pregnancy duration administration; (b) composition of ω-6 lipid acid or its metabolic precursor thereof, wherein said composition improve synthetic to phosphatide of described offspring's neurocyte or brain cell, thereby improve or strengthen offspring's intelligence.
In another embodiment; the invention provides the method for improving or strengthening offspring's intelligence; it comprises that the mother to described offspring comprises the composition of uridine, its acyl derivative, uridine phosphoric acid or CDP-choline in the pregnancy duration administration, thereby improves or strengthen offspring's intelligence.
In another embodiment, the invention provides the method for improving or strengthening offspring's intelligence, its mother who is included in described offspring is that the offspring is between lactation, to described mother's administration omega-fatty acid or its metabolic precursor thereof, wherein said omega-fatty acid or its metabolic precursor thereof improve synthetic to phosphatide of described offspring's neurocyte or brain cell, thereby improve or strengthen offspring's intelligence.
In another embodiment of method and composition of the present invention, omega-fatty acid or its metabolic precursor thereof are secreted in breast milk.In another embodiment, ω-6 lipid acid or its metabolic precursor thereof are secreted in breast milk.In another embodiment, uridine, its acyl derivative, uridine phosphoric acid or CDP-choline are secreted in breast milk.In another embodiment, choline is secreted in breast milk.In another embodiment, choline salt is secreted in breast milk.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method for improving or strengthening offspring's intelligence, its mother who is included in described offspring is that described offspring is between lactation, to described mother's administration ω-6 lipid acid or its metabolic precursor thereof, wherein said ω-6 lipid acid or its metabolic precursor thereof improve synthetic to phosphatide of described offspring's neurocyte or brain cell, thereby improve or strengthen offspring's intelligence.
In another embodiment, the invention provides the method for improving or strengthening offspring's intelligence, its mother who is included in described offspring is described offspring between lactation, comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline to described mother's administration; (b) composition of omega-fatty acid or its metabolic precursor thereof, wherein said composition improve synthetic to phosphatide of described offspring's neurocyte or brain cell, thereby improve or strengthen offspring's intelligence.
In another embodiment, the invention provides the method for improving or strengthening offspring's intelligence, its mother who is included in described offspring is described offspring between lactation, comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline to described mother's administration; (b) composition of ω-6 lipid acid or its metabolic precursor thereof, wherein said composition improve synthetic to phosphatide of described offspring's neurocyte or brain cell, thereby improve or strengthen offspring's intelligence.
In another embodiment; the invention provides the method for improving or strengthening offspring's intelligence; its mother who is included in described offspring is described offspring between lactation, comprises the composition of uridine, its acyl derivative, uridine phosphoric acid to described mother's administration, thereby improves or strengthen offspring's intelligence.
In another embodiment, strengthening or improve its cognitive function, neural function, intelligence, cynapse transmission or neurotransmitter levels and active individuality by composition of the present invention or method is not diagnosed as yet and suffers from cognitive impairment or dysmnesia.In another embodiment, described individuality is healthy.In another embodiment, described individuality does not suffer from cognitive impairment or dysmnesia as yet.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides and improve the method for neurone to the susceptibility that stimulates, it comprises described neurone contact with composition of the present invention, thereby the raising neurone is to the susceptibility of stimulation.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
Provide as this paper, administration polyunsaturated fatty acid and/or uridine improve the amount of kephalin level and synthetic, proteic level of spinous process neuroneme and synaptic membrane.Therefore, method and composition of the present invention improves and strengthens neurone to the susceptibility of stimulation and the size and the number of brain and the middle cynapse of central nervous system (CNS).
In another embodiment, the invention provides the method that improves average cynapse size in the individual brain, it comprises to described individual administration composition of the present invention, thereby improves average cynapse size in the individual brain.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method that improves the number of cynapse in the individual brain, it comprises to described individual administration omega-fatty acid or its metabolic precursor thereof, thereby improves the number of cynapse in the individual brain.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method that improves the number of cynapse in the individual brain, it comprises to described individual administration ω-6 lipid acid or its metabolic precursor thereof, thereby improves the number of cynapse in the individual brain.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method that improves the number of cynapse in the individual brain, it comprises to described individual administration and comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline; (b) composition of omega-fatty acid or its metabolic precursor thereof, thus the number of cynapse in the individual brain improved.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method that improves the number of cynapse in the individual brain, it comprises to described individual administration and comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline; (b) composition of ω-6 lipid acid or its metabolic precursor thereof, thus the number of cynapse in the individual brain improved.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
Measurement and appraisal procedure that individual brain and average cynapse size, number and cynapse active level in the central nervous system and neurotransmitter discharge are well known in the art, for example are disclosed in people (Estimating use-dependent synaptic gain in autonomicganglia by computational simulation and dynamic-clamp analysis.JNeurophysiol.2004Nov such as Wheeler DW; 92 (5): 2659-71), people (Estimating thenumber of release sites and probability of firing within the nerve terminal bystatistical analysis of synaptic charge.Synapse.2003Jan such as Viele K; 47 (1): 15-25) and people (Estimation of the number of synapses in the cerebral cortex:methodological considerations.Cereb Cortex.1999Oct-Nov such as DeFelipe J; 9 (7): 722-32).Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method that stimulates or strengthen the generation of individual brain cell membrane or neuron membrane, it comprises to described individual administration omega-fatty acid or its metabolic precursor thereof, thereby stimulates or strengthen the individual brain cell membrane or the generation of neuron membrane.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method that stimulates or strengthen the generation of individual brain cell membrane or neuron membrane, it comprises to described individual administration ω-6 lipid acid or its metabolic precursor thereof, thereby stimulates or strengthen the individual brain cell membrane or the generation of neuron membrane.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method that stimulates or strengthen the generation of individual brain cell membrane or neuron membrane, it comprises to described individual administration and comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline; (b) composition of omega-fatty acid or its metabolic precursor thereof, thus stimulate or strengthen the individual brain cell membrane or the generation of neuron membrane.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method that stimulates or strengthen the generation of individual brain cell membrane or neuron membrane, it comprises to described individual administration and comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline; (b) composition of ω-6 lipid acid or its metabolic precursor thereof, thus stimulate or strengthen the individual brain cell membrane or the generation of neuron membrane.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, method of the present invention improves the basic simultaneously ratio that keeps two or more phosphatide in target brain cell or the neurocyte of phosphatide level.In another embodiment, method of the present invention improves basic simultaneously three kinds or the ratio of more kinds of phosphatide that keeps in target brain cell or the neurocyte of phosphatide level.In another embodiment, method of the present invention improves basic simultaneously four kinds or the ratio of more kinds of phosphatide that keeps in target brain cell or the neurocyte of phosphatide level.In another embodiment, described phosphatide is selected from PC, PE, PS and sphingophospholipid (SM).In another embodiment, these ratios remain on above-mentioned neural function substantially and the brain function aspect is important.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, " keep substantially " being meant that the deviation with previous ratio is lower than 10%.In another embodiment, " keep substantially " being meant that deviation is lower than 15%.In another embodiment, described deviation is lower than 20%.In another embodiment, described deviation is lower than 25%.In another embodiment, described deviation is lower than 30%.In another embodiment, described deviation is lower than 35%.In another embodiment, described deviation is lower than 40%.In another embodiment, described deviation is lower than 45%.In another embodiment, described deviation is lower than 50%.In another embodiment, described deviation is lower than 55%.In another embodiment, described deviation is lower than 60%.In another embodiment, described deviation is lower than 65%.In another embodiment, described deviation is lower than 70%.In another embodiment, described deviation is lower than 75%.In another embodiment, described deviation is lower than 80%.In another embodiment, described deviation is lower than 85%.In another embodiment, described deviation is lower than 90%.In another embodiment, described deviation is lower than 95%.In another embodiment, described deviation is lower than 90%.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment of the inventive method, stimulate the synthetic spinous process branch that strengthens of phosphatide.In another embodiment, stimulate the synthetic spinous process that strengthens of phosphatide to outgrowth.In another embodiment, stimulating phosphatide to synthesize raising can be via activating the phosphatide group storehouse that Phospholipid hydrolase discharges.Some phosphatide group biologically actives, as: inositol 1,4,5-triphosphoric acid (IP 3), DG (DAG) and haemolysis platelet activation factor (lyso-PAF), it is further generating biological activity lipid PAF (1-0-alkyl-2-ethanoyl-sn-3-glycerol-3-phosphocholine) after the metabolism.
In another embodiment, stimulate the synthetic protection of phosphatide synaptic membrane to anti-stress.In another embodiment, described stress be oxidative stress.In another embodiment, described stress be any other type known in the art stress.
In another embodiment, stimulate the phosphatide synthetic all to strengthen the neurotransmitter Mediated Signal Transduction for these active every kind, thereby improve memory, intelligence and other cognitive functions.Stimulate in phosphatide synthetic above-mentioned active every kind and the The above results every kind all to represent an embodiment independently of the present invention.
In one embodiment, the individuality of method of the present invention is human.In another embodiment, described individuality is the women.In another embodiment, described individuality is the male sex.In another embodiment, described individuality is the women of gestation.In another embodiment, described individuality is the women of lactation.In another embodiment, described individuality is baby (infant).In another embodiment, described individuality is baby (baby).In another embodiment, described individuality is the child.In another embodiment, described individuality is children.In another embodiment, described individuality is a underage child.In another embodiment, described individuality is the grownup.In another embodiment, described individuality is the elderly (aging adult).In another embodiment, " old age " be meant any embodiment listed above.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, " baby " is meant that the age is at the individuality below 6 months.In another embodiment, this term is meant that the age is at the individuality below 5 months.In another embodiment, this term is meant that the age is at the individuality below 4 months.In another embodiment, this term is meant that the age is at the individuality below 3 months.In another embodiment, this term is meant that the age is at the individuality below 2 months.In another embodiment, this term is meant that the age is at the individuality below 1.5 months.In another embodiment, this term is meant that the age is at the individuality below 1 month.In another embodiment, this term is meant the individuality of age below 10 weeks.In another embodiment, this term is meant the individuality of age below 9 weeks.In another embodiment, this term is meant the individuality of age below 7 weeks.In another embodiment, this term is meant the individuality of age below 6 weeks.In another embodiment, this term is meant the individuality of age below 5 weeks.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, " baby " is meant that the age is at the individuality below 1 years old.In another embodiment, this term is meant that the age is at the individuality below 18 months.In another embodiment, this term is meant that the age is at the individuality below 6 months.In another embodiment, this term is meant that the age is at the individuality below 7 months.In another embodiment, this term is meant that the age is at the individuality below 8 months.In another embodiment, this term is meant that the age is at the individuality below 9 months.In another embodiment, this term is meant that the age is at the individuality below 10 months.In another embodiment, this term is meant that the age is at the individuality below 11 months.In another embodiment, this term is meant that the age is at the individuality below 13 months.In another embodiment, this term is meant that the age is at the individuality below 14 months.In another embodiment, this term is meant that the age is at the individuality below 16 months.In another embodiment, this term is meant that the age is at the individuality below 20 months.In another embodiment, this term is meant that the age is at the individuality below 2 years old.In another embodiment, this term is meant sucking individuality.In another embodiment, this term is meant and weans but be in individuality in above-mentioned the range of age.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, " child " is meant big individuality of 1-2 year.In another embodiment, this term is meant 6-24 month big individuality.In another embodiment, this term is meant 8-24 month big individuality.In another embodiment, this term is meant 10-24 month big individuality.In another embodiment, this term is meant 13-24 month big individuality.In another embodiment, this term is meant 14-24 month big individuality.In another embodiment, this term is meant 16-24 month big individuality.In another embodiment, this term is meant 18-24 month big individuality.In another embodiment, this term is meant 12-18 month big individuality.In another embodiment, this term is meant 13-18 month big individuality.In another embodiment, this term is meant 15-18 month big individuality.In another embodiment, this term is meant 12-20 month big individuality.In another embodiment, this term is meant 14-20 month big individuality.In another embodiment, this term is meant as yet not wean, but less than 20 months big individualities.In another embodiment, this term is meant as yet not wean, but less than 24 months big individualities.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, " children " are meant the individuality of age at under-18s.In another embodiment, this term is meant that the age is at the individuality below 17 years old.In another embodiment, this term is meant that the age is at the individuality below 16 years old.In another embodiment, this term is meant that the age is at the individuality below 15 years old.In another embodiment, this term is meant that the age is at the individuality below 14 years old.In another embodiment, this term is meant that the age is at the individuality below 13 years old.In another embodiment, this term is meant that the age is at the individuality below 12 years old.In another embodiment, this term is meant that the age is at the individuality below 11 years old.In another embodiment, this term is meant that the age is at the individuality below 10 years old.In another embodiment, this term is meant that the age is at the individuality below 9 years old.In another embodiment, this term is meant that the age is at the individuality below 8 years old.In another embodiment, this term is meant that the age is at the individuality below 7 years old.
In another embodiment, " underage child " is meant that the age is at the individuality below 7 years old.In another embodiment, this term is meant that the age is at the individuality below 6 years old.In another embodiment, this term is meant that the age is at the individuality below 5 years old.In another embodiment, this term is meant that the age is at the individuality below 4 years old.In another embodiment, this term is meant that the age is at the individuality below 3.5 years old.In another embodiment, this term is meant that the age is at the individuality below 3 years old.In another embodiment, this term is meant that the age is at the individuality below 2.5 years old.Every kind of possibility is represented an embodiment independently of the present invention.
In other embodiments, " grownup " is meant the individuality that surpasses one of child age upper limit listed above.In another embodiment, this term is meant the individuality that surpasses one of underage child upper age limit listed above.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment of method and composition of the present invention, omega-fatty acid, ω-6 lipid acid, its metabolic precursor thereof or composition of the present invention synthesize one of the effect that this paper lists of bringing into play by improving phosphatide.In another embodiment, described effect appears and not increase phosphatide synthetic.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, method and composition of the present invention comprises the uridine source.In another embodiment, method and composition of the present invention comprises the choline source.In another embodiment, " source " is meant and improves the compound of expecting the concentration of compound (uridine, choline etc.) in blood flow or the tissue.In another embodiment, " source " is meant that by the tissue of described individuality or enzymes metabolism be the compound of expectation compound.In another embodiment, " source " is meant by the compound of target cell metabolism for the expectation compound.In another embodiment, described uridine source is a cytidine, and it is converted into uridine by human liver.In another embodiment, described uridine source is cytidine 5 ' one phosphoric acid.In another embodiment, described uridine source is cytidine 5 ' bisphosphate.In another embodiment, described uridine source is cytidine 5 ' triphosphoric acid.In another embodiment, any other cytidine phosphates of being known in the art of described uridine source.In another embodiment, described uridine source is the CDP-choline.In another embodiment, any other uridine source of being known in the art, described uridine source.An embodiment independently of the present invention is represented in every kind of uridine source.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the uridine phosphoric acid that uses in the method for the present invention is uridine 5 ' one phosphoric acid.In another embodiment, described uridine phosphoric acid is uridine 5 ' bisphosphate.In another embodiment, described uridine phosphoric acid is uridine 5 ' triphosphoric acid.In another embodiment, described uridine phosphoric acid is any other uridine phosphoric acid known in the art.Every kind of possibility is represented an embodiment independently of the present invention.
In other embodiments, the uridine based compound except uridine itself is as uridine source or uridine precursor.In other embodiments, these are food or diet product such as algae, uridine salt such as uridine phosphoric acid, the acylate uridines etc. that are rich in uridine.In another embodiment, also acyl derivative or its mixture of administration uridine, for example United States Patent (USP) 5,470, those disclosed in 838.Every kind of uridine precursor is represented an embodiment independently of the present invention.
In another embodiment, method of the present invention also comprises the administration choline.In another embodiment, method of the present invention also comprises the administration choline salt.In another embodiment, method of the present invention comprises that also the administration metabolism is the compound of choline.In another embodiment, method of the present invention also comprises administration choline source.In another embodiment, one of administration above-claimed cpd increases ω-3 or ω-6 lipid acid and/or uridine influences the membrane phospholipid synthetic.Provide as this paper (embodiment), administration choline and ω-3 or ω-6 lipid acid show the level of phosphatide, synapsin and synaptic membrane in neurone and the cerebral tissue and the unexpected increase of memory, intelligence and cognitive function and neural function.
In another embodiment, any method and composition of the present invention includes administration omega-fatty acid and choline.In another embodiment, any method and composition of the present invention includes administration omega-fatty acid and choline salt.In another embodiment, any method and composition of the present invention includes administration ω-6 lipid acid and choline.In another embodiment, any method and composition of the present invention includes administration ω-6 lipid acid and choline salt.
In another embodiment, any method and composition of the present invention includes the composition that administration comprises omega-fatty acid, uridine and choline.In another embodiment, any method and composition of the present invention includes the composition that administration comprises omega-fatty acid, uridine and choline salt.In another embodiment, any method and composition of the present invention includes the composition that administration comprises ω-6 lipid acid, uridine and choline.In another embodiment, any method and composition of the present invention includes the composition of administration ω-6 lipid acid, uridine and choline salt.
In another embodiment, any method and composition of the present invention includes administration ω-6 lipid acid and omega-fatty acid.In another embodiment, any method and composition of the present invention includes administration ω-6 lipid acid, omega-fatty acid and uridine.In another embodiment, any method and composition of the present invention includes administration ω-6 lipid acid, omega-fatty acid and choline.In another embodiment, any method and composition of the present invention includes administration ω-6 lipid acid, omega-fatty acid and choline salt.In another embodiment, any method and composition of the present invention includes administration ω-6 lipid acid, omega-fatty acid, uridine and choline.In another embodiment, any method and composition of the present invention includes administration ω-6 lipid acid, omega-fatty acid, uridine and choline salt.
In another embodiment, method and composition of the present invention comprises the anti-inflammatory polyunsaturated fatty acid.In another embodiment, comprise two kinds of different omega-fatty acids.In another embodiment, one of described two kinds of omega-fatty acids are the anti-inflammatory polyunsaturated fatty acids.In another embodiment, one of described two kinds of omega-fatty acids are DHA.In another embodiment, one of described two kinds of omega-fatty acids are EPA.In another embodiment, described two kinds of omega-fatty acids are EPA and DHA.
In another embodiment, the ratio of described two kinds of omega-fatty acids is 0.05: 1.In another embodiment, described ratio is 0.1: 1.In another embodiment, described ratio is 0.15: 1.In another embodiment, described ratio is 0.2: 1.In another embodiment, described ratio is 0.3: 1.In another embodiment, described ratio is 0.4: 1.In another embodiment, described ratio is 0.5: 1.In another embodiment, described ratio is 0.6: 1.In another embodiment, described ratio is 0.7: 1.In another embodiment, described ratio is 0.8: 1.In another embodiment, described ratio is 0.9: 1.In another embodiment, described ratio is 1: 1.In another embodiment, DHA and EPA are included in (DHA: EPA) in one of aforementioned proportion.In another embodiment, DHA and EPA are included in (EPA: DHA) in one of aforementioned proportion.
In another embodiment, method and composition of the present invention comprises two kinds of different ω-6 lipid acid.
In another embodiment, the ratio of omega-fatty acid and ω-6 lipid acid is 1: 1 in method of the present invention or the composition.In another embodiment, described ratio is 1.5: 1.In another embodiment, described ratio is 2: 1.In another embodiment, described ratio is 3: 1.In another embodiment, described ratio is 4: 1.In another embodiment, described ratio is 5: 1.In another embodiment, described ratio is 6: 1.In another embodiment, described ratio is 8: 1.In another embodiment, described ratio is 10: 1.In another embodiment, described ratio is 12: 1.In another embodiment, described ratio is 15: 1.In another embodiment, described ratio is 20: 1.In another embodiment, described ratio is 30: 1.In another embodiment, described ratio is 40: 1.In another embodiment, described ratio is 50: 1.In another embodiment, described ratio is 60: 1.In another embodiment, described ratio is 80: 1.In another embodiment, described ratio is 100: 1.
Omega-fatty acid, ω-6 lipid acid, uridine, choline and/or choline salt every kind combination representative embodiment independently of the present invention.Every kind of different omega-fatty acids combination representative embodiment independently of the present invention.Every kind of different ω-6 lipid acid combination representative embodiment independently of the present invention.Every kind of proportional representation embodiment independently of the present invention.
In another embodiment, described choline source is a Yelkin TTS.In another embodiment, described choline source is a Yelkin TTS.In another embodiment, described choline source is a vagusstoff.In another embodiment, described choline source is cytidine diphosphate (citicholine) or α-glycerophosphoryl choline.In another embodiment, described choline source is the CDP-choline.In another embodiment, described choline source is any other choline source known in the art.An embodiment independently of the present invention is represented in every kind of choline source.
In another embodiment, described choline salt is a sulfonate, as: long alkyl chain sulfonate.In another embodiment, described choline salt is a choline chloride 60.In another embodiment, described choline salt is a choline bitartrate.In another embodiment, described choline salt is a choline citrate.In another embodiment, described choline salt is a choline tartrate.In another embodiment, described choline salt is an iron choline citrate complex.In another embodiment, described choline source is any other choline salt known in the art.Every kind of choline salt is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the composition that is used for the treatment of the paediatrics neurological disorder, described composition is made up of disclosed arbitrary composition in the method for the present invention.Every kind of composition is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the composition that is used to increase intelligence, described composition is made up of disclosed arbitrary composition in the method for the present invention.Every kind of composition is represented an embodiment independently of the present invention.
In another embodiment, method and composition of the present invention even their effect of performance in the individuality that has no lack of omega-fatty acid or ω-6 lipid acid.In another embodiment, method and composition of the present invention uses the polyunsaturated fatty acid of pharmacological dose.In another embodiment, use therapeutic dose.In another embodiment, described pharmacological dose is higher than from the diet that is rich in polyunsaturated fatty acid normal take in.In another embodiment, the film water that improves in the individuality that has no lack of polyunsaturated fatty acid of polyunsaturated fatty acid by the administration pharmacological dose and/or uridine is flat.In another embodiment, result of the present invention shows that polyunsaturated fatty acid is brought into play biochemical action in brain, thereby supports the purposes of the polyunsaturated fatty acid of pharmacological dose.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the dosage of the omega-fatty acid that comprises in the method and composition of the present invention is in the scope of about 400-2000mg/ day.In another embodiment, described dosage is in the scope of about 500-2000mg/ day.In another embodiment, described scope is about 600-2000mg/ day.In another embodiment, described scope is about 800-2000mg/ day.In another embodiment, described scope is about 1000-2000mg/ day.In another embodiment, described scope is about 1200-2000mg/ day.In another embodiment, described scope is about 1500-2000mg/ day.In another embodiment, described scope is about 400-3000mg/ day.In another embodiment, described dosage is in the scope of about 500-3000mg/ day.In another embodiment, described scope is about 600-3000mg/ day.In another embodiment, described scope is about 800-3000mg/ day.In another embodiment, described scope is about 1000-3000mg/ day.In another embodiment, described scope is about 1200-3000mg/ day.In another embodiment, described scope is about 1500-3000mg/ day.In another embodiment, described scope is about 2000-3000mg/ day.In another embodiment, described scope is about 400-4000mg/ day.In another embodiment, described dosage is in the scope of about 500-4000mg/ day.In another embodiment, described scope is about 600-4000mg/ day.In another embodiment, described scope is about 800-4000mg/ day.In another embodiment, described scope is about 1000-4000mg/ day.In another embodiment, described scope is about 1200-4000mg/ day.In another embodiment, described scope is about 1500-4000mg/ day.In another embodiment, described scope is about 2000-4000mg/ day.In another embodiment, described scope is about 3000-4000mg/ day.In another embodiment, described scope is about 400-1000mg/ day.In another embodiment, described scope is about 500-1000mg/ day.In another embodiment, described scope is about 600-1000mg/ day.In another embodiment, described scope is about 800-100mg/ day.
In another embodiment, the dosage of omega-fatty acid is at least 400mg/ day.In another embodiment, described dosage is at least 500mg/ day.In another embodiment, described dosage is at least 600mg/ day.In another embodiment, described dosage is at least 700mg/ day.In another embodiment, described dosage is at least 800mg/ day.In another embodiment, described dosage is at least 900mg/ day.In another embodiment, described dosage is at least 1g/ day.In another embodiment, described dosage is at least 1200mg/ day.In another embodiment, described dosage is at least 1.5g/ day.In another embodiment, described dosage is at least 2g/ day.
In another embodiment, the dosage of omega-fatty acid is 5-50mg/kg/ day.In another embodiment, described dosage is 2-100mg/kg/ day.In another embodiment, described dosage is 7-50mg/kg/ day.In another embodiment, described dosage is 10-50mg/kg/ day.In another embodiment, described dosage is 15-50mg/kg/ day.In another embodiment, described dosage is 20-50mg/kg/ day.In another embodiment, described dosage is 30-50mg/kg/ day.In another embodiment, described dosage is 5-30mg/kg/ day.In another embodiment, described dosage is 7-30mg/kg/ day.In another embodiment, described dosage is 10-30mg/kg/ day.In another embodiment, described dosage is 15-30mg/kg/ day.In another embodiment, described dosage is about 5mg/kg/ day.In another embodiment, described dosage is about 7mg/kg/ day.In another embodiment, described dosage is about 10mg/kg/ day.In another embodiment, described dosage is about 15mg/kg/ day.In another embodiment, described dosage is about 20mg/kg/ day.In another embodiment, described dosage is about 30mg/kg/ day.In another embodiment, described dosage is about 40mg/kg/ day.In another embodiment, described dosage is about 50mg/kg/ day.In another embodiment, described dosage is at least 5mg/kg/ day.In another embodiment, described dosage is at least 6mg/kg/ day.In another embodiment, described dosage is at least 8mg/kg/ day.In another embodiment, described dosage is at least 10mg/kg/ day.In another embodiment, described dosage is at least 15mg/kg/ day.In another embodiment, described dosage is at least 20mg/kg/ day.In another embodiment, described dosage is at least 30mg/kg/ day.In another embodiment, described dosage is at least 40mg/kg/ day.In another embodiment, described dosage is at least 50mg/kg/ day.In another embodiment, described dosage is at least 70mg/kg/ day.In another embodiment, one of above-mentioned dosage is to baby's administration.In another embodiment, one of above-mentioned dosage is to baby's administration.In another embodiment, one of above-mentioned dosage is to child's administration.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, give the special dosage of women of gestation to satisfy its needs.In another embodiment, this scope is about 200-2000mg/ day.In another embodiment, this scope is about 400-1700mg/ day.In another embodiment, this scope is about 600-1500mg/ day.In another embodiment, this scope is about 800-1300mg/ day.In another embodiment, this scope is about 200-3000mg/ day.In another embodiment, this scope is about 400-3000mg/ day.In another embodiment, this scope is about 600-3000mg/ day.In another embodiment, this scope is about 800-3000mg/ day.In another embodiment, this scope is about 1000-3000mg/ day.In another embodiment, this scope is about 2000-3000mg/ day.In another embodiment, Ren Shen women's dosage is about 1000mg/ day.In another embodiment, described dosage is about 1500mg/ day.In another embodiment, described dosage is about 2000mg/ day.In another embodiment, described dosage is about 3000mg/ day.
In another embodiment, give the individual special dosage of hypercholesterolemia to satisfy its needs.In another embodiment, the dosage of hypercholesterolemia individuality is in the scope of about 200-4000mg/ day.In another embodiment, the dosage of hypercholesterolemia individuality is in the scope of about 400-3500mg/ day.In another embodiment, the dosage of hypercholesterolemia individuality is in the scope of about 600-3000mg/ day.In another embodiment, the dosage of hypercholesterolemia individuality is in the scope of about 1000-2500mg/ day.In another embodiment, the dosage of hypercholesterolemia individuality is in the scope of about 1500-2300mg/ day.In another embodiment, the dosage of hypercholesterolemia individuality is about 2000mg/ day.
In another embodiment of method and composition of the present invention, comprise DHA by one of above-mentioned dosage.In another embodiment, the dosage of DHA is 1-50mg/kg/ day.In another embodiment, the dosage of DHA is 400-1000mg/ day.In another embodiment, comprise EPA by one of above-mentioned dosage.In another embodiment, the dosage of EPA is 1-50mg/kg/ day.In another embodiment, the dosage of EPA is 400-1000mg/ day.Every kind of dosage is represented an embodiment independently of the present invention.
In other embodiments, the dosage that is included in ω-6 lipid acid in the method and composition of the present invention is any dosage of above-mentioned omega-fatty acid.In another embodiment, comprise arachidonic acid by one of above-mentioned dosage.In another embodiment, arachidonic dosage is 1-50mg/kg/ day.In another embodiment, arachidonic dosage is 400-1000mg/ day.Every kind of dosage is represented an embodiment independently of the present invention.
In another embodiment, 20 carbon acids (EPA) are with another kind of ω-3 or the administration of ω-6 lipid acid.In another embodiment, EPA adds with the dosage of about 200mg/ day.In another embodiment, described dosage is 100-300mg/ day.In another embodiment, this scope is 150-250mg/ day.In another embodiment, this scope is 170-230mg/ day.In another embodiment, this scope is 100-1000mg/ day.In another embodiment, this scope is 150-800mg/ day.In another embodiment, this scope is 200-600mg/ day.In another embodiment, this scope is 300-500mg/ day.In another embodiment, described dosage is about 300mg/ day.In another embodiment, described dosage is about 400mg/ day.In another embodiment, described dosage is about 500mg/ day.In another embodiment, described dosage is about 600mg/ day.In another embodiment, described dosage is about 800mg/ day.In another embodiment, described dosage is about 1000mg/ day.
In another embodiment, the dosage of EPA is 1-12mg/kg/ day.In another embodiment, described dosage is 1.5-12mg/kg/ day.In another embodiment, described dosage is 2-12mg/kg/ day.In another embodiment, described dosage is 3-12mg/kg/ day.In another embodiment, described dosage is 4-12mg/kg/ day.In another embodiment, described dosage is 5-12mg/kg/ day.In another embodiment, described dosage is 6-12mg/kg/ day.In another embodiment, described dosage is 8-12mg/kg/ day.In another embodiment, described dosage is 1-8mg/kg/ day.In another embodiment, described dosage is 1.5-8mg/kg/ day.In another embodiment, described dosage is 3-8mg/kg/ day.In another embodiment, described dosage is 4-8mg/kg/ day.In another embodiment, described dosage is about 1mg/kg/ day.In another embodiment, described dosage is about 1.5mg/kg/ day.In another embodiment, described dosage is about 2mg/kg/ day.In another embodiment, described dosage is about 3mg/kg/ day.In another embodiment, described dosage is about 4mg/kg/ day.In another embodiment, described dosage is about 6mg/kg/ day.In another embodiment, described dosage is about 8mg/kg/ day.In another embodiment, described dosage is about 10mg/kg/ day.In another embodiment, described dosage is about 12mg/kg/ day.In another embodiment, one of above-mentioned dosage is to baby's administration.In another embodiment, one of above-mentioned dosage is to baby's administration.In another embodiment, one of above-mentioned dosage is to child's administration.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, to women's administration of gestation EPA of high dosage more.In another embodiment, described dosage is about 1200mg/ day.In another embodiment, described dosage is about 1500mg/ day.In another embodiment, described dosage is about 1800mg/ day.In another embodiment, described dosage is about 2000mg/ day.In another embodiment, described dosage is about 2500mg/ day.In another embodiment, described dosage is about 3000mg/ day.In another embodiment, described dosage is 500-3000mg/ day.In another embodiment, described dosage is 800-3000mg/ day.In another embodiment, described dosage is 1000-3000mg/ day.In another embodiment, described dosage is 1500-3000mg/ day.In another embodiment, described dosage is 2000-3000mg/ day.In another embodiment, described dosage is 500-2000mg/ day.In another embodiment, described dosage is 800-2000mg/ day.In another embodiment, described dosage is 1000-2000mg/ day.In another embodiment, described dosage is 1500-2000mg/ day.
Every kind of dosage of omega-fatty acid, ω-6 lipid acid or other EPA is represented an embodiment independently of the present invention.
In another embodiment, the dosage of the uridine that comprises in the method and composition of the present invention (comprises end value) at 10-500mg/ between day.In another embodiment, described dosage is 20-500mg/ day.In another embodiment, described dosage is 30-500mg/ day.In another embodiment, described dosage is 50-500mg/ day.In another embodiment, described dosage is 100-500mg/ day.In another embodiment, described dosage is 150-500mg/ day.In another embodiment, described dosage is 200-500mg/ day.In another embodiment, described dosage is 300-500mg/ day.In another embodiment, the dosage of uridine is at 10-400mg/ between day.In another embodiment, described dosage is 20-400mg/ day.In another embodiment, described dosage is 30-400mg/ day.In another embodiment, described dosage is 50-400mg/ day.In another embodiment, described dosage is 100-400mg/ day.In another embodiment, described dosage is 150-400mg/ day.In another embodiment, described dosage is 200-400mg/ day.In another embodiment, the dosage of uridine is at 10-300mg/ between day.In another embodiment, described dosage is 20-300mg/ day.In another embodiment, described dosage is 30-300mg/ day.In another embodiment, described dosage is 50-300mg/ day.In another embodiment, described dosage is 100-300mg/ day.In another embodiment, described dosage is 150-300mg/ day.In another embodiment, described dosage is 200-300mg/ day.In another embodiment, described dosage is about 50mg/ day.In another embodiment, described dosage is about 70mg/ day.In another embodiment, described dosage is about 100mg/ day.In another embodiment, described dosage is about 150mg/ day.In another embodiment, described dosage is about 200mg/ day.In another embodiment, described dosage is about 300mg/ day.In another embodiment, described dosage is about 400mg/ day.In another embodiment, described dosage is about 500mg/ day.
In another embodiment, the dosage of uridine is 0.1-6mg/kg/ day.In another embodiment, described dosage is 0.2-6mg/kg/ day.In another embodiment, described dosage is 0.3-6mg/kg/ day.In another embodiment, described dosage is 0.5-6mg/kg/ day.In another embodiment, described dosage is 1-6mg/kg/ day.In another embodiment, described dosage is 1.5-6mg/kg/ day.In another embodiment, described dosage is 2-6mg/kg/ day.In another embodiment, described dosage is 3-6mg/kg/ day.In another embodiment, described dosage is 0.1-3mg/kg/ day.In another embodiment, described dosage is 0.15-3mg/kg/ day.In another embodiment, described dosage is 0.2-3mg/kg/ day.In another embodiment, described dosage is 0.3-3mg/kg/ day.In another embodiment, described dosage is 0.5-3mg/kg/ day.In another embodiment, described dosage is 0.8-3mg/kg/ day.In another embodiment, described dosage is 1-3mg/kg/ day.In another embodiment, described dosage is about 0.1mg/kg/ day.In another embodiment, described dosage is about 0.15mg/kg/ day.In another embodiment, described dosage is about 0.2mg/kg/ day.In another embodiment, described dosage is about 0.3mg/kg/ day.In another embodiment, described dosage is about 0.4mg/kg/ day.In another embodiment, described dosage is about 0.6mg/kg/ day.In another embodiment, described dosage is about 0.8mg/kg/ day.In another embodiment, described dosage is about 1mg/kg/ day.In another embodiment, described dosage is about 1.5mg/kg/ day.In another embodiment, described dosage is about 2mg/kg/ day.In another embodiment, described dosage is about 3mg/kg/ day.In another embodiment, described dosage is about 4mg/kg/ day.In another embodiment, described dosage is about 6mg/kg/ day.In another embodiment, one of above-mentioned dosage is to baby's administration.In another embodiment, one of above-mentioned dosage is to baby's administration.In another embodiment, one of above-mentioned dosage is to child's administration.Every kind of possibility is represented an embodiment independently of the present invention.
Every kind of uridine dosage is represented an embodiment independently of the present invention.
In another embodiment, the dosage of the choline that comprises in the method and composition of the present invention (comprises end value) at 100mg-10g/ between day.In another embodiment, described dosage is 1g-3g.In another embodiment, described dosage is 150mg-8g.In another embodiment, described dosage is 200mg-6g.In another embodiment, described dosage is 300mg-5g.In another embodiment, described dosage is 400mg-4.5g.In another embodiment, described dosage is 500mg-4g.In another embodiment, described dosage is 600mg-4g.In another embodiment, described dosage is 800mg-3.5g.In another embodiment, described dosage is 1.2g-3g.In another embodiment, described dosage is 1.5g-2.5g.In another embodiment, described dosage is about 0.5g.In another embodiment, described dosage is about 0.7g.In another embodiment, described dosage is about 1g.In another embodiment, described dosage is about 1.2g.In another embodiment, described dosage is about 1.5g.In another embodiment, described dosage is about 2g.In another embodiment, described dosage is about 2.5g.In another embodiment, described dosage is about 3g.In another embodiment, described dosage is about 4g.
In another embodiment, the dosage of choline is 1-100mg/kg/ day.In another embodiment, described dosage is 2-100mg/kg/ day.In another embodiment, described dosage is 3-100mg/kg/ day.In another embodiment, described dosage is 5-100mg/kg/ day.In another embodiment, described dosage is 8-100mg/kg/ day.In another embodiment, described dosage is 10-100mg/kg/ day.In another embodiment, described dosage is 20-100mg/kg/ day.In another embodiment, described dosage is 30-100mg/kg/ day.In another embodiment, described dosage is 50-100mg/kg/ day.In another embodiment, described dosage is 1-50mg/kg/ day.In another embodiment, described dosage is 1.5-50mg/kg/ day.In another embodiment, described dosage is 2-50mg/kg/ day.In another embodiment, described dosage is 3-50mg/kg/ day.In another embodiment, described dosage is 5-50mg/kg/ day.In another embodiment, described dosage is 8-50mg/kg/ day.In another embodiment, described dosage is 10-50mg/kg/ day.In another embodiment, described dosage is about 1mg/kg/ day.In another embodiment, described dosage is about 1.5mg/kg/ day.In another embodiment, described dosage is about 2mg/kg/ day.In another embodiment, described dosage is about 3mg/kg/ day.In another embodiment, described dosage is about 5mg/kg/ day.In another embodiment, described dosage is about 7mg/kg/ day.In another embodiment, described dosage is about 10mg/kg/ day.In another embodiment, described dosage is about 15mg/kg/ day.In another embodiment, described dosage is about 20mg/kg/ day.In another embodiment, described dosage is about 30mg/kg/ day.In another embodiment, described dosage is about 40mg/kg/ day.In another embodiment, described dosage is about 50mg/kg/ day.In another embodiment, described dosage is about 60mg/kg/ day.In another embodiment, described dosage is about 80mg/kg/ day.In another embodiment, described dosage is about 100mg/kg/ day.In another embodiment, one of above-mentioned dosage is to baby's administration.In another embodiment, one of above-mentioned dosage is to baby's administration.In another embodiment, one of above-mentioned dosage is to child's administration.Every kind of possibility is represented an embodiment independently of the present invention.
Every kind in the above-mentioned dosage all is amounts of choline Equivalent; Therefore, the actual dose of compound choline (as: choline chloride 60 or choline tartrate) will be correspondingly higher.
Every kind of choline dosage is represented an embodiment independently of the present invention.
In another embodiment, composition of the present invention is by long term administration.In another embodiment, " for a long time " is meant at least 1 week of administration.In another embodiment, this term is meant at least 2 weeks of administration.In another embodiment, this time bar is at least 10 days.In another embodiment, this time bar was at least 3 weeks.In another embodiment, this time bar was at least 4 weeks.In another embodiment, this time bar was at least 5 weeks.In another embodiment, this time bar was at least 6 weeks.In another embodiment, this time bar is at least 2 months.In another embodiment, this time bar is at least 3 months.In another embodiment, this time bar is at least 4 months.In another embodiment, this time bar is at least 6 months.In another embodiment, this time bar is at least 6 months.In another embodiment, this time bar is at least 1 year.In another embodiment, this time bar is at least 2 years.In another embodiment, this time bar is at least 3 years.In another embodiment, this time bar is at least 5 years.In another embodiment, this time bar is at least 10 years.
In another embodiment, this time bar was 1 week.In another embodiment, this term is meant 2 weeks of administration.In another embodiment, this time bar is 10 days.In another embodiment, this time bar was 3 weeks.In another embodiment, this time bar was 4 weeks.In another embodiment, this time bar was 5 weeks.In another embodiment, this time bar was 6 weeks.In another embodiment, this time bar is 2 months.In another embodiment, this time bar is 3 months.In another embodiment, this time bar is 4 months.In another embodiment, this time bar is 6 months.In another embodiment, this time bar is 6 months.In another embodiment, this time bar is 1 year.In another embodiment, this time bar is 2 years.In another embodiment, this time bar is 3 years.In another embodiment, this time bar is 5 years.In another embodiment, this time bar is 10 years,
In another embodiment, the administration of the polyunsaturated fatty acid composition of the present composition continues one of above-mentioned time bar.In another embodiment, the administration of the ω of the present composition-3 composition continues one of above-mentioned time bar.In another embodiment, the administration of the ω of the present composition-6 composition continues one of above-mentioned time bar.In another embodiment, the administration of the uridine composition of the present composition continues one of above-mentioned time bar.In another embodiment, the administration of the choline of the present composition or choline salt composition continues one of above-mentioned time bar.
Every kind of time bar is represented an embodiment independently of the present invention.
In another embodiment, " contact " be meant composition of the present invention directly to described individuality or brain cell administration.In another embodiment, " contact " be meant composition of the present invention indirectly to described individuality or brain cell administration.Therefore, in another embodiment, method of the present invention comprises such method, wherein said individuality contacts with compound or composition, described compound or composition are metabolised to ω-3 or ω-6 lipid acid in cerebrospinal fluid, blood flow etc., any other active transport process of round-robin or passive transport process contact with described brain cell in vivo by diffusion or compound known in the art for described afterwards ω-3 or ω-6 lipid acid.In another embodiment, described compound is ω-3 or ω-6 lipid acid by the target cell metabolism.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, use the derivative of ω-3 or ω-6 lipid acid in the method and composition of the present invention.In another embodiment, described derivative is ω-6 a derivative of fatty acid gamma-linolenic acid.In another embodiment, described derivative is any other derivative of ω known in the art-3 or ω-6 lipid acid.Every kind of derivative is represented an embodiment independently of the present invention.
In another embodiment, the invention provides increases the individual neurocyte or the spinous process ramose method of brain cell, it comprises to described individual administration omega-fatty acid or its metabolic precursor thereof, wherein said omega-fatty acid or its metabolic precursor thereof improve described neurocyte synthetic to phosphatide, thereby increase its spinous process branch.In another embodiment, the invention provides increases the individual neurocyte or the spinous process ramose method of brain cell, it comprises to described individual administration ω-6 lipid acid or its metabolic precursor thereof, wherein said ω-6 lipid acid or its metabolic precursor thereof increase described neurocyte synthetic to phosphatide, thereby increase the spinous process branch of neurocyte.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides increases the individual neurocyte or the spinous process ramose method of brain cell, and it comprises to described individual administration and comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline; (b) composition of omega-fatty acid or its metabolic precursor thereof, wherein said composition increase described neurocyte synthetic to phosphatide, thereby increase its spinous process branch.In another embodiment, the invention provides increases the individual neurocyte or the spinous process ramose method of brain cell, and it comprises to described individual administration and comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline; (b) composition of ω-6 lipid acid or its metabolic precursor thereof, wherein said composition increase described neurocyte synthetic to phosphatide, thereby increase the spinous process branch of neurocyte.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the spinous process that increases individual neurocyte or the brain cell method to outgrowth, it comprises to described individual administration and comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline; (b) composition of omega-fatty acid or its metabolic precursor thereof, wherein said composition increase described neurocyte synthetic to phosphatide, thereby increase its spinous process to outgrowth.In another embodiment, the invention provides the spinous process that increases individual neurocyte or the brain cell method to outgrowth, it comprises to described individual administration and comprises (a) uridine, its acyl derivative, uridine phosphoric acid or CDP-choline; (b) composition of ω-6 lipid acid or its metabolic precursor thereof, wherein said composition increase described neurocyte synthetic to phosphatide, thereby the spinous process that increases individual neurocyte or brain cell is to outgrowth.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides the method for the spinous process of increase neurocyte to outgrowth, it comprises to described individual administration omega-fatty acid or its metabolic precursor thereof, wherein said omega-fatty acid or its metabolic precursor thereof increase described neurocyte synthetic to phosphatide, thereby increase its spinous process to outgrowth.In another embodiment, the invention provides the method for the spinous process of individual neurocyte of increase or brain cell to outgrowth, it comprises to described individual administration ω-6 lipid acid or its metabolic precursor thereof, wherein said ω-6 lipid acid or its metabolic precursor thereof increase described neurocyte synthetic to phosphatide, thereby the spinous process that increases individual neurocyte or brain cell is to outgrowth.In another embodiment, this method to as if developmental brain or its neurocyte.In another embodiment, described to as if be not diagnosed as the grownup who suffers from any cognition or neurological disorder.Every kind of possibility is represented an embodiment independently of the present invention.
In another embodiment, the invention provides a kind of test kit, it is included in compound or the composition that uses in the enforcement method of the present invention.
In another embodiment, " pharmaceutical composition " is meant dietary supplement.In another embodiment, this term is meant infant formala.In another embodiment, this term is meant the infant food through processing.In another embodiment, this term is meant accessory substance.In another embodiment, this term is meant the food of any classification that is rich in omega-fatty acid.In another embodiment, this term is meant the food that is rich in ω-6 lipid acid.In another embodiment, this term is meant the food that is rich in uridine.In another embodiment, this term is meant the food that is rich in choline.In another embodiment, this term is meant the food that is rich in choline salt.
In another embodiment, " food " is meant solid food.In another embodiment, this term is meant beverage.In another embodiment, this term is meant the powder drink mixes.In another embodiment, this term is meant preparation, functional foodstuff, dietary supplement or the nutritive food based on food.
In another embodiment, food can be some forms, comprising: liquid, suspension, powder, semisolid and solid.Semisolid is intended to comprise ice milk (custards), dessert pudding, concentrated cream, mousse, ice cream, yoghourt and adds sugar-gelatin (sweetened gelatin).Be not limited to specific embodiment, solid form can be prepared as similar to energy bar bar-shaped, sheet, cooky, biscuit, dough (pasta) or expanded material such as puffed rice or rice cake sample food.Some embodiments require individual with snack food prod dissolving, suspension or hydration again.
Every type pharmaceutical composition is represented an embodiment independently of the present invention.
In another embodiment, the present invention relates to the purposes of ω-3 or ω-6 lipid acid and/or its analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicine, hydrate, N-oxide compound or their combination.Therefore, in another embodiment, method of the present invention comprises the analogue of administration polyunsaturated fatty acid.In another embodiment, method of the present invention comprises the derivative of administration polyunsaturated fatty acid.In another embodiment, method of the present invention comprises the isomer of administration polyunsaturated fatty acid.In another embodiment, method of the present invention comprises the metabolite of administration polyunsaturated fatty acid.In another embodiment, method of the present invention comprises the pharmacologically acceptable salts of administration polyunsaturated fatty acid.In another embodiment, method of the present invention comprises the medicine of administration polyunsaturated fatty acid.In another embodiment, method of the present invention comprises the hydrate of administration polyunsaturated fatty acid.In another embodiment, method of the present invention comprises the N-oxide compound of administration polyunsaturated fatty acid.In another embodiment, method of the present invention comprises the arbitrary combination of analogue, derivative, isomer, metabolite, pharmacologically acceptable salts, medicine, hydrate or the N-oxide compound of administration polyunsaturated fatty acid.
In another embodiment of method and composition of the present invention, polyunsaturated fatty acid is as the triglyceride level administration.
In another embodiment, term " isomer " comprises, but in another embodiment, is not limited to optically active isomer and analogue thereof, constitutional isomer and analogue thereof, conformer and analogue thereof etc.
In another embodiment, the present invention also comprises the polyunsaturated fatty acid derivative.Term " derivative " includes but not limited to ether derivant, acid derivative, amide derivatives, ester derivative etc.In addition, the present invention also comprises the hydrate of polyunsaturated fatty acid compound." hydrate " includes but not limited to semihydrate, monohydrate, dihydrate, trihydrate etc. to term.
The present invention also comprises the metabolite of polyunsaturated fatty acid compound.Term " metabolite " is meant any material that generates from another material by metabolism or metabolic process.
The present invention also comprises the medicine of polyunsaturated fatty acid compound.Term " medicine " is meant the composition (pharmaceutical composition) that is suitable for pharmaceutical use, as defined herein.
In addition, the present invention includes pure (Z) of the polyunsaturated fatty acid compound of this paper definition-and (E)-isomer and composition thereof, and pure (RR, SS)-and (RS, SR)-enantiomorph to and composition thereof.
Pharmaceutical composition and medication
In another embodiment, contain the pharmaceutical composition of polyunsaturated fatty acid and/or uridine can be by any method known to those skilled in the art for example by parenteral, the cancer knurl, through mucous membrane, in skin, intramuscular, intravenously, intracutaneous, subcutaneous, intraperitoneal, ventricle, in encephalic, intravaginal or the tumour to individual administration.
In another embodiment of method and composition of the present invention, therefore described drug composition oral administration is formulated as the form that is suitable for oral administration, that is: solid or liquid preparation.Suitable solid orally ingestible comprises tablet, capsule, pill, granule, bolus etc.Suitable liquid oral medicine comprises solution, suspensoid, dispersion agent, emulsion, finish etc.In another embodiment of the present invention, activeconstituents is formulated in the capsule.According to this embodiment, composition of the present invention also comprises inert support or thinner, hard gelatin capsule except active compound.
In another embodiment, described pharmaceutical composition comes administration through intravenously, intra-arterial, intramuscularly liquid preparation.Suitable liquid preparation comprises solution, suspensoid, dispersion agent, emulsion, finish etc.In another embodiment, therefore described pharmaceutical composition intravenous administration is formulated as the form that is suitable for intravenous administration.In another embodiment, therefore the administration of described pharmaceutical composition intra-arterial is formulated as the form that is suitable for the intra-arterial administration.In another embodiment, therefore described pharmaceutical composition intramuscular administration is formulated as the form that is suitable for intramuscular administration.
In another embodiment, therefore described pharmaceutical composition is formulated as the form that is suitable for topical partly to the body surface administration.In another embodiment, suitable topical formulations comprises gelifying agent, ointment, emulsion, lotion, drops etc.
In another embodiment, described pharmaceutical composition is as the suppository administration, for example: rectal suppository or urethral suppositories.In another embodiment, described pharmaceutical composition carries out administration by the subcutaneous implantation of piller (pellet).In another embodiment, described piller provides polyunsaturated fatty acid and/or the uridine controlled release in for some time.
In another embodiment, described active compound is for example sent in the liposome at vesica.
In other embodiments, carrier or the thinner that uses in the method for the present invention includes but not limited to: natural gum, starch (as: W-Gum, pregelatinized Starch), sugar (as: lactose, N.F,USP MANNITOL, sucrose, glucose), cellulose materials (as: Microcrystalline Cellulose), acrylate (as: polymethacrylate), lime carbonate, magnesium oxide, talcum or its mixture.
In other embodiments, the pharmaceutically acceptable carrier of liquid preparation is the aqueous solution or non-aqueous solution, suspension, emulsion or oil.Examples of non-aqueous is propylene glycol, polyoxyethylene glycol and injectable organic ester such as ethyl oleate.Aqueous carrier comprises water, alcohol/aqueous solution, emulsion or suspension, comprises salt solution and buffering medium.The example of oil is the oil in animal oil, vegetables oil or synthetic source, for example: peanut oil, soybean oil, sweet oil, Oleum Helianthi, Oils,glyceridic,cod-liver, other sea hydrobionts oil or from the lipid of milk or eggs.
In another embodiment, parenteral carrier (being used for subcutaneous, intravenously, intra-arterial or intramuscularly) comprises sodium chloride solution, woods lattice glucose, glucose and sodium-chlor, lactated Ringer's solution and expressed oil.Intravenous vehicles comprises that liquid and nutritious supplementary, electrolyte replenisher are as based on supplement of woods lattice glucose etc.Example is sterile liquid Ru Shui and oil, adds or do not add tensio-active agent and the acceptable assistant agent of other pharmacy.Generally speaking, water, salt solution, D/W and associated sugars solution and polyvalent alcohol such as propylene glycol or polyoxyethylene glycol are preferred liquid vehicles, particularly for injectable solutions.The example of oil is the oil in animal oil, vegetables oil or synthetic source, for example: peanut oil, soybean oil, sweet oil, Oleum Helianthi, Oils,glyceridic,cod-liver, other sea hydrobionts oil or from the lipid of milk or egg.
In other embodiments, described composition also comprises tackiness agent (as: Sudan Gum-arabic, W-Gum, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropylcellulose, hydroxypropylcellulose, polyvidone), disintegrating agent (as: W-Gum, yam starch, alginic acid, silicon-dioxide, croscarmellose sodium, Crospovidone, guar gum, primojel), buffer reagent (as: the Tris-HCl of various pH and ionic strength, acetate, phosphoric acid salt), prevent additive such as the albumin or the gelatin of surface adsorption, washing composition (as: polysorbas20, tween 80, polyoxypropylene F68 (Pluronic F68), bile salt), proteinase inhibitor, tensio-active agent (as: sodium lauryl sulphate), penetration enhancer, solubility promoter (as: glycerine, polyethylene glycerine), antioxidant (as: xitix, sodium metabisulphite, Butylated Hydroxyanisole), stablizer (as: hydroxypropylcellulose, Vltra tears), tackifier (as: carbomer, colloid silica, ethyl cellulose, guar gum), sweeting agent (as: aspartame, citric acid), sanitas (as: Thiomersalate, benzylalcohol, parabens), lubricant (as: stearic acid, Magnesium Stearate, polyoxyethylene glycol, sodium lauryl sulphate), glidant (as: colloid silica), softening agent (as: Unimoll DA, triethyl citrate), emulsifying agent (as: carbomer, hydroxypropylcellulose, sodium lauryl sulphate), polymer coating agent (as: the husky amine of poloxamer or pool Lip river), Drug coating and membrane-forming agent (as: ethyl cellulose, acrylate, polymethacrylate) and/or assistant agent.In the above-mentioned vehicle every kind is all represented an embodiment independently of the present invention.
In another embodiment, pharmaceutical composition provided herein is a controlled release composition, that is: the composition that discharges of polyunsaturated fatty acid and/or uridine for some time after administration wherein.Controlled release composition or the composition that continues to discharge are included in the preparation in the lipotropy bank (as: lipid acid, wax, oil).In another embodiment, described composition is an immediate release composition, that is: whole composition of discharging immediately after administration of polyunsaturated fatty acids and/or uridine wherein.
In another embodiment, described pharmaceutical composition is sent in controlled release system.For example: can use intravenous infusion, implantable osmotic pump, transdermal patch, liposome or other this reagent of administering mode administration.In one embodiment, can use pump (, above-mentioned referring to Langer; Sefton, CRCCrit.Ref.Biomed.Eng.14:201 (1987); People such as Buchwald, Surgery 88:507 (1980); People such as Saudek, N.Engl.J.Med.321:574 (1989).In another embodiment, can use macromolecular material; For example in microballoon or implant, use.In yet another embodiment, with controlled release system place treatment target such as brain near, a part that so only needs body dose is (referring to for example Goodson, in Medical Applications of Controlled Release, above-mentioned, vol.2, pp.115-138 (1984); With Langer R, Science 249:1527-1533 (1990).
In another embodiment, described composition also comprise active substance mixed among the particulate preparation of macromolecular compound such as poly(lactic acid), polyglycolic acid, hydrogel etc. or on, perhaps be incorporated on liposome, micro emulsion, micelle, single or multiple lift vesica, blood shadow or the spheroplast.) such composition will influence in the physical condition, solubleness, stability, body clearance rate in the rate of release and body.
The present invention also comprise with polymkeric substance (as: the husky amine of poloxamer or pool Lip river) coated granules composition and with at the compound of tissue specificity acceptor, part or antigenic antibody coupling or with the compound of the ligand coupling of tissue specificity acceptor.
The present invention also comprises by the water-soluble polymers compound of the covalently bound modification of multipolymer, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone or the polyproline of polyoxyethylene glycol, polyoxyethylene glycol and polypropylene glycol for example.Knownly compare with the compound of corresponding unmodified, the compound of modification is in the transformation period in blood after the intravenous injection significantly longer (people such as Abuchowski, 1981; People such as Newmark, 1982 and people such as Katre, 1987).Such modification also can improve immunogenicity and the reactivity that solubleness, the elimination of compound in the aqueous solution assembled, strengthened the physical and chemical stability of compound and reduce compound greatly.Therefore, by than unmodified compound still less dosage or biologic activity in the such body that polymkeric substance-the compound adducts may obtain to expect of low frequency ground administration more.
The preparation that comprises the pharmaceutical composition of active ingredient by mixing, granulation or tabletting method preparation is known in this area.Described active treatment composition usually and pharmacy can be accepted and the mixed with excipients compatible with described activeconstituents.For oral administration, the derivative of polyunsaturated fatty acid and/or uridine or the tolerance of its physiology such as salt, ester, N-oxide compound etc. are mixed with the conventional additives that is used for this purpose such as carrier, stablizer or inert diluent, and be converted into suitable form of medication such as tablet, coated tablet, hard-gelatin capsules or Gelseal, aqueous pharmaceutical, alcoholic solution agent or oily solution by ordinary method.For parenteral admin, the derivative of polyunsaturated fatty acid and/or uridine or the tolerance of its physiology such as salt, ester, N-oxide compound etc. are converted into solution, suspensoid or emulsion, if desired, then with transforming for the conventional and suitable material of this purpose such as solubility promoter or other materials.
In another embodiment, active ingredient is formulated into described composition as neutral pharmacologically acceptable salts form.Pharmacologically acceptable salts comprises the acid salt (forming with the free amine group of polypeptide or antibody molecule) that forms with mineral acid example hydrochloric acid or phosphoric acid or organic acid such as acetate, oxalic acid, tartrate, amygdalic acid etc.The salt that forms from free carboxy can also be from the mineral alkali for example oxyhydroxide of sodium, potassium, ammonium, calcium or iron and organic bases such as Isopropylamine, Trimethylamine 99,2-ethyl amido alcohol, Histidine, PROCAINE HCL, PHARMA GRADE etc.
In above-mentioned additive, vehicle, preparation and the medication every kind is all represented an embodiment independently of the present invention.
Experiment is described in detail
Embodiment 1
It is synthetic to handle PC-12 cell raising phosphatide with omega-fatty acid
Material and experimental technique
Reagent
(Boston MA) obtains from Perkin-Elmer 14 The choline chloride 60 of C mark.(Plymouth Meeting PA) obtains DHA, oleic acid or palmitinic acid from Biomol.(Piscataway NJ) obtains from AmershamBiosciences Corp 14The C-choline.
Cell culture
The PC-12 cell is remained in DMEM (DMEM)+10% foetal calf serum (FBS).For experimentizing, cell is grown in 35 millimeters (mm) culture dish of quintuplicate collagen bed board.Cell is cultivated 18 hours (hr) in the DMEM that does not contain serum that contains 28 μ M choline+/-5 micromoles (μ M) DHA, oleic acid or palmitinic acid.Then in the DMEM that does not contain serum that contains 10 micromoles (μ M) choline with 0.5 microcurie (μ Ci)/ml's 14C-choline mark 2.5 hours.
Mark phosphatide quantitatively
With tissue homogenizer (Polytron PT 10-35, Kinematica AG is Switzerland) with cell homogenate in the ice-cold deionized water of 100 volumes; Equal portions with 1ml mix with 3ml chloroform+carbinol mixture (2: 1 volume/volume) then, violent vortex 30 seconds.In cooled on ice after 1 hour, mixture is successively mixed with the ice-cold deionized water of 3ml chloroform+carbinol mixture (2: 1 volume/volume) and 1ml.With the violent vortex of mixture, place in the cold house spend the night (18 hours) then.By centrifugal (10 minutes, 4 ℃; 1000g) organic phase of separating mixture (lower floor) and water (upper strata).The upper strata of one equal portions (2ml) is used to measure CDP-choline (seeing below) mutually, and, is used for the phosphatide analysis the equal parts vacuum-drying of 0.1-0.4ml lower floor.Measure total phospholipids content in the residual 0.1ml lower floor equal parts by measuring phosphorus.The 0.4ml lower floor equal parts of remnants is duplicated in 40 μ l methyl alcohol, use silicon-dioxide G plate (Adsorbosil
Figure A20068002700800651
Alltech) carry out tlc, moving phase is by chloroform/ethanol/triethylamine/water (30: 34: 30: the system that 8) forms.The solution of diphenyl hexatriene with 0.1% in sherwood oil is differentiated the down corresponding band of ultraviolet lamp with the phosphatide standard substance after spraying on the plate.Scrape on the band slave plate with each phosphatide classification (PC, PE, SM, PS and PI), be extracted in the 1ml methyl alcohol; Vacuum-drying also is used to measure phosphorus content.By with the use KH that carries out with each mensuration 2PO 4Typical curve comparative measurement total phosphorus content.In each sample, add 0.5ml 4.5%HClO4/27%H 2SO 4And with each test tube 180 ℃ the heating 3 hours.After being cooled to room temperature, add 5ml colouring reagents (being respectively 10: 1 the diluting soln that contains 2.5mg/ml ammonium molybdate, 8.2mg/ml sodium acetate and 100mg/ml xitix), test tube was cultivated 2 hours down at 37 ℃.Optical density with spectrophotometer measurement 820nm.Phosphorus content be multiply by 25 obtain the phosphatide quality.
Statistical analysis
Data are through one-way analysis of variance (variance analysis), and then Si Shi t checks and analyzes.
The result
For estimating omega-fatty acid to the influence of phosphatide synthetic, DHA exist or not in the presence of pre-cultivate 18 hours after, with the PC-12 cell with 14The choline of C mark is cultivated.Then measure mixing of mark in the phosphatide.The oleic acid and the palmitinic acid that do not belong to omega-fatty acid are used as negative control.By cultivating in advance with DHA, the synthetic significance ground of phosphatidylcholine (PC) improves, but oleic acid or palmitinic acid are somebody's turn to do effect, as (Fig. 1) that increase proves that mix of mark among the PC.Therefore, it is synthetic to handle raising cell phosphatide with omega-fatty acid.
Embodiment 2
Omega-fatty acid improves the synthetic of multiple phosphatide in the dose-dependently mode
For further characterizing omega-fatty acid to phosphatide synthetic hormesis, with the DHA pre-treatment PC-12 cell of various dose, and make its choline that is exposed to mark, as described in embodiment 1, measure in the phosphatide then 14Mixing of C mark.Improved phosphatide synthetic (Fig. 2) with the DHA pre-treatment.The synthetic increase is a dose-dependently.Therefore, omega-fatty acid stimulates phosphatide synthetic in the dose-dependently mode.
Embodiment 3
It is synthetic to improve phosphatide with ω-6 fatty acid treatment SHSY-5Y cell Material and experimental technique
Cell culture
The SHSY-5Y cell grows in DMEM+10%FBS in the 35mm culture dish near being paved with.Cell was cultivated 18 hours in the DMEM+1%FBS that does not contain serum that contains 30 μ M choline+/-10 μ M DHA, arachidonic acid or palmitinic acid.Then with cell marking, as quantitative mark phosphatide as described in the embodiment 1.
The preparation of DHA-BSA mixture
With DHA be dissolved in the ethanol to concentration be 100 micromoles, freezing at-80 ℃ of equal portions with 10 microlitres.For each experiment, equal portions are diluted to 10 micromoles in ethanol, the final solution in substratum of intended volume is mixed with isopyknic BSA solution (1gm/ml).
The result
Next study ω-6 lipid acid to human nerve's blastoma clone---phosphatide synthetic influence in the SHSY-5Y cell.In this embodiment, it is synthetic that arachidonic acid (a kind of ω-6 lipid acid) improves phosphatide, but DHA or palmitinic acid do not have this effect (Fig. 3 A).
Embodiment 4
ω-6 lipid acid improves the synthetic of multiple phosphatide in the dose-dependently mode
Further characterized arachidonic acid to phosphatide synthetic influence in the SHSY-5Y cell, as the omega-fatty acid and PC-12 cell described among the embodiment 2.Arachidonic acid improves the synthetic of total phospholipids, PC and phosphatidylethanolamine in the dose-dependently mode under a series of dosage, as for DHA being seen (Fig. 3 B).Therefore, ω-6 lipid acid stimulates the synthetic of multiple phosphatide in the dose-dependently mode.
Embodiment 5
The administration polyunsaturated fatty acid improves the kephalin level, and the adding uridine causes further collaborative the raising
Material and experimental technique
Diet
(Harlan Teklad, Madison WI) form reference standard diet (table 4), and it contains 0.1% choline chloride 60 (CC), and corresponding per daily dose is 50mg/kg/ day by Teklad Global 16% protein rodent diet.UMP is with 0.5%UMP2Na +The form of w/w provides, and adds in the control diet, also by Harlan Teklad preparation, corresponding to 240mg/kg/ day UMP.The dosage of DHA is 300mg/kg/ day, is 5% gum arabic solution of 200 microlitres (mcL)/day, and the group of not accepting DHA is only accepted carrier (5% Sudan Gum-arabic).(Elysian MN) provides DHA, and (Wagenigen NL) provides UMP by Numico by Nu-Chek Prep.All do not show significant body weight change for any group at experimental session.
Table 4. reference standard diet
Figure A20068002700800671
The collection of brain
, with gerbil jird anesthesia its head was immersed in liquid nitrogen 2 minutes with ketamine and xylazine (80 and 10mg/kg body weight, intraperitoneal), broken end is put to death then.Take out brain (30 seconds) and be stored in-80 ℃ rapidly immediately with rongeur.
The measurement of kephalin
Refrigerated brain hemisphere is weighed, and (Switzerland) homogenate in the ice-cold deionized water of 100 volumes is analyzed as described in embodiment 1 then for Polytron PT 10-35, KinematicaA G with tissue homogenizer.
DNA and protein determination
Measure the protein in the full brain homogenate sample so as to use dihomocinchonine acid reagent (PerkinElmer, Norwalk, C T, USA).The measurement of DNA by measure sample in photofluorometer in the presence of bisbenzimidazole the emission at the 460nm place carry out, bisbenzimidazole is the fluorescence dye (American Hoechst Corporation) of a kind of Hoechst of being called H 33258, it has the maximum excitation wavelength of 356nm, and maximum emission wavelength is 458nm when combining with DNA.
The result
With body weight is that the gerbil jird of 80-100g is divided into 4 groups, 8 every group, and the enriching substance of describing in the administration table 1:
Table 1. treatment group
Group Enriching substance Amount/method
1 Control diet+carrier (5% Sudan Gum-arabic)
2 UMP sodium+carrier (5% Sudan Gum-arabic) 0.5% of Na-UMP mouse grain
3 DHA Gavage 300mg/kg every day
4 DHA+UMP sodium The same
After 4 weeks, put to death animal, measure 1 except that the total phospholipids of the brain hemisphere of decerebellation and brain stem and the content of PC, phosphatidylethanolamine (PE), sphingophospholipid (SM), phosphatidylinositols (PI) and phosphatidylserine (PS).Omega-fatty acid (DHA) makes the total phospholipids level be increased to the level (Fig. 4 and table 2 and 3) that significance ground is higher than control group.The combination of DHA and UMP causes synergitic further raising (26%) (that is: be higher than observed rising in DHA group (12%) and the UMP group (5%) and).Observed similar result (table 2 and table 3) for each phosphatide.No matter whether the value of phosphatide is normalized to proteinic amount (Fig. 4 A and table 2) or, has all observed statistical significance to the amount (Fig. 4 B and table 3) of DNA.
Table 2:DHA, UMP or two kinds of processing are to the influence of kephalin level, and the phosphatide level is standardized to protein level.Data representation be mean value+/-standard error of mean (SEM).Statistical analysis uses two-way analysis of variance and Tukey check." *" represent P＜0.05 compared with the control; " *"-P＜0.01; " * *"-P＜0.001.
Processing/lipid Total PL PC PE SM PS PI
Contrast 351±8 152±6 64±4 45±2 33±3 21±2
UMP 367±22 171±8 * 84±8 * 52±5 35±3 31±2 **
DHA 392±20 185±12 * 78±5 * 56±3 * 39±3 32±2 **
UMP+DHA 442±24 *** 220±12 *** 113±6 *** 73±4 *** 46±6 *** 36±6 ***
Table 3:DHA, UMP or two kinds of processing are to the influence of kephalin level, and the phosphatide level is standardized to dna level.Statistical analysis/data representation such as table 2.
Processing/lipid Total PL PC PE SM PS PI
Contrast 885±45 332±12 176±13 112±5 79±8 54±5
UMP 878±18 368±10 * 195±9 111±4 86±7 78±6 **
DHA 909±77 366±13 * 196±18 126±8 98±7 84±13 **
UMP+DHA 1058±25 *** 462±26 *** 261±30 *** 169±11 *** 110±5 *** 85±10 ***
These results have confirmed the result of above embodiment, show that omega-fatty acid and ω-6 lipid acid all improve the synthetic and kephalin level of kephalin, had both improved the level that the total phospholipids level also improves independent phosphatide.These results show that further the combination of polyunsaturated fatty acid and uridine causes further collaborative the raising.In addition, these results show that it is general phenomenon that polyunsaturated fatty acid stimulates the phosphatide synthetic, is not limited to specific phosphatide or experimental model.
Constitute the ratio approximately equal of four kinds of structure phosphatide (these four kinds of phosphatide: PC, PE, PS and sphingophospholipid) raising of a large amount of cytolemma in the brain, these four kinds of compounds all improve about 20% for every kind.Therefore, kept the ratio of four kinds of structure phosphatide in the film.Correspondingly, film quality improves and does not destroy normal membrane structure and function.These results have proved conclusively the data that obtain from previous embodiment, for composition for improved of the present invention and cerebral function improvement provide further evidence.
Embodiment 6
Reduce brain CDP-choline level and improve the kephalin level to gerbil jird administration omega-fatty acid
Material and experimental technique
CDP-choline assay method
With upper strata (water) the phase vacuum-drying of equal portions (2ml), duplicate and inject HPLC.The exsiccant sample duplicates in 100-200 μ l water and goes up analysis by HPLC at anion-exchange column (AlltechHypersil APS-2,5mm, 250X 4.6mm).The CDP-choline buffer A (H of linear gradient 3PO 4, 1.75mM, pH 2.9) and B (NaH 2PO 2, 500mM, pH 4.5) wash-out, described linear gradient be in 30 minutes from 0 to 100%B.Use this system, the material of near-earth co-elute such as UMP divide and open mutually in CDP-choline and time of 40 minutes in the constant gradient system.The retention time of CDP-choline is 9.5 minutes.Finish the back and washed pillar to remove the Nucleotide of reservation with buffer B in each experiment every several days.Each Nucleotide peak detects at the 280nm place with uv-absorbing, by relatively and by add the Nucleotide standard substance in sample identifying with the position of true standard product.
The result
For measuring of the influence of administration polyunsaturated fatty acid, measure the brain CDP-choline level in the animal in the previous embodiment to CDP-choline level.Administration DHA and/or UMP have reduced CDP-choline level (Fig. 5 A) and CDP-thanomin level (Fig. 5 B).The CDP-choline level that makes DHA reduces by 26% (comparing with the group of the carrier of only accepting control diet and DHA), reduces by 21% (comparing with the group of the carrier of the diet of only accepting to contain UMP and DHA) (all being P＜0.05) in the gerbil jird that UMP-handles.Two-way analysis of variance finds that DHA has significance influence [F (1,28)=31.7; P＜0.001].
In another research, in standard diet, add UMP and and do not handle significance ground with DHA simultaneously and improve PC, PE and PI level in the brain, improve 13%, 29% and 48% (table 5A) respectively.Administration DHA and do not have UMP also significance ground to improve level (respectively improve 22%, 20% and 52%) and the sphingophospholipid level (improve 24%) of these phosphatide in brain.UMP+DHA all improves whole phosphatide, this improve improve due to separately greater than UMP or DHA and.
Then, studied the time-histories of these raisings.After handling for 1 week, UMP does not produce the influence of significance, and UMP+DHA makes brain PC (21%) and PS (38%) have slight but the raising of significance.Handle the significance that 3 weeks caused all 5 kinds of phosphatide with UMP+DHA and improve (21-48%), independent UMP causes less but still is the raising (table 5B) of significance.
Table 5:UMP and/or polyunsaturated fatty acid are to the influence of kephalin level
Figure A20068002700800711
Therefore, under these conditions, the administration polyunsaturated fatty acid is attributable to the conversion increase of CDP-choline to PC and relevant phosphatide to the influence of kephalin.
Embodiment 7
Improve the synapsin level to gerbil jird administration omega-fatty acid and/or uridine
Material and experimental technique
Synapsin level determination method
Synapsin is measured with slot blot method and Western blotting.For Western blotting, the equal portions of brain homogenate thing are mixed with 2X KFL sample loading buffer, boiled 5 minutes, carry out gel electrophoresis then.The protein of application of sample equivalent is also used SDS-PAGE (4-20%; Bio-Rad, Hercules, CA USA) separates.Then protein transduction is moved on the pvdf membrane (Immobilon-P, Millipore, Billerica, MA, USA).(CA USA) seals remaining binding site 30 minutes in Tris buffer saline-tween (TBST) for Varnation, Glendale with 4% skim-milk.2X KFL sample loading buffer is prepared as follows: mix 3.76ml 1M TRIS, pH 6.8; 6ml 20% sodium lauryl sulphate; 6ml glycerine; 1.5ml mercaptoethanol; 2ml1% tetrabromophenol sulfonphthalein and 10.74ml water.
For the slot blot method, two covers are come equal portions (the 18-21 μ l of the brain homogenate thing in the comfortable deionized water; Contain 20 μ g protein) use slot blot microfilter device [Minifold (R) II Slot BlotSystem (SCR 072/0); Schleicher﹠amp; Schuell, Inc., Keene, NH, USA] by the direct trace of vacuum filtration in polyvinylidene fluoride film (Immobilon-P, Millipore, Billerica, MA, USA) on.(CA USA) sealed 30 minutes in TBST remaining binding site for Varnation, Glendale with 4% skim-milk.Then film (from slot blot method and Western blotting) is cleaned 5 times in the TBST damping fluid, immerse and contain in the important antibody TBST solution of (mouse anti-NF-70, rabbit resist-NF-M, mouse anti-PSD-95 and mouse anti syntaxin-1).Overnight incubation is cultivated trace 1 hour with the suitable secondary antibody that is connected peroxidase also with after the TBST buffer solution for cleaning 5 times.Then trace is cleaned 5 times in the TBST damping fluid, (NJ USA) detects and development protein-antibody complex with Kodak X-AR egative film for Amersham Biosciences, Piscataway to use the ECL system.The SupervistaS-12 scanner of transparency adapter is equipped with in use, and (CA is USA) with the film digitizing for UMAX Technologies, Freemont.Use the reactive band of Public Domain NIH Image program relative immunity by optical densitometric method.The absorbancy area under curve is standardized as the per-cent of the absorbancy that control group produces in identical trace.Protein level is expressed as these the per-cent in the control animal.
The result
The brain level of 4 kinds of synapsins in the animal of the UMP of amount and DHA is accepted described in the embodiment 5 in measurement.After handling for 3 or 4 weeks, spinous process neuroneme albumen NF-70 and NF-M have raise 43% (P＜0.01) or 102% (P＜0.001) and 19% (P＜0.05) or 48% (P＜0.01) respectively (Fig. 6).The level of postsynaptic density albumen PSD-95 and vesicle protein syntaxin-1 38% and 41% (all being P＜0.001) that raise after 3 weeks raise 35% (P＜0.01) or 25% (P＜0.05) (Fig. 7) after 1 week.
These results prove that further administration polyunsaturated fatty acid and uridine improve the amount of synaptic membrane.These improve with the phosphatide level in observed those are similar, show cynapse level rising in the brain.
Embodiment 8
DHA, EPA and AA improve the kephalin level
Material and experimental technique
To adult gerbil jird administration reference standard diet (table 4), contain or do not contain 0.5%UMP and/or 300mg/kg/ day DHA, EPA or AA.Do not accept the group drug administration carrier (5% Sudan Gum-arabic) of DHA.
The result
The administration UMP and/or the gerbil jird in 3 weeks of polyunsaturated fatty acid are put to death, measure the level of various kephalins.As shown in table 6, DHA, EPA and AA have improved the phosphatide level.
Table 6: the kephalin level behind administration polyunsaturated fatty acid and/or the uridine
Handle Total PL PC PE SM PS PI
Contrast+carrier 333±9 113±6 63±4 19±1 25±2 15±1
The UMP+ carrier 332±5 131±2 70±1 22±1 29±1 16±1
Contrast+DHA 344±16 133±6 77±2 24±2 34±3 18±2
Contrast+EPA 347±19 125±8 76±4 26±3 31±1 22±2
U＝MP+DHA 374±17 147±6 88±3 28±3 39±2 22±2
UMP+EPA 407±22 148±3 91±4 30±1 41±2 26±2
UMP+AA 389±28 127±8 88±10 25±2 31±3 22±2
Embodiment 9
Omega-fatty acid and uridine improve the number of the dendritic spine in adult and developmental gerbil jird and the rat brain
In two weeks, give normal adult gerbil jird control diet every day or be supplemented with UMP (240mg uridine/kg) and DHA (gavage, diet 300mg/kg).After processing finished, with the animal sacrificed by decapitation, with carbocyanine film tracer agent DiI (C18) 3 (" DiI, " Molecular Probes, Eugene OR) dyeed the fixed hippocampal slices.Obtain the image of hippocampal neuron from the two-photon microfilm.In accepting the animal of DHA+UMP, dendritic spine density in the hippocampus CA1 cone neurone (number of sour jujube in the dendron of per unit length) significance ground improves and (improves 27%, compared with the control p=.001; (Fig. 8).
In another research, make the rat of gestation freely consume 10 days before childbirth, freely consume 20 days the control diet that contains choline during lactation or be supplemented with this diet of the uridine of UMP form, also accept DHA or its dilution by gavage half every day of every group.Put to death young mouse then, check that brain section is to measure the number of hippocampus dendritic spine.Independent UMP and independent DHA have improved the level of dendritic spine number, and both combinations cause further raising (table 7).
Table 7: the raising of dendritic spine number in the developmental animal behind administration UMP and the DHA
Handle The number of sour jujube Comparison is according to increasing (%)
Contrast 53 -
UMP 68 28％
DHA
70 32％
UMP+DHA 75 42％
Embodiment 10
DHA and UMP improve study
Material and experimental technique
Gerbil jird can freely obtain food and water until experiment test same day, in that day, at first its fasting was spent the night in 17 hours, provided food from 11AM to 6PM then.Gerbil jird is from 3 monthly ages, and the 4 weeks beginning dietary supplementation before the behavior training has mouse grain and/or the 300mg/kg DHA (every group of n=8) of UMP, finishes until training.At first every day animal is operated, continue 4 days, so that the conventional contact of their customs.Make them be familiar with the labyrinth again in 4 days then, this is by placing the food grain labyrinth arm and allow to seek in 3 minutes and carry out everywhere.Gerbil jird is accepted 1 test/day, between testing at every turn with all surface 10% ethanol disinfection.Training comprises for all tests, and the food grain is placed two identical labyrinth arm far-ends.Gerbil jird is placed the center, labyrinth, allow to find in 2 minutes the food grain.When gerbil jird entered in the labyrinth arm that the food grain is housed and before has been in test once more, the working memory mistake took place.When gerbil jird entered the labyrinth arm that the food grain is not housed in the previous test, the reference memory mistake took place.The per-cent of the food grain that record finds.
The result
For measuring uridine and/or DHA influence to study, contain to animals administer uridine and/or DHA diet animal and it is carried out recall tests.DHA and UMP have improved the per-cent (Fig. 9) of the animal that can finish the work.
Embodiment 11
Kephalin level in mother's administration DHA gestation and lactation and UMP raising offspring
As described in example 9 above, to rat administration DHA gestation and lactation and/or uridine.In birth back 20 days, put to death rat, obtain the brain sample, measure phosphatide.Individually dosed DHA makes PC, PI, PE and the sphingophospholipid (SM) of each cell (DNA) in the brain improve 36%, 166%, 38% and 78% respectively.UMP significantly is extended to the effect of DHA 66%, 210%, 68% and 99% (table 8) of contrast.These improve greater than observed raising in adult animals.When being normalized to protein, obtain similar result (table 9).Therefore, can improve phosphatide level among the offspring to mother's administration DHA gestation and lactation and/or uridine.
Table 8: the 20th day the average phosphatide level (nmol/mg protein) in young mouse birth back.Compared with the control: *P＜.05, *P＜.001.Value in the bracket is a raising percentage ratio compared with the control.
Total phospholipids PC PE SM PI
Contrast 277.3 94.2 76.7 4.73 2.28
UMP 282.2 95.3 75.6 5.27 3.92
DHA 322.8 **(16) 115.7(23) 95.7 *(24) 7.52 *(59) 5.49 **(141)
UMP+DHA 348.4 **(26) 139.8 **(48) 115.6 **(51) 8.41 *(78) 6.32 **(177)
Table 9: the 20th day the average phosphatide level (nmol/ micrograms of DNA) in young mouse birth back.Compared with the control: *P＜.05, *P＜.001.Value in the bracket is a raising percentage ratio compared with the control.
Total phospholipids PC PE SM PI
Contrast 26.5 8.85 7.25 0.444 0.215
UMP 24.78 8.11 6.56 0.458 0.352
DHA 33.80 **(30) 12.02 *(36) 9.98 **(38) 0.792 *(78) 0.571 **(166)
UMP+DHA 36.71 **(41) 14.73 **(66) 12.21 **(68) 0.884 *(99) 0.667 **(210)
Embodiment 12
Lipid in the neurone in the omega-fatty acid raising Short-term Culture thing is synthetic
Material and experimental technique
The rat hippocampus cell was cultivated for 3 weeks in Neutrobasal plus B27 substratum, to reaching fully matured.Test the same day, cell and DMEM+ choline are cultivated, add or do not add DHA.Add 14The C-choline was cultivated cell 2 hours again, as extraction as described in the embodiment 1 with measure new formation 14The PC of C mark.
The result
For measuring the influence of DHA, neurone DHA+ choline pre-treatment to phosphatide in the neurone in the Short-term Culture thing.Compare with a cell of administration choline (" contrast "), DHA makes phosphatide has syntheticly improved (Figure 10 more than 2 times; P=0.04).These results have confirmed that DHA improves the phosphatide level in brain cell and the neurocyte.

Claims (73)

1. the method for the amount of a synaptic membrane that improves individual neurocyte or brain cell, it comprises the pharmaceutical composition that comprises omega-fatty acid or its metabolic precursor thereof to described individual administration, thereby improves the amount of the synaptic membrane of neurocyte or brain cell phosphatide.
2. the process of claim 1 wherein that described phosphatide is phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositols, phosphatidylserine or sphingophospholipid.
3. the process of claim 1 wherein that described omega-fatty acid is docosahexenoic acid, timnodonic acid, clupanodonic acid, alpha-linolenic acid or its metabolic precursor thereof.
4. the process of claim 1 wherein that described omega-fatty acid or its metabolic precursor thereof are by improving the described level that synthesizing of phosphatide described in described neurocyte or the brain cell improves phosphatide.
5. the method for claim 1, it also comprises to described individual administration uridine, its acyl derivative, uridine phosphoric acid or CDP-choline.
6. the method for claim 1, it also comprises to described individual administration choline, its metabolic precursor thereof or choline salt.
7. the process of claim 1 wherein described individuality be 0-6 month big.
8. the process of claim 1 wherein described individuality be 7-24 month big.
9. the process of claim 1 wherein that described pharmaceutical composition is an infant formala.
10. the method for the amount of a synaptic membrane that improves individual neurocyte or brain cell, it comprises the pharmaceutical composition that comprises ω-6 lipid acid or its metabolic precursor thereof to described individual administration, thereby improves the amount of the synaptic membrane of neurocyte or brain cell.
11. the method for claim 10, wherein said phosphatide are phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositols, phosphatidylserine or sphingophospholipid.
12. the method for claim 10, wherein said ω-6 lipid acid are arachidonic acid, linolic acid or its metabolic precursor thereof.
13. the method for claim 10, wherein said ω-6 lipid acid or its metabolic precursor thereof are by improving the described level that synthesizing of phosphatide described in described neurocyte or the brain cell improves phosphatide.
14. the method for claim 10, it also comprises to described individual administration uridine, its acyl derivative, uridine phosphoric acid or CDP-choline.
15. the method for claim 10, it also comprises to described individual administration choline, its metabolic precursor thereof or choline salt.
16. the method for claim 10, wherein said individuality be 0-6 month big.
17. the method for claim 10, wherein said individuality be 7-24 month big.
18. the method for claim 10, wherein said pharmaceutical composition is an infant formala.
19. the method improving or strengthen individual intelligence, it comprises the pharmaceutical composition that comprises omega-fatty acid or its metabolic precursor thereof to described individual administration, thereby improves or strengthen individual intelligence.
20. the method for claim 19, wherein said omega-fatty acid are docosahexenoic acid, timnodonic acid, clupanodonic acid, alpha-linolenic acid or its metabolic precursor thereof.
21. the method for claim 19, wherein said omega-fatty acid or its metabolic precursor thereof improve the synthetic of phosphatide in the brain cell of described individuality.
22. the method for claim 19, it also comprises to described individual administration uridine, its acyl derivative, uridine phosphoric acid or CDP-choline.
23. the method for claim 19, it also comprises to described individual administration choline, its metabolic precursor thereof or choline salt.
24. the method for claim 19, wherein said individuality be 0-6 month big.
25. the method for claim 19, wherein said individuality be 7-24 month big.
26. the method for claim 19, wherein said pharmaceutical composition is an infant formala.
27. the method improving or strengthen individual intelligence, it comprises the pharmaceutical composition that comprises ω-6 lipid acid or its metabolic precursor thereof to described individual administration, thereby improves or strengthen individual intelligence.
28. the method for claim 27, wherein said ω-6 lipid acid are arachidonic acid, linolic acid or its metabolic precursor thereof.
29. the method for claim 27, wherein said ω-6 lipid acid or its metabolic precursor thereof improve the synthetic of phosphatide in the brain cell of described individuality.
30. the method for claim 27, it also comprises to described individual administration uridine, its acyl derivative, uridine phosphoric acid or CDP-choline.
31. the method for claim 27, it also comprises to described individual administration choline, its metabolic precursor thereof or choline salt.
32. the method for claim 27, wherein said individuality be 0-6 month big.
33. the method for claim 27, wherein said individuality be 7-24 month big.
34. the method for claim 27, wherein said pharmaceutical composition is an infant formala.
35. the method improving or strengthen offspring's intelligence, it comprises that the mother to described offspring comprises the pharmaceutical composition of omega-fatty acid or its metabolic precursor thereof in the pregnancy duration administration, thereby improves or strengthen offspring's intelligence.
36. the method for claim 35, wherein said omega-fatty acid are docosahexenoic acid, timnodonic acid, clupanodonic acid, alpha-linolenic acid or its metabolic precursor thereof.
37. the method for claim 35, wherein said omega-fatty acid or its metabolic precursor thereof improve the synthetic of phosphatide in described offspring's the brain cell.
38. the method for claim 35, it also comprises to described mother's administration uridine, its acyl derivative, uridine phosphoric acid or CDP-choline.
39. the method for claim 35, it also comprises to described mother's administration choline, its metabolic precursor thereof or choline salt.
40. the method improving or strengthen offspring's intelligence, it comprises that the mother to described offspring comprises the pharmaceutical composition of ω-6 lipid acid or its metabolic precursor thereof in the pregnancy duration administration, thereby improves or strengthen offspring's intelligence.
41. the method for claim 40, wherein said ω-6 lipid acid are arachidonic acid, linolic acid or its metabolic precursor thereof.
42. the method for claim 40, wherein said ω-6 lipid acid or its metabolic precursor thereof improve the synthetic of phosphatide described in described offspring's the brain cell.
43. the method for claim 40, it also comprises to described mother's administration uridine, its acyl derivative, uridine phosphoric acid or CDP-choline.
44. the method for claim 40, it also comprises to described mother's administration choline, its metabolic precursor thereof or choline salt.
45. the method improving or strengthen offspring's intelligence, its mother who is included in described offspring is described offspring between lactation, comprises the pharmaceutical composition of omega-fatty acid or its metabolic precursor thereof to described mother's administration, thereby improves or strengthen offspring's intelligence.
46. the method for claim 45, wherein said omega-fatty acid are docosahexenoic acid, timnodonic acid, clupanodonic acid, alpha-linolenic acid or its metabolic precursor thereof.
47. the method for claim 45, wherein said omega-fatty acid or its metabolic precursor thereof are secreted in described mother's milk.
48. the method for claim 45, it also comprises to described mother's administration uridine, its acyl derivative, uridine phosphoric acid or CDP-choline.
49. the method for claim 45, it also comprises to described mother's administration choline, its metabolic precursor thereof or choline salt.
50. the method improving or strengthen offspring's intelligence, its mother who is included in described offspring is described offspring between lactation, comprises the pharmaceutical composition of ω-6 lipid acid or its metabolic precursor thereof to described mother's administration, thereby improves or strengthen offspring's intelligence.
51. the method for claim 50, wherein said ω-6 lipid acid are arachidonic acid, linolic acid or its metabolic precursor thereof.
52. the method for claim 50, wherein said ω-6 lipid acid or its metabolic precursor thereof are secreted in described mother's milk.
53. the method for claim 50, it also comprises to described mother's administration uridine, its acyl derivative, uridine phosphoric acid or CDP-choline.
54. the method for claim 50, it also comprises to described mother's administration choline, its metabolic precursor thereof or choline salt.
55. one kind is improved the size of cynapse in the individual brain or the method for number, it comprises the pharmaceutical composition that comprises omega-fatty acid or its metabolic precursor thereof to described individual administration, thereby improves the size or the number of cynapse in the individual brain.
56. the method for claim 55, wherein said omega-fatty acid are docosahexenoic acid, timnodonic acid, clupanodonic acid, alpha-linolenic acid or its metabolic precursor thereof.
57. the method for claim 55, wherein said omega-fatty acid or its metabolic precursor thereof improve the synthetic of phosphatide in the brain cell of described individuality.
58. the method for claim 55, it also comprises to described individual administration uridine, its acyl derivative, uridine phosphoric acid or CDP-choline.
59. the method for claim 55, it also comprises to described individual administration choline, its metabolic precursor thereof or choline salt.
60. one kind is improved the size of cynapse in the individual brain or the method for number, it comprises the pharmaceutical composition that comprises ω-6 lipid acid or its metabolic precursor thereof to described individual administration, thereby improves the size or the number of cynapse in the individual brain.
61. the method for claim 60, wherein said ω-6 lipid acid are arachidonic acid, linolic acid or its metabolic precursor thereof.
62. the method for claim 60, wherein said ω-6 lipid acid or its metabolic precursor thereof improve the synthetic of phosphatide in the brain cell of described individuality.
63. the method for claim 60, it also comprises to described individual administration uridine, its acyl derivative, uridine phosphoric acid or CDP-choline.
64. the method for claim 60, it also comprises to described individual administration choline, its metabolic precursor thereof or choline salt.
65. the method improving or strengthen offspring's intelligence, it comprises that the mother to described offspring comprises the pharmaceutical composition of uridine, its acyl derivative, uridine phosphoric acid or CDP-choline in the pregnancy duration administration, thereby improves or strengthen offspring's intelligence.
66. the method for claim 65, wherein said uridine, its acyl derivative, uridine phosphoric acid or CDP-choline improve the synthetic of phosphatide in described offspring's the brain cell.
67. the method for claim 65, it also comprises to described mother's administration choline, its metabolic precursor thereof or choline salt.
68. method of improving or strengthening offspring's intelligence; its mother who is included in described offspring is that described offspring is between lactation; comprise the pharmaceutical composition of uridine, its acyl derivative, uridine phosphoric acid to described mother's administration, thereby improve or strengthen offspring's intelligence.
69. the method for claim 68, wherein said uridine, its acyl derivative, uridine phosphoric acid or CDP-choline are secreted in described mother's milk.
70. the method for claim 68, it also comprises to described mother's administration choline, its metabolic precursor thereof or choline salt.
71. a pharmaceutical composition, it comprises (a) uridine, its acyl derivative, uridine phosphoric acid; (b) ω-6 lipid acid or its metabolic precursor thereof.
72. the pharmaceutical composition of claim 71, it also comprises choline, its metabolic precursor thereof or choline salt.
73. the pharmaceutical composition of claim 71, wherein said ω-6 lipid acid are arachidonic acid, linolic acid or its metabolic precursor thereof.
CN200680027008.0A 2005-05-23 2006-05-23 Composition and its application method containing polyunsaturated fatty acid and/or uridine Active CN101495490B (en)

Applications Claiming Priority (9)

Application Number Priority Date Filing Date Title
US68335205P 2005-05-23 2005-05-23
US60/683,352 2005-05-23
US71607705P 2005-09-13 2005-09-13
US60/716,077 2005-09-13
US75505806P 2006-01-03 2006-01-03
US60/755,058 2006-01-03
US76175306P 2006-01-25 2006-01-25
US60/761,753 2006-01-25
PCT/US2006/019778 WO2006127627A2 (en) 2005-05-23 2006-05-23 Compostions containing pufa and/or uridine and methods of use thereof

Publications (2)

Publication Number Publication Date
CN101495490A true CN101495490A (en) 2009-07-29
CN101495490B CN101495490B (en) 2018-05-08

Family

ID=40925381

Family Applications (2)

Application Number Title Priority Date Filing Date
CNA2006800269454A Pending CN101506218A (en) 2005-05-23 2006-05-23 Compositions containing pufa and methods of use thereof
CN200680027008.0A Active CN101495490B (en) 2005-05-23 2006-05-23 Composition and its application method containing polyunsaturated fatty acid and/or uridine

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CNA2006800269454A Pending CN101506218A (en) 2005-05-23 2006-05-23 Compositions containing pufa and methods of use thereof

Country Status (1)

Country Link
CN (2) CN101506218A (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104168766A (en) * 2011-10-21 2014-11-26 翁特拉制药公司 Methods and compositions for treating or preventing attention deficit hyperactivity disorder
CN109071559A (en) * 2016-05-04 2018-12-21 亲神经剂生物科学有限公司 For treating the method and composition of rett's syndrome

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012125020A1 (en) * 2011-03-14 2012-09-20 N.V. Nutricia Method for treating neurotrauma
CN103356664A (en) * 2012-04-05 2013-10-23 日本水产株式会社 Brain atrophy prevention agent
WO2014171813A1 (en) * 2013-04-17 2014-10-23 N.V. Nutricia Nutritional composition for improving brain function in phenylketonuria
AU2017289278A1 (en) * 2016-06-27 2019-01-17 Ohio State Innovation Foundation Liponucleotide-based therapy for ARDS

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030114415A1 (en) * 2001-12-14 2003-06-19 Wurtman Richard J. Compositions and methods for treating and preventing memory impairment using citicoline

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030114415A1 (en) * 2001-12-14 2003-06-19 Wurtman Richard J. Compositions and methods for treating and preventing memory impairment using citicoline

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104168766A (en) * 2011-10-21 2014-11-26 翁特拉制药公司 Methods and compositions for treating or preventing attention deficit hyperactivity disorder
CN109071559A (en) * 2016-05-04 2018-12-21 亲神经剂生物科学有限公司 For treating the method and composition of rett's syndrome

Also Published As

Publication number Publication date
CN101506218A (en) 2009-08-12
CN101495490B (en) 2018-05-08

Similar Documents

Publication Publication Date Title
JP5566604B2 (en) Composition containing PUFA and / or uridine and method using the same
CN101495490A (en) Compostions containing pufa and/or uridine and methods of use thereof
US20160158177A1 (en) Nutritional composition for improving brain function in phenylketonuria
DE602004004905T2 (en) CALCIUM-ENRICHED SMALL-NURVES ON SOYABASIS
JP2008518961A (en) How to adjust animal weight and size with glycine
RU2429851C2 (en) Compositions containing pufa and/or uridine, and methods of application thereof
AU2012203650B2 (en) Compositions containing PUFA and methods of use thereof
AU2014274585B2 (en) Compositions containing pufa and/or uridine and methods of use thereof
AU2012203329B2 (en) Compostions containing PUFA and/or uridine and methods of use thereof
US20160235778A1 (en) Compositions containing pufa, uridine and choline and methods of use thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant