CN101495490B - Composition and its application method containing polyunsaturated fatty acid and/or uridine - Google Patents

Composition and its application method containing polyunsaturated fatty acid and/or uridine Download PDF

Info

Publication number
CN101495490B
CN101495490B CN200680027008.0A CN200680027008A CN101495490B CN 101495490 B CN101495490 B CN 101495490B CN 200680027008 A CN200680027008 A CN 200680027008A CN 101495490 B CN101495490 B CN 101495490B
Authority
CN
China
Prior art keywords
another embodiment
individual
brain
dosage
uridine
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.)
Active
Application number
CN200680027008.0A
Other languages
Chinese (zh)
Other versions
CN101495490A (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

Landscapes

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

Abstract

The present invention provides enhancing brain growth；Improve or increase intelligence；The method for improving or strengthening the synthesis and level of nerve cell or brain cell to phosphatide, cynapse, synapsin and synaptic membrane, it includes contacting individual or its pregnant or lactation mother with the composition comprising omega-3 fatty acid, 6 aliphatic acid of ω and/or uridine, its metabolic precursor thereof or combinations thereof.

Description

Composition and its application method containing polyunsaturated fatty acid and/or uridine
Invention field
The present invention provides enhancing brain growth；Improve or increase intelligence；Improve or enhancing nerve cell or brain cell to phosphatide, Cynapse, the synthesis of synapsin and synaptic membrane and level method, it include by individual or its gestation or lactation mother and Composition contact comprising omega-fatty acid, ω -6 aliphatic acid and/or uridine, its metabolic precursor thereof or combinations thereof.
Background of invention
The factor of correct brain growth and intellectual level is not sufficiently defined.It is badly in need of the treatment of paediatrics neurological disorder in this area Method.
Summary of the invention
The present invention provides enhancing brain growth；Improve or increase intelligence；Improve or enhancing nerve cell or brain cell to phosphatide, Cynapse, the synthesis of synapsin and synaptic membrane and level method, it include by individual or its gestation or lactation mother and Composition contact comprising omega-fatty acid, ω -6 aliphatic acid and/or uridine, its metabolic precursor thereof or combinations thereof.
In one embodiment, the present invention provides the side of the amount of the synaptic membrane of the nerve cell for improving individual or brain cell Method, it is included to the pharmaceutical composition of the individual administration comprising omega-fatty acid or its metabolic precursor thereof, so as to improve neural thin The amount of the synaptic membrane of born of the same parents or brain cell phosphatide.
In another embodiment, the present invention provides the side of the amount of the synaptic membrane of the nerve cell for improving individual or brain cell Method, it is included to the pharmaceutical composition of the individual administration comprising ω -6 aliphatic acid or its metabolic precursor thereof, so as to improve neural thin The amount of the synaptic membrane of born of the same parents or brain cell.
In another embodiment, the present invention provides the side of the amount of the synaptic membrane of the nerve cell for improving individual or brain cell Method, it includes including (a) omega-fatty acid or its metabolic precursor thereof to the individual administration；(b) uridine, its acyl derivative, The pharmaceutical composition of uridine phosphate or CDP-choline, so as to improve the amount of the synaptic membrane of nerve cell or brain cell.
In another embodiment, the present invention provides the side of the amount of the synaptic membrane of the nerve cell for improving individual or brain cell Method, it includes including (a) ω -6 aliphatic acid or its metabolic precursor thereof to the individual administration；(b) uridine, its acyl derivative, The pharmaceutical composition of uridine phosphate or CDP-choline, so as to improve the amount of the synaptic membrane of nerve cell or brain cell.
In another embodiment, the method that the present invention provides the intelligence for improving or strengthening individual, it is included to described Pharmaceutical composition of the body administration comprising omega-fatty acid or its metabolic precursor thereof, so as to improve or strengthen the intelligence of individual.
In another embodiment, the method that the present invention provides the intelligence for improving or strengthening individual, it is included to described Pharmaceutical composition of the body administration comprising ω -6 aliphatic acid or its metabolic precursor thereof, so as to improve or strengthen the intelligence of individual.
In another embodiment, the method that the present invention provides the intelligence for improving or strengthening individual, it is included to described Body administration includes (a) omega-fatty acid or its metabolic precursor thereof；Uridine, its acyl derivative, uridine phosphate or CDP-choline (b) Pharmaceutical composition so that improve or strengthen individual intelligence.
In another embodiment, the method that the present invention provides the intelligence for improving or strengthening individual, it is included to described Body administration includes (a) ω -6 aliphatic acid or its metabolic precursor thereof；Uridine, its acyl derivative, uridine phosphate or CDP-choline (b) Pharmaceutical composition so that improve or strengthen individual intelligence.
In another embodiment, the present invention is provided and improved or the method for the intelligence of enhancing offspring, it is included to after described The mother in generation includes omega-fatty acid or the pharmaceutical composition of its metabolic precursor thereof in gestation administration, so that after improving or strengthening The intelligence in generation.
In another embodiment, the present invention is provided and improved or the method for the intelligence of enhancing offspring, it is included to after described The mother in generation includes ω -6 aliphatic acid or the pharmaceutical composition of its metabolic precursor thereof in gestation administration, so that after improving or strengthening The intelligence in generation.
In another embodiment, the present invention is provided and improved or the method for the intelligence of enhancing offspring, it is included to after described The mother in generation includes (a) omega-fatty acid or its metabolic precursor thereof in gestation administration；Uridine, its acyl derivative, urine (b) The pharmaceutical composition of glycosides phosphoric acid or CDP-choline, so as to improve or strengthen the intelligence of offspring.
In another embodiment, the present invention is provided and improved or the method for the intelligence of enhancing offspring, it is included to after described The mother in generation includes (a) ω -6 aliphatic acid or its metabolic precursor thereof in gestation administration；Uridine, its acyl derivative, urine (b) The pharmaceutical composition of glycosides phosphoric acid or CDP-choline, so as to improve or strengthen the intelligence of offspring.
In another embodiment, the method that the present invention provides the intelligence for improving or strengthening offspring, it is included in the rear During the mother in generation is offspring's lactation, to drug regimen of described mother administration comprising omega-fatty acid or its metabolic precursor thereof Thing, so as to improve or strengthen the intelligence of offspring.
In another embodiment, the method that the present invention provides the intelligence for improving or strengthening offspring, it is included in the rear During the mother in generation is offspring's lactation, to drug regimen of described mother administration comprising ω -6 aliphatic acid or its metabolic precursor thereof Thing, so as to improve or strengthen the intelligence of offspring.
In another embodiment, the method that the present invention provides the intelligence for improving or strengthening offspring, it is included in the rear During the mother in generation is offspring's lactation, (a) omega-fatty acid or its metabolic precursor thereof are included to described mother administration；(b) Uridine, its acyl derivative, the pharmaceutical composition of uridine phosphate or CDP-choline, so as to improve or strengthen the intelligence of offspring.
In another embodiment, the method that the present invention provides the intelligence for improving or strengthening offspring, it is included in the rear During the mother in generation is offspring's lactation, (a) ω -6 aliphatic acid or its metabolic precursor thereof are included to described mother administration；(b) Uridine, its acyl derivative, the pharmaceutical composition of uridine phosphate or CDP-choline, so as to improve or strengthen the intelligence of offspring.
In another embodiment, the present invention provides the method for improving the size or number of cynapse in individual brain, it includes To the pharmaceutical composition of the individual administration comprising omega-fatty acid or its metabolic precursor thereof, so as to improve cynapse in individual brain Size or number.
In another embodiment, the method that the present invention provides the size or number of cynapse in the brain for improving individual, it is wrapped Include to the pharmaceutical composition of the individual administration comprising ω -6 aliphatic acid or its metabolic precursor thereof, so as to improve cynapse in individual brain Size or number.
In another embodiment, the method that the present invention provides the size or number of cynapse in the brain for improving individual, it is wrapped Include to the individual administration and include (a) omega-fatty acid or its metabolic precursor thereof；Uridine, its acyl derivative, uridine phosphate (b) Or the pharmaceutical composition of CDP-choline, so as to improve the size or number of cynapse in individual brain.
In another embodiment, the method that the present invention provides the size or number of cynapse in the brain for improving individual, it is wrapped Include to the individual administration and include (a) ω -6 aliphatic acid or its metabolic precursor thereof；Uridine, its acyl derivative, uridine phosphate (b) Or the pharmaceutical composition of CDP-choline, so as to improve the size or number of cynapse in individual brain.
In another embodiment, the present invention is provided and improved or the method for the intelligence of enhancing offspring, it is included to after described The mother in generation includes the pharmaceutical composition of uridine, its acyl derivative, uridine phosphate or CDP-choline in gestation administration, from And improve or strengthen the intelligence of offspring.
In another embodiment, the method that the present invention provides the intelligence for improving or strengthening offspring, it is included in the rear During the mother in generation is offspring's lactation, the medicine of uridine, its acyl derivative, uridine phosphate is included to described mother administration Composition, so as to improve or strengthen the intelligence of offspring.
In another embodiment, the present invention is provided comprising (a) uridine, its acyl derivative, uridine phosphate；(b) ω- The pharmaceutical composition of 6 aliphatic acid or its metabolic precursor thereof.
In another embodiment, either method of the invention and composition include giving for omega-fatty acid and choline Medicine.In another embodiment, either method of the invention and composition include the administration of omega-fatty acid and choline salt. In another embodiment, the administration of either method of the invention and composition including ω -6 aliphatic acid and choline.In another reality Apply in scheme, the administration of either method of the invention and composition including ω -6 aliphatic acid and choline salt.
In another embodiment, either method of the invention and composition include comprising omega-fatty acid, uridine and The administration of the composition of choline.In another embodiment, either method of the invention and composition include including ω -3 fat The administration of the composition of fat acid, uridine and choline salt.In another embodiment, either method of the invention and composition wrap Include the administration of the composition comprising ω -6 aliphatic acid, uridine and choline.In another embodiment, either method of the invention and Composition includes the administration of the composition comprising ω -6 aliphatic acid, uridine and choline salt.
In another embodiment, either method of the invention and composition include ω -6 aliphatic acid and omega-fatty acid Administration.In another embodiment, either method of the invention and composition include ω -6 aliphatic acid, omega-fatty acid and The administration of uridine.In another embodiment, either method of the invention and composition include ω -6 aliphatic acid, ω -3 fat The administration of acid and choline.In another embodiment, either method of the invention and composition include ω -6 aliphatic acid, ω -3 The administration of aliphatic acid and choline salt.In another embodiment, either method of the invention and composition include ω -6 fat The administration of acid, omega-fatty acid, uridine and choline.In another embodiment, either method of the invention and composition wrap Include the administration of ω -6 aliphatic acid, omega-fatty acid, uridine and choline salt.
Brief description
Fig. 1：DHA improves the phosphatide synthesis in PC12 cells.PC12 cells and aliphatic acid overnight incubation, are then containing C14 Cultivated in the culture medium of the choline of mark.Diagram is described to phosphatidyl with the decays per minute (dpm) of every microgram (μ g) DNA C is mixed in choline14Mark.DHA：Docosahexaenoic acid.OA：Oleic acid.PA：Palmitic acid.*- p ＜ 0.05.
Fig. 2：The increase that DHA synthesizes phosphatide is dose-dependent.*- p ＜ 0.05.**- p ＜ 0.001.
Fig. 3：A. arachidonic acid improves the phosphatide synthesis in SHSY-5Y cells.DHA：Docosahexaenoic acid.AA：Flower Raw tetraenoic acid.PA：Palmitic acid.*：P ＜ 0.05.**：P ＜ 0.001.The increase that B.AA synthesizes phosphatide is dose-dependent.
Fig. 4：In whole animal research, DHA and UMP collaborations improve cephalin level.*：It is higher than control group to conspicuousness (one-way analysis of variance (one-way ANOVA)).The phosphatide pmol numbers of A. every milligram (mg) protein.UMP+DHA conspicuousnesses Ground is higher than control (p ＜ 0.05) (one-way analysis of variance [F (3,28)=4.12；P=0.015]).Two-way analysis of variance (two-wayANOVA) display that compared with control group, the influence [F (1,28)=8.78 of the significance,statistical of DHA；P= 0.006].B. per the phosphatide pmol numbers of μ gDNA.UMP+DHA conspicuousnesses it is higher than control (p=0.020) (one-way analysis of variance [F (3,28)=3.215；P=0.038]).
Fig. 5：Influences of the DHA to brain CDP-choline horizontal (A) and CDP- ethanol amine level (B).The group receiving pair of 8 gerbil jirds According to diet or the diet containing UMP, give DHA (in 5% carrier of gum arabic solution) through gavage or be only given 5% I Primary gum-solution, continues 28 days.At the 29th day, gather brain and measure CDP-choline.Data representation is average value ± SEM.Use Single factor test or two-way analysis of variance, then Tukey, which is examined, carries out statistical analysis.a：When the value with control diet adding carrier group Compared to when, P ＜ 0.05；b：When compared with the value of UMP diet adding carrier groups, P ＜ 0.05.
Fig. 6：The influence of UMP diet and DHA to brain NF-70 (A) and NF-M (B) level, gerbil jird receive described in Fig. 5 legends Diet, continue 21 days (groups on the left side) or 28 days (group on the right).The 22nd day and the 29th day, gather brain and measure NF-70. Value is expressed as average value ± SEM.Examined using one-way analysis of variance and Tukey and carry out statistical analysis, A. and control diet+ The value of vehicle group is compared,**：P ＜ 0.01；***：P ＜ 0.001；B).*P ＜ 0.05；**P ＜ 0.01.Cytoskeletal protein β-micro-pipe Protein level does not observe significant difference between group.
Fig. 7：The influence of UMP diet and DHA to brain PSD-95 and the level of synapsin -1.A) gerbil jird or receiving control drink 5% gum arabic for adding and being administered by gavage is eaten, or the diet for receiving to contain UMP (0.5%) adds and passes through tube feed The DHA (300mg/kg) being dissolved in carrier of method administration, continues 7 days (groups on the left side) or 21 days (group on the right).Following One day, collection brain simultaneously measures PSD-95 (A) or synapsin -1 (B).A. value is expressed as average value ± SEM.Use single factor test Variance analysis, then Tukey, which is examined, carries out statistical analysis.When compared with the value of control diet adding carrier group,**：P ＜ 0.01；***：P ＜ 0.001；B).*P ＜ 0.05；**P ＜ 0.01.
Fig. 8：Dendritic spines density improves in adult gerbil jird hippocampus.
Fig. 9：The influence of uridine and/or DHA to study.
Figure 10：The influence that DHA synthesizes phosphatide in the hippocampal neuron of culture.The longitudinal axis：14CDPM/50 μ l samples.
Detailed description of the invention
The present invention provides enhancing brain growth；Improve or increase intelligence；Improve or enhancing nerve cell or brain cell to phosphatide, Cynapse, the synthesis of synapsin and synaptic membrane and level method, it include by individual or its gestation or lactation mother and Contacted comprising omega-fatty acid, ω -6 aliphatic acid, uridine or the composition of its metabolic precursor thereof or combinations thereof.
In one embodiment, the method that the present invention provides the phospholipid level for the nerve cell for improving individual, it includes To the individual administration omega-fatty acid or its metabolic precursor thereof, so as to improve the phospholipid level of the nerve cell of individual.Another In embodiment, the object of this method is developmental brain or its nerve cell.In another embodiment, the object is not It is diagnosed as the adult with any cognition or neurological disorder.Every kind of possibility represents the independent embodiment party of the present invention Case.
In the another embodiment of the method and composition of the present invention, omega-fatty acid, ω -6 aliphatic acid, uridine, courage Alkali, choline salt or its combination are in administered in pharmaceutical compositions.
In another embodiment, the method that the present invention provides the phospholipid level for the brain cell for improving individual, it includes will The brain cell and omega-fatty acid or its metabolic precursor thereof, so as to improve the phospholipid level of the brain cell of individual.Another In embodiment, the object of this method is developmental brain or its nerve cell.In another embodiment, the object is not It is diagnosed as the adult with any cognition or neurological disorder.Every kind of possibility represents the independent embodiment party of the present invention Case.
In another embodiment, the present invention provides the side improved or strengthen the synthesis of nerve cell or brain cell to phosphatide Method, it is included to the individual or brain cell administration omega-fatty acid or its metabolic precursor thereof, so as to improve or strengthen nerve cell Or synthesis of the brain cell to phosphatide.In another embodiment, the object of this method is developmental brain or its nerve cell. In another embodiment, the object is to have not been diagnosed as the adult with any cognition or neurological disorder.Every kind of possibility generation The independent embodiment of the table present invention.
As herein provided, it is being provided in embodiment 1 and 5 the result shows that, to nerve cell and brain cell administration 20 A kind of two carbon acids (DHA) (omega-fatty acid) improve their phosphatide synthesis, such as by marking the incorporation of choline to increase Proved.Administration omega-fatty acid improves the level (embodiment 2) of total phospholipids, phosphatidyl choline and phosphatidyl-ethanolamine, Show that the effect is not limited to specific phosphatide.PC12 cells show neuronal cell difference in functionality and in the art often by with Make the cell line model of neuronal cell.It is being provided in embodiment 12 the result shows that, omega-fatty acid improve Short-term Culture thing in Neuron in phosphatide synthesis.
In another embodiment, the present invention provides the side of the amount of the synaptic membrane of the nerve cell for improving individual or brain cell Method, it is included to the individual administration omega-fatty acid or its metabolic precursor thereof, so as to improve the nerve cell or brain cell of individual Synaptic membrane amount.In another embodiment, the object of this method is developmental brain or its nerve cell.In another implementation In scheme, the object is to have not been diagnosed as the adult with any cognition or neurological disorder.Every kind of possibility represents the present invention An independent embodiment.
The method for measuring the amount of synaptic membrane in the brain of individual is well known in the art, such as is described in Oertner TG et al. (Facilitation at single synapses probed with optical quantalanalysis.Nat Neurosci.2002 Jul；5(7)：657-64)；Bloodgood BL et al. (Neuronal activity regulates diffusion across the neck of dendritic spines.Science.2005 Nov 4；310(5749)： 866-9)；El Fakhri G et al. (Generalizedfive-dimensional dynamic and spectral factor analysis.Med Phys.2006Apr；33(4)：1016-24) and Pautler RG.Biological applications ofmanganese-enhanced magnetic resonance imaging.Methods Mol Med.2006；124：In 365-86).Every kind of method represents the independent embodiment of the present invention.
In the another embodiment of the method and composition of the present invention, the composition of administration improves the individual nerve The synthesis of cell or brain cell to phosphatide.In another embodiment, omega-fatty acid improve the individual nerve cell or Synthesis of the brain cell to phosphatide.In another embodiment, ω -6 aliphatic acid improves the individual nerve cell or brain cell Synthesis to phosphatide.In another embodiment, uridine, its acyl derivative, uridine phosphate or CDP-choline improve described Synthesis of the nerve cell or brain cell of body to phosphatide.In another embodiment, choline improves the individual nerve cell Or synthesis of the brain cell to phosphatide.In another embodiment, choline salt improves the individual nerve cell or brain cell pair The synthesis of phosphatide.Every kind of possibility represents the independent embodiment of the present invention.
The phosphatide improved by the method and composition of the present invention is phosphatidic acid in another embodiment.Term " phosphatide Acid " is synonymous with term " phosphatide " in another embodiment.In another embodiment, the phosphatide is phosphatidyl choline (" PC″；Embodiment 1).In another embodiment, the phosphatide is phosphatidyl-ethanolamine (" PE "；Embodiment 2).In another implementation In scheme, the phosphatide is phosphatidylserine (" PS ").In another embodiment, the phosphatide is phosphatidylinositols (" PI″).In another embodiment, the phosphatide is sphingomyelins.In another embodiment, the phosphatide is phosphoglyceride. In another embodiment, the phosphatide is any other phosphatide known in the art.Every kind of possibility represents the one of the present invention A independent embodiment.
In another embodiment, the PI greatly improved by the method for the present invention is used as one or more second messengers point The bank of son.In another embodiment, the second messenger molecule is Isosorbide-5-Nitrae, 5- InsP3s (IP3).In another implementation In scheme, the second messenger molecule is diacylglycerol (DAG).In another embodiment, by the present invention method and Composition improves protein kinase C (PKC) signal transduction.In another embodiment, swashed by the method and composition of the present invention IP living3Downstream signal transduction approach.In another embodiment, intracellular Ca2+ is improved by the method and composition of the present invention It is horizontal.In another embodiment, the downstream signal transduction approach of DAG is activated by the method and composition of the present invention.Another In one embodiment, the downstream signal transduction approach of PKC is activated by the method and composition of the present invention.In another embodiment In, pass through the downstream signal transduction approach of calcium in the method and composition active cell of the present invention.
In another embodiment, the sphingomyelins improved by the method and composition of the present invention is used as ceramide source. Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, the brain growth in premature is improved by the signal transduction of one of above approach.It is every kind of Possibility represents the independent embodiment of the present invention.
In another embodiment, the DHA in method and composition of the invention and/or uridine are as the big of cellular phospholipid Measure precursor.In another embodiment, uridine is played a role by activating the P2Y acceptors of the UMP formed from uridine.In another reality Apply in scheme, DHA is played a role by activating syntaxin -3.In another embodiment, using the group of these mechanism Close.
In another embodiment, as indicated in the data by this paper, be administered the effectively treatment of DHA and/or uridine and/ Or prevention forms the illness characterized by being damaged by Synaptic formation or myelin.In another embodiment, the illness is development disease Disease.In another embodiment, the illness is paediatrics neurological disorder.Every kind of possibility represents the independent reality of the present invention Apply scheme.
As herein provided, to its pyrimidine metabolic the gerbil jird administration polyunsaturated fatty acid and/or urine similar to the mankind Glycosides improves neural process nerve fibril albumen NF-70 and NF-M, postsynaptic density albumen PSD-95 and vesicle protein cynapse and melts The level (embodiment 7) of hop protein 1.Therefore, the synaptic membrane in polyunsaturated fatty acid raising brain cell and nerve cell is administered Level.In another embodiment, under the conditions of used herein, method and composition of the invention is also improving neuron It is useful in signal transduction.In another embodiment, under the conditions of used herein, method and composition of the invention is also increasing It is useful in strong nervous function.In another embodiment, under the conditions of used herein, method and composition of the invention also exists It is useful into outgrowth to improve neural process.Every kind of possibility represents the independent embodiment of the present invention.
The omega-fatty acid used in the method and composition of the present invention is ω -3 how unsaturateds in another embodiment Aliphatic acid (PUFA).In another embodiment, the omega-fatty acid is DHA (embodiment 1-2).DHA is a kind of ω -3, more Undersaturated 22- carbon fatty acids, also referred to as 4,7,10,13,16,19-docosahexaenoic acid.
In another embodiment, the omega-fatty acid is alpha-linolenic acid (cis 9,12,15-oc-tadecatrienoic acid).Another In one embodiment, the omega-fatty acid is parinaric acid (stearidonic acid).In another implementation In scheme, the omega-fatty acid is eicosatrienoic acid (ETA；11,14,17-Eicosatrienoic acid).In another embodiment In, the omega-fatty acid is eicosatetraenoic acid (8,11,14,17- eicosatetraenoic acid).In another embodiment, institute It is eicosapentaenoic acid (EPA to state omega-fatty acid；5,8,11,14,17-Eicosapentaenoic acid).In another embodiment, institute It is that eicosahexaenoic acid (is also referred to as " EPA " to state omega-fatty acid；5,7,9,11,14,17- eicosahexaenoic acid).In another reality Apply in scheme, the omega-fatty acid is clupanodonic acid (DPA；7,10,13,16,19-docosapentaenoic acid). In another embodiment, the omega-fatty acid is nisioic acid (6,9,12,15,18,21- tetracosa carbon, six alkene Acid).In another embodiment, the omega-fatty acid is any other omega-fatty acid known in the art.Every kind of ω -3 Aliphatic acid represents the independent embodiment of the present invention.
In another embodiment, the omega-fatty acid is anti-inflammatory polyunsaturated fatty acid.In another embodiment, The anti-inflammatory polyunsaturated fatty acid is eicosapentaenoic acid (EPA；5,8,11,14,17-Eicosapentaenoic acid).In another reality Apply in scheme, the anti-inflammatory polyunsaturated fatty acid is DHA.In another embodiment, the anti-inflammatory polyunsaturated fatty acid It is any other anti-inflammatory polyunsaturated fatty acid known in the art.Every kind of possibility represents the independent implementation of the present invention Scheme.
As herein provided, it is horizontal (embodiment 8) to improve cephalin by DHA, EPA and AA.Therefore, work as described herein With not being that specific polyunsaturated fatty acid is distinctive, but it may extend to insatiable hunger more than ω -3 and ω -6 under the conditions of used herein And fatty acid families.
In another embodiment, the omega-fatty acid is the metabolic precursor thereof of DHA.In another embodiment, it is described Metabolic precursor thereof is EPA).In another embodiment, the metabolic precursor thereof is clupanodonic acid (DPA；7,10,13,16, 19- clupanodonic acids).Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, " metabolic precursor thereof " refers to the compound for improving fatty acid concentration in blood flow or tissue. In another embodiment, " metabolic precursor thereof " refers to the compound that aliphatic acid is metabolized as by the individual tissue or enzyme.Another In embodiment, " metabolic precursor thereof " refers to the compound that aliphatic acid is metabolized as by target cell.Every kind of possibility represents the present invention's One independent embodiment.
In the another embodiment of the method and composition of the present invention, the metabolic precursor thereof of omega-fatty acid is α-flax Acid, it is as EPA (eicosapentaenoic acid) and the precursor of DHA (docosahexaenoic acid).In another embodiment, the generation It is any other omega-fatty acid precursor known in the art to thank to precursor.Every kind of omega-fatty acid precursor represents one of the present invention Independent embodiment.
" polyunsaturated fatty acid " refers to omega-fatty acid in another embodiment.In another embodiment, the term Refer to ω -6 aliphatic acid.In another embodiment, which refers to the aliphatic acid with two or more double bonds.Another In embodiment, which refers to the aliphatic acid with two double bonds.In another embodiment, which refers to there is three The aliphatic acid of double bond.In another embodiment, which refers to the aliphatic acid with more than three double bonds.Every kind of possibility generation The independent embodiment of the table present invention.
In another embodiment, the present invention provides the side of the amount of the synaptic membrane of the nerve cell for improving individual or brain cell Method, it is included to individual administration ω -6 aliphatic acid or its metabolic precursor thereof, so as to improve the nerve cell or brain cell of individual Synaptic membrane amount.In another embodiment, the object of this method is developmental brain or its nerve cell.In another implementation In scheme, the object is to have not been diagnosed as the adult with any cognition or neurological disorder.Every kind of possibility represents the present invention An independent embodiment.
In another embodiment, the present invention provides the side of the phospholipid level of the nerve cell for improving individual or brain cell Method, it is included to individual administration ω -6 aliphatic acid or its metabolic precursor thereof, so as to improve the nerve cell or brain cell of individual Phospholipid level.In another embodiment, the object of this method is developmental brain or its nerve cell.In another embodiment party In case, the object is to have not been diagnosed as the adult with any cognition or neurological disorder.Every kind of possibility represents the present invention's One independent embodiment.
In another embodiment, the method that the present invention provides the phospholipid level for improving brain cell, it is included the brain Cell and ω -6 aliphatic acid or its metabolic precursor thereof, so as to improve the phospholipid level of brain cell.In another embodiment, should The object of method is developmental brain or its nerve cell.In another embodiment, the object is to have not been diagnosed as suffering from appointing What cognition or the adult of neurological disorder.Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, the present invention provides the side improved or strengthen the synthesis of nerve cell or brain cell to phosphatide Method, it is included to the individual or brain cell administration ω -6 aliphatic acid or its metabolic precursor thereof, so as to improve or strengthen nerve cell Or synthesis of the brain cell to phosphatide.In another embodiment, the object of this method is developmental brain or its nerve cell. In another embodiment, the object is to have not been diagnosed as the adult with any cognition or neurological disorder.Every kind of possibility generation The independent embodiment of the table present invention.
As herein provided, it is being provided in embodiment 3 the result shows that, arachidonic is administered to nerve cell and brain cell Sour (a kind of ω -6 aliphatic acid) improves their phosphatide synthesis, as proved thereafter by the incorporation increase of mark choline. SHSY-5Y cells come from human neuroblastoma, are used as the model system of neuronal function.In another embodiment, The raising of phosphatide synthesis causes its level rise.
In another embodiment, ω -6 aliphatic acid is omega 6 polyunsaturated fatty acid (PUFA).In another implementation In scheme, ω -6 aliphatic acid is arachidonic acid (embodiment 3).Arachidonic acid is a kind of ω -6,20- carbon fatty acids, Also referred to as Arachidonic Acid.In another embodiment, ω -6 aliphatic acid is arachidonic generation Thank to precursor.Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, ω -6 aliphatic acid is linoleic acid (9,12- octadecadienoic acid).In another implementation In scheme, ω -6 aliphatic acid is conjugated linoleic acid (CLA).In another embodiment, ω -6 aliphatic acid is γ-Asia Numb acid (18:3(6,9,12)).In another embodiment, ω -6 aliphatic acid be eicosadienoic acid (11, 14- eicosadienoic acids).In another embodiment, ω -6 aliphatic acid is height-gamma-Linolenic acid (8,11,14- bis- ten carbon Trienic acid).In another embodiment, ω -6 aliphatic acid is two dodecadienoic acids (13,16- bis- ten two carbon diene Acid).In another embodiment, ω -6 aliphatic acid is docosatetraenoic acid (7,10,13,16- bis- ten two carbon tetraenes Acid).In another embodiment, ω -6 aliphatic acid is 4,7,10,13,16- clupanodonic acids.In another embodiment party In case, ω -6 aliphatic acid is dihomo-gamma-linolenic acid (DGLA).In another embodiment, ω -6 aliphatic acid is this Any other ω -6 aliphatic acid known to field.Every kind of ω -6 aliphatic acid represents the independent embodiment of the present invention.
In the another embodiment of the method and composition of the present invention, the metabolic precursor thereof of ω -6 aliphatic acid is linoleic acid. In another embodiment, the metabolic precursor thereof is trans vaccenic acid (TVA) (a kind of linoleic acid source).In another embodiment In, the metabolic precursor thereof is any other ω -6 fatty acid precursor known in the art.Every kind of ω -6 fatty acid precursors represent this One independent embodiment of invention.
In another embodiment, the present invention provides a kind of pharmaceutical composition, it includes (a) uridine, its acyl derivative, Uridine phosphate；ω -6 aliphatic acid or its metabolic precursor thereof (b).
In another embodiment, the present invention provides a kind of pharmaceutical composition, it includes (a) uridine, its acyl derivative, Uridine phosphate；Omega-fatty acid or its metabolic precursor thereof (b).
In another embodiment, pharmaceutical composition of the invention also includes choline.In another embodiment, the medicine Compositions also include choline salt.In another embodiment, described pharmaceutical composition also includes the metabolic precursor thereof of choline salt.Often Kind possibility represents the independent embodiment of the present invention.
In another embodiment, ω -6 aliphatic acid present in pharmaceutical composition of the invention or its metabolic precursor thereof are these Any ω -6 aliphatic acid or metabolic precursor thereof disclosed in text.In another embodiment, present in pharmaceutical composition of the invention Omega-fatty acid or its metabolic precursor thereof are any omega-fatty acid disclosed herein or metabolic precursor thereof.In another embodiment, Uridine, its acyl derivative or uridine phosphate present in the pharmaceutical composition of the present invention be any uridine disclosed herein, its Acyl derivative or uridine phosphate.In another embodiment, choline present in pharmaceutical composition of the invention or its choline Salt is any choline disclosed herein or choline salt.
In another embodiment, ω -6 aliphatic acid present in pharmaceutical composition of the invention or its metabolic precursor thereof can press Any dosage disclosed herein exists.In another embodiment, omega-fatty acid present in pharmaceutical composition of the invention Or its metabolic precursor thereof can be existed by any dosage disclosed herein.In another embodiment, in pharmaceutical composition of the invention Existing uridine, its acyl derivative or uridine phosphate can be existed by any dosage disclosed herein.In another embodiment, Choline present in the pharmaceutical composition of the present invention or its choline salt can be existed by any dosage disclosed herein.
Every kind of ω -6 aliphatic acid or its metabolic precursor thereof；Omega-fatty acid or its metabolic precursor thereof；Uridine, its acyl derivative or Uridine phosphate；Choline or its choline salt；And its dosage represents the independent embodiment of the present invention.
In another embodiment, the present invention provides the side of the phospholipid level of the nerve cell for improving individual or brain cell Method, it includes including (a) uridine, its acyl derivative, uridine phosphate or CDP-choline to the individual administration；ω -3 (b) The composition of aliphatic acid or its metabolic precursor thereof, so as to improve the nerve cell of individual or the phospholipid level of brain cell.In another reality Apply in scheme, the object of this method is developmental brain or its nerve cell.In another embodiment, the object is not examine Break as the adult with any cognition or neurological disorder.Every kind of possibility represents the independent embodiment of the present invention.
As herein provided, omega-fatty acid and ω -6 aliphatic acid each synergistically improve phosphatide with uridine (such as UMP) Synthesis and phospholipid level.In another embodiment, the uridine phosphate is uridine monophosphate (UMP).
In another embodiment, the method that the present invention provides the phospholipid level for improving brain cell, it is included the brain Cell is with including (a) uridine, its acyl derivative, uridine phosphate or CDP-choline；Omega-fatty acid or its metabolic precursor thereof (b) Composition contact, so as to improve the phospholipid level of brain cell.In another embodiment, the object of this method is developmental Brain or its nerve cell.In another embodiment, the object be have not been diagnosed as with it is any cognition or neurological disorder into Year people.Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, the present invention provides the side of the phospholipid level of the nerve cell for improving individual or brain cell Method, it includes including (a) uridine, its acyl derivative, uridine phosphate or CDP-choline to the individual administration；ω -6 (b) The composition of aliphatic acid or its metabolic precursor thereof, so as to improve the nerve cell of individual or the phospholipid level of brain cell.In another reality Apply in scheme, the object of this method is developmental brain or its nerve cell.In another embodiment, the object is not examine Break as the adult with any cognition or neurological disorder.Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, the method that the present invention provides the phospholipid level for improving brain cell, it is included the brain Cell is with including (a) uridine, its acyl derivative, uridine phosphate or CDP-choline；ω -6 aliphatic acid or its metabolic precursor thereof (b) Composition contact, so as to improve the phospholipid level of brain cell.In another embodiment, the object of this method is developmental Brain or its nerve cell.In another embodiment, the object be have not been diagnosed as with it is any cognition or neurological disorder into Year people.Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, the present invention provides the side improved or strengthen the synthesis of nerve cell or brain cell to phosphatide Method, it includes including (a) uridine, its acyl derivative, uridine phosphate or CDP-choline to the individual or brain cell administration；With (b) omega-fatty acid or the composition of its metabolic precursor thereof, so as to improve or strengthen nerve cell or synthesis of the brain cell to phosphatide. In another embodiment, the object of this method is developmental brain or its nerve cell.In another embodiment, it is described right As if having not been diagnosed as the adult with any cognition or neurological disorder.Every kind of possibility represents the independent reality of the present invention Apply scheme.
In another embodiment, the present invention provides the side improved or strengthen the synthesis of nerve cell or brain cell to phosphatide Method, it includes including (a) uridine, its acyl derivative, uridine phosphate or CDP-choline to the individual or brain cell administration；With (b) ω -6 aliphatic acid or the composition of its metabolic precursor thereof, so as to improve or strengthen nerve cell or synthesis of the brain cell to phosphatide. In another embodiment, the object of this method is developmental brain or its nerve cell.In another embodiment, it is described right As if having not been diagnosed as the adult with any cognition or neurological disorder.Every kind of possibility represents the independent reality of the present invention Apply scheme.
In another embodiment, the present invention provides the side of the amount of the synaptic membrane of the nerve cell for improving individual or brain cell Method, it includes including (a) uridine, its acyl derivative, uridine phosphate or CDP-choline to the individual or brain cell administration；With (b) omega-fatty acid or the composition of its metabolic precursor thereof, so as to improve the amount of the nerve cell of individual or the synaptic membrane of brain cell. In another embodiment, the object of this method is developmental brain or its nerve cell.In another embodiment, it is described right As if having not been diagnosed as the adult with any cognition or neurological disorder.Every kind of possibility represents the independent reality of the present invention Apply scheme.
In another embodiment, the present invention provides the side of the amount of the synaptic membrane of the nerve cell for improving individual or brain cell Method, it includes including (a) uridine, its acyl derivative, uridine phosphate or CDP-choline to the individual or brain cell administration；With (b) ω -6 aliphatic acid or the composition of its metabolic precursor thereof, so as to improve the amount of the nerve cell of individual or the synaptic membrane of brain cell. In another embodiment, the object of this method is developmental brain or its nerve cell.In another embodiment, it is described right As if having not been diagnosed as the adult with any cognition or neurological disorder.Every kind of possibility represents the independent reality of the present invention Apply scheme.
In the another embodiment of the method and composition of the present invention, stimulate phosphatide to synthesize and improve target brain cell or target god Through the phospholipid level in cell.In another embodiment, many aspects such as cynapse of the sufficient phospholipid level in nervous function Signal transduction, neurotransmitter function, neural process branch and be important to outgrowth etc., and in another embodiment, Also it is critically important in terms of correct brain function.
In another embodiment, the present invention provides the method for improving the brain PC levels in individual, it is included to described The composition of the body administration present invention, wherein the composition improves the conjunction of the individual nerve cell or brain cell to phosphatide Into so that the brain PC improved in individual is horizontal.In another embodiment, the object of this method is developmental brain or its nerve Cell.In another embodiment, the object is to have not been diagnosed as the adult with any cognition or neurological disorder.It is every kind of can Energy property represents the independent embodiment of the present invention.
In another embodiment, the present invention provides the method for improving the brain SM levels in individual, it is included to described The composition of the body administration present invention, wherein the composition improves the conjunction of the individual nerve cell or brain cell to phosphatide Into so that the brain SM improved in individual is horizontal.In another embodiment, the object of this method is developmental brain or its nerve Cell.In another embodiment, the object is to have not been diagnosed as the adult with any cognition or neurological disorder.It is every kind of can Energy property represents the independent embodiment of the present invention.
In another embodiment, the present invention provides the method for improving the brain PI levels in individual, it is included to described The composition of the body administration present invention, wherein the composition improves the conjunction of the individual nerve cell or brain cell to phosphatide Into so that the brain PI improved in individual is horizontal.In another embodiment, the object of this method is developmental brain or its nerve Cell.In another embodiment, the object is to have not been diagnosed as the adult with any cognition or neurological disorder.It is every kind of can Energy property represents the independent embodiment of the present invention.
In another embodiment, the present invention provides the method for improving the brain PE levels in individual, it is included to described The composition of the body administration present invention, wherein the composition improves the conjunction of the individual nerve cell or brain cell to phosphatide Into so that the brain PE improved in individual is horizontal.In another embodiment, the object of this method is developmental brain or its nerve Cell.In another embodiment, the object is to have not been diagnosed as the adult with any cognition or neurological disorder.It is every kind of can Energy property represents the independent embodiment of the present invention.
In another embodiment, the present invention provides the method for improving the brain PS levels in individual, it is included to described The composition of the body administration present invention, wherein the composition improves the conjunction of the individual nerve cell or brain cell to phosphatide Into so that the brain PS improved in individual is horizontal.In another embodiment, the object of this method is developmental brain or its nerve Cell.In another embodiment, the object is to have not been diagnosed as the adult with any cognition or neurological disorder.It is every kind of can Energy property represents the independent embodiment of the present invention.
In another embodiment, the present invention provides the method for improving the cognitive function in individual, it is included to described The composition of the body administration present invention, wherein the composition improves the conjunction of the individual nerve cell or brain cell to phosphatide Into so as to improve the cognitive function in individual.In another embodiment, the object of this method is developmental brain or its nerve Cell.In another embodiment, the object is to have not been diagnosed as the adult with any cognition or neurological disorder.It is every kind of can Energy property represents the independent embodiment of the present invention.
As herein provided, DHA and UMP improves animal performance (embodiment 10) in memory test.Therefore, it is of the invention Method and composition improve and strengthen memory and other cognitive functions in be effective.
As herein provided, polyunsaturated fatty acid is administered and/or uridine improves cephalin level and synthesis, neural process The level of nerve fibril albumen and the amount of synaptic membrane.Therefore, the compositions and methods of the invention improve and enhancing recognizes work( Energy, nervous function, intelligence, cynapse transmission and neurotransmitter levels and activity.
In another embodiment, the present invention provides the method for improving the nervous function in individual, it is included to described The composition of the body administration present invention, wherein said composition improve the synthesis of the individual nerve cell or brain cell to phosphatide, So as to improve the nervous function in individual.In another embodiment, the object of this method is that developmental brain or its nerve are thin Born of the same parents.In another embodiment, the object is to have not been diagnosed as the adult with any cognition or neurological disorder.Every kind of possibility Property represent the present invention an independent embodiment.
In another embodiment, the nervous function improved by the method for the present invention is cynapse transmission.In another implementation In scheme, the cynapse transmission is adjacent with motor neuron.In another embodiment, the cynapse transmission and intrerneuron It is adjacent.In another embodiment, the cynapse transmission is adjacent with sensory neuron.Each type of cynapse transmission represents Ben Fa A bright independent embodiment.
In another embodiment, the nervous function for improving or strengthening is the function of neurotransmitter.In an embodiment In, improve or the function of enhancing neurotransmitter is occurred by improving the horizontal of neurotransmitter in cynapse.In another embodiment, Improve or enhancing neurotransmitter function is occurred by improving release of the neurotransmitter into cynapse.In another embodiment, change Kind or enhancing neurotransmitter function occurs without changing the level of neurotransmitter or release in cynapse.Every kind of possibility represents Ben Fa A bright independent embodiment.
In another embodiment, " improvement " cognitive function or nervous function or intelligence refer to realize that it improves 10%. In another embodiment, which refers to realize that it improves 20%.In another embodiment, which refers to realize its improvement 30%.In another embodiment, which refers to realize that it improves 40%.In another embodiment, which refers to reality Existing its improves 50%.In another embodiment, which refers to realize that it improves 60%.In another embodiment, the art Language refers to realize that it improves 70%.In another embodiment, which refers to realize that it improves 80%.In another embodiment In, which refers to realize that it improves 90%.In another embodiment, which refers to realize that it improves 100%.It is every kind of can Energy property represents the independent embodiment of the present invention.
In another embodiment, cognitive function or nervous function or intelligence are evaluated compared with the function before starting treatment Improvement.In another embodiment, the improvement is evaluated compared with untreated individual.In another embodiment, root According to the standard of standardization the improvement is evaluated such as examining.Each type of cognitive activities, which improve, represents of the invention one Independent embodiment.
In another embodiment, by the linking number between neuron in the individual brain come evaluate cognitive function or The improvement of nervous function or intelligence.In another embodiment, by the individual brain or the individual brain specific region In the number of capillary evaluate the improvement.In another embodiment, the improvement is evaluated by nervous activity. In another embodiment, the improvement is evaluated by nervous function.In another embodiment, commented by linguistic function Improvement described in valency.In another embodiment, the improvement is evaluated by ability to exchange.In another embodiment, pass through Acetylcholine or the level of other neurotransmitters or the brain chemical substance related with cognitive function are measured to evaluate the improvement. In another embodiment, the individual brain is scanned by PET scanner (PET) to evaluate the improvement. In another embodiment, the individual brain is scanned by Magnetic resonance imaging (MRI) to evaluate the improvement.In another implementation In scheme, described improvement (Peila R et al., Stroke.32 are evaluated by cognitive ability screening instrument (CASI)：2882-9, 2001).In another embodiment, described change is evaluated by testing experiment (embodiment 13) such as example disclosed herein It is kind.In another embodiment, (Mini-Mental test) (Tsai L et al., The is tested using the slight state of mind Mini-MentalState Test and computerized tomography.Am J Psychiatry.1979Apr；136 (4A)：436-8).The other methods that evaluating recognizing ability improves are well known in the art, are described in such as Antonova E et al. (Schizophr Res.2004 Oct1；70(2-3)：117-45) and Cognitive Function Analysis In (Greenwood Pub Group, 1998).Every kind of method represents the independent embodiment of the present invention.
In another embodiment, the present invention provides neurotransmitter in the brain for improving individual or central nervous system (CNS) Amount or level method, the described method includes to the individual administration omega-fatty acid or its metabolic precursor thereof, wherein the ω- 3 aliphatic acid or its metabolic precursor thereof improve the synthesis of phosphatide in the brain or central nervous system, thus improve individual brain or in The amount or level of neurotransmitter in pivot nervous system.In another embodiment, the object of this method be developmental brain or its Nerve cell.In another embodiment, the object is to have not been diagnosed as the adult with any cognition or neurological disorder.Often Kind possibility represents the independent embodiment of the present invention.
In another embodiment, the present invention provide improve individual brain or central nervous system in neurotransmitter amount or Horizontal method, the described method includes ω -6 aliphatic acid or its metabolic precursor thereof is administered to the individual, wherein the ω -6 is fatty Acid or its metabolic precursor thereof improve the synthesis of phosphatide in the brain or central nervous system, so as to improve the brain or nervous centralis of individual The amount or level of neurotransmitter in system.In another embodiment, the object of this method is that developmental brain or its nerve are thin Born of the same parents.In another embodiment, the object is to have not been diagnosed as the adult with any cognition or neurological disorder.Every kind of possibility Property represent the present invention an independent embodiment.
In another embodiment, the present invention provide improve individual brain or central nervous system in neurotransmitter amount or Horizontal method, the described method includes include (a) uridine, its acyl derivative, uridine phosphate or CDP- to the individual administration Choline；Omega-fatty acid or the composition of its metabolic precursor thereof, wherein the composition improve in brain or central nervous system (b) The synthesis of phosphatide, so as to improve the amount or level of neurotransmitter in individual brain or central nervous system.In another embodiment In, the object of this method is developmental brain or its nerve cell.In another embodiment, the object is to have not been diagnosed as suffering from There is the adult of any cognition or neurological disorder.Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, the present invention provide improve individual brain or central nervous system in neurotransmitter amount or Horizontal method, the described method includes include (a) uridine, its acyl derivative, uridine phosphate or CDP- to the individual administration Choline；ω -6 aliphatic acid or the composition of its metabolic precursor thereof, the composition improve in brain or central nervous system phosphatide (b) Synthesis so that improve individual brain or central nervous system in neurotransmitter amount or level.In another embodiment, should The object of method is developmental brain or its nerve cell.In another embodiment, the object is to have not been diagnosed as suffering from appointing What cognition or the adult of neurological disorder.Every kind of possibility represents the independent embodiment of the present invention.
In one embodiment, its level or activity or release by the present invention method influence neurotransmitter be acetyl Choline.In another embodiment, the neurotransmitter is dopamine.In another embodiment, the neurotransmitter is paddy Propylhomoserin.In another embodiment, the neurotransmitter is thrombocytin.In another embodiment, the neurotransmitter is 5- Hydroxytryptamine (5-HT).In another embodiment, the neurotransmitter is GABA.In another embodiment, the nerve is passed Matter is any other neurotransmitter known in the art.Each type of neurotransmitter represents the independent implementation of the present invention Scheme.
In another embodiment, the present invention provides raising or the brain cell of enhancing individual repeats to discharge effectively into cynapse The method of the ability of the neurotransmitter of amount, the described method includes to the individual administration omega-fatty acid or its metabolic precursor thereof, its Described in omega-fatty acid or its metabolic precursor thereof improve synthesis of the brain cell to phosphatide, so as to improve or strengthen individual brain thin Born of the same parents repeat to discharge the ability of a effective amount of neurotransmitter into cynapse.In another embodiment, the object of this method is development In brain or its nerve cell.In another embodiment, the object is to have not been diagnosed as suffering from any cognition or neurological disorder Adult.Every kind of possibility represents the independent embodiment of the present invention.
As herein provided, dendritic spines density rise (embodiment 9) in the animal of DHA and/or uridine is administered.Therefore, The composition of the present invention, which improves in brain the number of cynapse and size and strengthens brain cell and pass through neurotransmitter, carries out signal transduction Ability.
In another embodiment, the present invention provides raising or the brain cell of enhancing individual repeats to discharge effectively into cynapse The method of the ability of the neurotransmitter of amount, the described method includes to individual administration ω -6 aliphatic acid or its metabolic precursor thereof, its Described in ω -6 aliphatic acid or its metabolic precursor thereof improve synthesis of the brain cell to phosphatide, so as to improve or strengthen individual brain Cell repeats to discharge the ability of a effective amount of neurotransmitter into cynapse.In another embodiment, the object of this method is hair Brain or its nerve cell in educating.In another embodiment, the object is had not been diagnosed as with any cognition or nerve barrier The adult hindered.Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, the present invention provides raising or the brain cell of enhancing individual repeats to discharge effectively into cynapse The method of the ability of the neurotransmitter of amount, the described method includes to it is described individual administration comprising (a) uridine, its acyl derivative, Uridine phosphate or CDP-choline；Omega-fatty acid or the composition of its metabolic precursor thereof, wherein composition raising described in (b) Synthesis of the brain cell to phosphatide, so that the brain cell for improving or strengthening individual repeats to discharge a effective amount of neurotransmitter into cynapse Ability.In another embodiment, the object of this method is developmental brain or its nerve cell.In another embodiment In, the object is to have not been diagnosed as the adult with any cognition or neurological disorder.Every kind of possibility represents the one of the present invention A independent embodiment.
In another embodiment, the present invention provides raising or the brain cell of enhancing individual repeats to discharge effectively into cynapse The method of the ability of the neurotransmitter of amount, the described method includes to it is described individual administration comprising (a) uridine, its acyl derivative, Uridine phosphate or CDP-choline；ω -6 aliphatic acid or the composition of its metabolic precursor thereof, wherein composition raising described in (b) Synthesis of the brain cell to phosphatide, so that the brain cell for improving or strengthening individual repeats to discharge a effective amount of neurotransmitter into cynapse Ability.In another embodiment, the object of this method is developmental brain or its nerve cell.In another embodiment In, the object is to have not been diagnosed as the adult with any cognition or neurological disorder.Every kind of possibility represents the one of the present invention A independent embodiment.
As herein provided, polyunsaturated fatty acid is administered and/or uridine improves cephalin level and synthesis, neural process The level of nerve fibril albumen and the amount of synaptic membrane.Therefore, the compositions and methods of the invention improve and strengthen nerve and pass Matter discharges and amount.
In another embodiment, the method that the present invention provides the intelligence for improving or strengthening individual, it is included to described Omega-fatty acid or its metabolic precursor thereof is administered in body, wherein the omega-fatty acid or its metabolic precursor thereof improve the nerve cell of individual Or synthesis of the brain cell to phosphatide, so as to improve or strengthen the intelligence of individual.In another embodiment, the object of this method is Developmental brain or its nerve cell.In another embodiment, the object is to have not been diagnosed as suffering from any cognition or nerve The adult of obstacle.Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, the method that the present invention provides the intelligence for improving or strengthening individual, it is included to described ω -6 aliphatic acid or its metabolic precursor thereof is administered in body, wherein ω -6 aliphatic acid or its metabolic precursor thereof improve the individual nerve The synthesis of cell or brain cell to phosphatide, so as to improve or strengthen the intelligence of individual.In another embodiment, pair of this method As if developmental brain or its nerve cell.In another embodiment, the object be have not been diagnosed as with it is any cognition or The adult of neurological disorder.Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, the method that the present invention provides the number of cynapse spine in the brain for improving individual or its region, It includes the composition to the individual administration present invention, wherein the composition raising individual nerve cell or brain are thin Synthesis of the born of the same parents to phosphatide, so as to improve the brain of individual or the number of the cynapse spine in its region.In another embodiment, the party The object of method is developmental brain or its nerve cell.In another embodiment, the object is had not been diagnosed as with any Cognition or the adult of neurological disorder.Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, the method that the present invention provides the intelligence for improving or strengthening individual, it is included to described Body administration includes (a) uridine, its acyl derivative, uridine phosphate or CDP-choline；Omega-fatty acid or its metabolic precursor thereof (b) Composition, wherein the composition improves the synthesis of the individual nerve cell or brain cell to phosphatide, thus improve or Strengthen the intelligence of individual.In another embodiment, the object of this method is developmental brain or its nerve cell.In another reality Apply in scheme, the object is to have not been diagnosed as the adult with any cognition or neurological disorder.Every kind of possibility represents Ben Fa A bright independent embodiment.
In another embodiment, the method that the present invention provides the intelligence for improving or strengthening individual, it is included to described Body administration includes (a) uridine, its acyl derivative, uridine phosphate or CDP-choline；ω -6 aliphatic acid or its metabolic precursor thereof (b) Composition, wherein the composition improves the synthesis of the individual nerve cell or brain cell to phosphatide, thus improve or Strengthen the intelligence of individual.In another embodiment, the object of this method is developmental brain or its nerve cell.In another reality Apply in scheme, the object is to have not been diagnosed as the adult with any cognition or neurological disorder.Every kind of possibility represents Ben Fa A bright independent embodiment.
In another embodiment, improved by the method and composition of the present invention or the intelligence of enhancing is language intelligence. In another embodiment, the intelligence is musical intelligence.In another embodiment, the intelligence is space intelligence.Another In one embodiment, the intelligence is limb motion intelligence (bodily intelligence).In another embodiment, institute It is interpersonal intelligence to state intelligence.In another embodiment, the intelligence is introspection intelligence (intrapersonal intelligence).In another embodiment, the intelligence is interpersonal intelligence.In another embodiment, the intelligence is Logical mathematics intelligence.In another embodiment, the intelligence is the intelligence of any other type known in the art.Per species The intelligence of type represents the independent embodiment of the present invention.
In another embodiment, the present invention provide promote or enhancing brain reparation method, it include to the individual to Medicine omega-fatty acid or its metabolic precursor thereof, so as to promote or strengthen brain reparation.In another embodiment, the object of this method is Developmental brain or its nerve cell.Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, the present invention provide promote or enhancing brain reparation method, it include to the individual to Medicine ω -6 aliphatic acid or its metabolic precursor thereof, so as to promote or strengthen brain reparation.In another embodiment, the object of this method is Developmental brain or its nerve cell.In another embodiment, the object is to have not been diagnosed as suffering from any cognition or nerve The adult of obstacle.Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, the present invention provide promote or enhancing brain reparation method, it include to the individual to Pack contains (a) uridine, its acyl derivative, uridine phosphate or CDP-choline；The group of omega-fatty acid or its metabolic precursor thereof (b) Compound, so as to promote or strengthen brain reparation.In another embodiment, the object of this method is that developmental brain or its nerve are thin Born of the same parents.In another embodiment, the object is to have not been diagnosed as the adult with any cognition or neurological disorder.Every kind of possibility Property represent the present invention an independent embodiment.
In another embodiment, the present invention provides the method for promoting or strengthening brain reparation, it is included to individual to pack Containing (a) uridine, its acyl derivative, uridine phosphate or CDP-choline；The combination of ω -6 aliphatic acid or its metabolic precursor thereof (b) Thing, so as to promote or strengthen brain reparation.In another embodiment, the object of this method is that developmental brain or its nerve are thin Born of the same parents.In another embodiment, the object is to have not been diagnosed as the adult with any cognition or neurological disorder.Every kind of possibility Property represent the present invention an independent embodiment.
In another embodiment, promote or strengthen the brain reparation after apoplexy.In another embodiment, promote or strengthen Brain reparation after brain damage.In another embodiment, promoting or strengthen known in the art must carry out any of brain reparation Brain reparation after other events, disease or illness.Every kind of possibility represents another embodiment of the present invention.
In another embodiment, the present invention is provided and improved or the method for the intelligence of enhancing offspring, it is included to after described Omega-fatty acid or its metabolic precursor thereof is administered in gestation in the mother in generation, wherein the omega-fatty acid or its metabolic precursor thereof carry Synthesis of the nerve cell or brain cell of the high offspring to phosphatide, so as to improve or strengthen the intelligence of offspring.
When being administered to gestation or lactation mother, the compositions and methods of the invention effectively cause to the offspring Polyunsaturated fatty acid and/or uridine is administered.As herein provided, polyunsaturated fatty acid is administered and/or uridine improves brain Phospholipid level and the amount of synthesis, the level of neural process nerve fibril albumen and synaptic membrane.Therefore, the composition of the present invention is administered Improve the brain growth of the offspring of gestation or lactation mother and increase intelligence and cognitive function and intelligence.
As herein provided, the cynapse obtained in the offspring of pregnant and lactation the animal of DHA and/or uridine is administered The horizontal increase (embodiment 9) of spine number.In addition, it is administered to gestation and lactation mother in DHA and/or uridine raising offspring Phospholipid level (embodiment 11).Therefore, when the composition of the present invention is administered to gestation and lactation mother, it is energetically Influence the brain growth in offspring.
The result of this experiment is also shown that the method and composition of the present invention is treating the paediatrics nerve related with brain growth Efficiency in disease.In another embodiment, method of the invention or composition are used in premature's moderate stimulation brain growth. In another embodiment, method of the invention or composition are used to treat A Sibogeer syndromes.In another embodiment, The object is rett's syndrome.In another embodiment, which is tourette's syndrome.In another embodiment, this is right As if angelman syndrome.In another embodiment, which is familial dysautonomia.In another implementation In scheme, which is dislexia.In another embodiment, which is peripheral nerve disease.In another embodiment, The object is incoordination.In another embodiment, which is deformable dystonia.
In another embodiment, which is ADHD.In another embodiment, it is believed that ADHD is drawn by shortage dopamine Rise.
In another embodiment, method and composition of the invention is used to treat brain damage.In another embodiment, institute Damage is stated by radiation-actuate.In another embodiment, the reasons for injury is in perinatal period cerebral anoxia.In another embodiment In, the reasons for injury is in perinatal period cerebrum ischemia.In another embodiment, the perinatal period cerebral anoxia and/or ischemic Secondary to maternal infuries.In another embodiment, method and composition of the invention is used to treat as caused by one of above illness Brain paralysis.
In another embodiment, method and composition of the invention is used to treat Down syndrome or trisomy 21.
In another embodiment, method and composition of the invention is used to treat underfed impaired secondary to source of parents Brain growth or development.In another embodiment, the impaired brain growth or development are bad secondary to infant nutrition.Another In one embodiment, the impaired brain growth or development are secondary to metabolic disease.
In another embodiment, method and composition of the invention is used to treat autism.In another embodiment, The method and composition of the present invention is used to treat and the relevant syndrome of autism.In another embodiment, the syndrome It is autism (autish).In another embodiment, the syndrome be it is known in the art any other with autism phase The syndrome of pass.
In another embodiment, method and composition of the invention is used to treat any other paediatrics known in the art Neurogenic disease.Every kind of disease represents the independent embodiment of the present invention.
In another embodiment, the present invention provides individual method of the treatment with one of above-mentioned disease or illness, its Composition including the present invention is administered to the individual, wherein the composition improves the individual nerve cell or brain cell The amount of middle synaptic membrane, so as to treat the individual with one of above-mentioned disease or illness.
In another embodiment, the present invention provides individual method of the treatment with one of above-mentioned disease or illness, its Composition including the present invention is administered to the individual, wherein the composition improves the size or number of the individual brain cynapse Mesh, so as to treat the individual with one of above-mentioned disease or illness.
In another embodiment, the present invention provides individual method of the treatment with one of above-mentioned disease or illness, its Composition including the present invention is administered to the individual, wherein the composition improves the individual nerve cell or brain cell Phospholipid level, so as to treat the individual with one of above-mentioned disease or illness.
In another embodiment, the present invention provides individual method of the treatment with one of above-mentioned disease or illness, its Composition including the present invention is administered to the individual, wherein the composition improves the individual nerve cell or brain cell Neurotransmitter levels, so as to treat the individual with one of above-mentioned disease or illness.
In another embodiment, the present invention provides individual method of the treatment with neurogenic disease or illness, it is wrapped The composition to the individual administration present invention is included, wherein the composition is improved in the individual nerve cell or brain cell The amount of synaptic membrane, so as to treat the individual with neurogenic disease or illness.
In another embodiment, the present invention provides individual method of the treatment with neurogenic disease or illness, it is wrapped The composition to the individual administration present invention is included, wherein the composition improves the size or number of the individual brain cynapse Mesh, so as to treat the individual with neurogenic disease or illness.
In another embodiment, the present invention provides individual method of the treatment with neurogenic disease or illness, it is wrapped The composition to the individual administration present invention is included, wherein the composition improves the individual nerve cell or brain cell Phospholipid level, so as to treat the individual with neurogenic disease or illness.
In another embodiment, the present invention provides individual method of the treatment with neurogenic disease or illness, it is wrapped The composition to the individual administration present invention is included, wherein the composition improves the individual nerve cell or brain cell Neurotransmitter levels, so as to treat the individual with neurogenic disease or illness.
In another embodiment, the neurogenic disease or illness treated by the method and composition of the present invention are to dash forward Touch film and lack the disease or illness being characterized.In another embodiment, the numerical abnormality of cynapse is low.In another embodiment In, cynapse average-size is extremely small.In another embodiment, the disease or illness are with the presynaptic in the given area of brain Neuron, which lacks, to be characterized.In another embodiment, the disease or illness to carry out the presynaptic of given function in brain Neuron, which lacks, to be characterized.In another embodiment, the disease or illness are with the postsynaptic neuronal in the given area of brain Member, which lacks, to be characterized.In another embodiment, the disease or illness to carry out the postsynaptic neuronal of given function in brain Member, which lacks, to be characterized.In another embodiment, institute in the inappropriate release or cynapse of the disease or illness and neurotransmitter It is related to state the response shortage of neurotransmitter levels deficiency or acceptor to the neurotransmitter.In another embodiment, the disease Disease or illness are genetic diseases.In another embodiment, the disease or illness be metabolic disease or endocrine system disease, Or trophic disturbance.
In another embodiment, the disease or illness are the breaking-outs (seizures) related with maternal infuries.In another reality Apply in scheme, the breaking-out is secondary to cerebral anoxia.In another embodiment, the breaking-out is secondary to ischemic.In another implementation In scheme, the disease or illness are the results of the neure damage as caused by toxin.In another embodiment, the damage Caused by high fever.In another embodiment, the disease or illness are nuclear icterus.In another embodiment, the disease Or illness is phenylketonuria.In another embodiment, the disease or illness are idiopathys.In another embodiment party In case, the disease or illness are circadian rhythm or sleep-disorder.In another embodiment, the disease or illness are secondary In infection or the cognitive disorder of immunologic derangement.In another embodiment, the cognitive disorder is by brain tumor or its operative treatment Or chemotherapy causes.In another embodiment, the disease or illness are the breaking-out obstacle (seizure secondary to infection disturbance).In another embodiment, the infection is meningitis.In another embodiment, the infection is this The infection of any other type known to field.
Every kind of method, disease and illness represent the independent embodiment of the present invention.
In another embodiment, the present invention is provided and improved or the method for the intelligence of enhancing offspring, it is included to after described ω -6 aliphatic acid or its metabolic precursor thereof is administered in gestation in the mother in generation, wherein ω -6 aliphatic acid or its metabolic precursor thereof carry Synthesis of the nerve cell or brain cell of the high offspring to phosphatide, so as to improve or strengthen the intelligence of offspring.
In another embodiment, the present invention is provided and improved or the method for the intelligence of enhancing offspring, it is included to after described The mother in generation includes (a) uridine, its acyl derivative, uridine phosphate or CDP-choline in gestation administration；ω -3 fat (b) The composition of fat acid or its metabolic precursor thereof, wherein the nerve cell or brain cell of the composition raising offspring are to phosphatide Synthesis, so as to improve or strengthen the intelligence of offspring.
In another embodiment, the present invention is provided and improved or the method for the intelligence of enhancing offspring, it is included to after described The mother in generation includes (a) uridine, its acyl derivative, uridine phosphate or CDP-choline in gestation administration；ω -6 fat (b) The composition of fat acid or its metabolic precursor thereof, wherein the nerve cell or brain cell of the composition raising offspring are to phosphatide Synthesis, so as to improve or strengthen the intelligence of offspring.
In another embodiment, the present invention is provided and improved or the method for the intelligence of enhancing offspring, it is included to after described The mother in generation includes the composition of uridine, its acyl derivative, uridine phosphate or CDP-choline in gestation administration, so as to change Kind or enhancing offspring intelligence.
In another embodiment, the method that the present invention provides the intelligence for improving or strengthening offspring, it is included in the rear During the mother in generation is offspring's lactation, omega-fatty acid or its metabolic precursor thereof is administered to described mother, wherein the ω -3 is fatty Acid or its metabolic precursor thereof improve the synthesis of the nerve cell or brain cell of the offspring to phosphatide, so as to improve or strengthen offspring's Intelligence.
In the another embodiment of the 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 aliphatic acid or its metabolic precursor thereof are secreted in breast milk.In another embodiment In, uridine, its acyl derivative, uridine phosphate or CDP-choline are secreted in breast milk.In another embodiment, choline quilt Secretion is in breast milk.In another embodiment, choline salt is secreted in breast milk.Every kind of possibility represents one of the present invention Independent embodiment.
In another embodiment, the method that the present invention provides the intelligence for improving or strengthening offspring, it is included in the rear During the mother in generation is offspring's lactation, ω -6 aliphatic acid or its metabolic precursor thereof is administered to described mother, wherein the ω -6 Aliphatic acid or its metabolic precursor thereof improve the synthesis of the nerve cell or brain cell of the offspring to phosphatide, so that after improving or strengthening The intelligence in generation.
In another embodiment, the method that the present invention provides the intelligence for improving or strengthening offspring, it is included in the rear The mother in generation be offspring's lactation during, to described mother administration comprising (a) uridine, its acyl derivative, uridine phosphate or CDP-choline；Omega-fatty acid or the composition of its metabolic precursor thereof, wherein the composition improve the nerve of the offspring (b) The synthesis of cell or brain cell to phosphatide, so as to improve or strengthen the intelligence of offspring.
In another embodiment, the method that the present invention provides the intelligence for improving or strengthening offspring, it is included in the rear The mother in generation be offspring's lactation during, to described mother administration comprising (a) uridine, its acyl derivative, uridine phosphate or CDP-choline；ω -6 aliphatic acid or the composition of its metabolic precursor thereof, wherein the composition improve the nerve of the offspring (b) The synthesis of cell or brain cell to phosphatide, so as to improve or strengthen the intelligence of offspring.
In another embodiment, the method that the present invention provides the intelligence for improving or strengthening offspring, it is included in the rear During the mother in generation is offspring's lactation, the combination of uridine, its acyl derivative, uridine phosphate is included to described mother administration Thing, so as to improve or strengthen the intelligence of offspring.
In another embodiment, strengthen or improve its cognitive function, neural work(by the composition or method of the present invention The individual of energy, intelligence, cynapse transmission or neurotransmitter levels and activity is not yet diagnosed as suffering from cognitive impairment or memory disorders. In another embodiment, the individual is healthy.In another embodiment, the individual not yet with cognitive impairment or Memory disorders.Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, the present invention, which provides, improves neuron to the method for the sensitiveness of stimulation, it is included institute The composition that neuron is stated with the present invention contacts, so as to improve sensitiveness of the neuron to stimulation.In another embodiment, should The object of method is developmental brain or its nerve cell.In another embodiment, the object is to have not been diagnosed as suffering from appointing What cognition or the adult of neurological disorder.Every kind of possibility represents the independent embodiment of the present invention.
As herein provided, polyunsaturated fatty acid is administered and/or uridine improves cephalin level and synthesis, neural process The level of nerve fibril albumen and the amount of synaptic membrane.Therefore, method and composition of the invention improves and strengthens neuron The size and number of cynapse in sensitiveness and brain and central nervous system (CNS) to stimulation.
In another embodiment, the method that the present invention provides average cynapse size in the brain for improving individual, it include to The composition of the individual administration present invention, so as to improve average cynapse size in individual brain.In another embodiment, should The object of method is developmental brain or its nerve cell.In another embodiment, the object is to have not been diagnosed as suffering from appointing What cognition or the adult of neurological disorder.Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, the method that the present invention provides the number of cynapse in the brain for improving individual, it is included to institute Individual administration omega-fatty acid or its metabolic precursor thereof are stated, so as to improve the number of cynapse in individual brain.In another embodiment In, the object of this method is developmental brain or its nerve cell.In another embodiment, the object is to have not been diagnosed as suffering from There is the adult of any cognition or neurological disorder.Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, the method that the present invention provides the number of cynapse in the brain for improving individual, it is included to institute Individual administration ω -6 aliphatic acid or its metabolic precursor thereof are stated, so as to improve the number of cynapse in individual brain.In another embodiment In, the object of this method is developmental brain or its nerve cell.In another embodiment, the object is to have not been diagnosed as suffering from There is the adult of any cognition or neurological disorder.Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, the method that the present invention provides the number of cynapse in the brain for improving individual, it is included to institute State individual administration and include (a) uridine, its acyl derivative, uridine phosphate or CDP-choline；Omega-fatty acid or its metabolism (b) The composition of precursor, so as to improve the number of cynapse in individual brain.In another embodiment, the object of this method is development In brain or its nerve cell.In another embodiment, the object is to have not been diagnosed as suffering from any cognition or neurological disorder Adult.Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, the method that the present invention provides the number of cynapse in the brain for improving individual, it is included to institute State individual administration and include (a) uridine, its acyl derivative, uridine phosphate or CDP-choline；ω -6 aliphatic acid or its metabolism (b) The composition of precursor, so as to improve the number of cynapse in individual brain.In another embodiment, the object of this method is development In brain or its nerve cell.In another embodiment, the object is to have not been diagnosed as suffering from any cognition or neurological disorder Adult.Every kind of possibility represents the independent embodiment of the present invention.
Average cynapse size, number and the horizontal and neural of synaptic activity in the brain and central nervous system of individual are passed The measurement of matter release and appraisal procedure are well known in the art, e.g., as disclosed in Wheeler DW et al. (Estimating use- dependent synaptic gain in autonomicganglia by computational simulation and dynamic-clamp analysis.JNeurophysiol.2004 Nov；92(5)：2659-71), Viele K et al. (Estimating thenumber of release sites and probability of firing within the nerve terminal bystatistical analysis of synaptic charge.Synapse.2003 Jan；47 (1)：15-25) and DeFelipe J et al. (Estimation of the number of synapses in the cerebral cortex：methodological considerations.Cereb Cortex.1999 Oct-Nov；9(7)： In 722-32).Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, the present invention provides the generation of the brain cell membrane or neuron membrane that stimulate or strengthen individual Method, it is included to the individual administration omega-fatty acid or its metabolic precursor thereof, so as to stimulate or strengthen individual brain cell The generation of film or neuron membrane.In another embodiment, the object of this method is developmental brain or its nerve cell. In another embodiment, the object is to have not been diagnosed as the adult with any cognition or neurological disorder.Every kind of possibility generation The independent embodiment of the table present invention.
In another embodiment, the present invention provides the generation of the brain cell membrane or neuron membrane that stimulate or strengthen individual Method, it is included to individual administration ω -6 aliphatic acid or its metabolic precursor thereof, so as to stimulate or strengthen individual brain cell The generation of film or neuron membrane.In another embodiment, the object of this method is developmental brain or its nerve cell. In another embodiment, the object is to have not been diagnosed as the adult with any cognition or neurological disorder.Every kind of possibility generation The independent embodiment of the table present invention.
In another embodiment, the present invention provides the generation of the brain cell membrane or neuron membrane that stimulate or strengthen individual Method, it include to it is described individual administration includes (a) uridine, its acyl derivative, uridine phosphate or CDP-choline；(b) The composition of omega-fatty acid or its metabolic precursor thereof, so as to stimulate or strengthen the life of individual brain cell membrane or neuron membrane Into.In another embodiment, the object of this method is developmental brain or its nerve cell.In another embodiment, institute It is to have not been diagnosed as the adult with any cognition or neurological disorder to state object.Every kind of possibility represents the independence of the present invention Embodiment.
In another embodiment, the present invention provides the generation of the brain cell membrane or neuron membrane that stimulate or strengthen individual Method, it include to it is described individual administration includes (a) uridine, its acyl derivative, uridine phosphate or CDP-choline；(b) The composition of ω -6 aliphatic acid or its metabolic precursor thereof, so as to stimulate or strengthen the life of individual brain cell membrane or neuron membrane Into.In another embodiment, the object of this method is developmental brain or its nerve cell.In another embodiment, institute It is to have not been diagnosed as the adult with any cognition or neurological disorder to state object.Every kind of possibility represents the independence of the present invention Embodiment.
In another embodiment, method of the invention improves phospholipid level basic holding target brain cell or neural thin at the same time The ratio of two or more phosphatide in born of the same parents.In another embodiment, method of the invention improves phospholipid level base at the same time The ratio of three or more phosphatide in this holding target brain cell or nerve cell.In another embodiment, it is of the invention Method improves the phospholipid level ratio for keeping four kinds or more kind phosphatide in target brain cell or nerve cell basic at the same time.Another In one embodiment, the phosphatide is selected from PC, PE, PS and sphingomyelins (SM).In another embodiment, the base of these ratios Originally it is important in terms of being maintained at above-mentioned nervous function and brain function.Every kind of possibility represents the independent implementation of the present invention Scheme.
In another embodiment, " keep " referring to substantially and the deviation of previous proportionalities is less than 10%.In another embodiment party In case, " basic to keep " refers to that deviation is less than 15%.In another embodiment, the deviation is less than 20%.In another implementation In scheme, the deviation is less than 25%.In another embodiment, the deviation is less than 30%.In another embodiment, institute Deviation is stated less than 35%.In another embodiment, the deviation is less than 40%.In another embodiment, the deviation is low In 45%.In another embodiment, the deviation is less than 50%.In another embodiment, the deviation is less than 55%. In another embodiment, the deviation is less than 60%.In another embodiment, the deviation is less than 65%.In another implementation In scheme, the deviation is less than 70%.In another embodiment, the deviation is less than 75%.In another embodiment, institute Deviation is stated less than 80%.In another embodiment, the deviation is less than 85%.In another embodiment, the deviation is low In 90%.In another embodiment, the deviation is less than 95%.In another embodiment, the deviation is less than 90%.Often Kind possibility represents the independent embodiment of the present invention.
In the another embodiment of the method for the present invention, phosphatide is stimulated to synthesize enhancing neural process branch.In another embodiment party In case, phosphatide is stimulated to synthesize enhancing neural process to outgrowth.In another embodiment, stimulating phosphatide to synthesize raising can be via sharp The phosphoester groups storehouse of phosphatide enzyme r e lease living.Some phosphoester groups have bioactivity, such as：Inositol Isosorbide-5-Nitrae, 5- triphosphoric acids (IP3), two Acylglycerol (DAG) and haemolysis platelet activating factor (lyso-PAF), it generates bioactivity lipid after further metabolism PAF (l-0- alkyl -2- acetyl group-sn-3- glycerol-3-phosphocholines).
In another embodiment, phosphatide is stimulated to synthesize protection synaptic membrane to resisting stress.In another embodiment, it is described It stress be oxidative stress.In another embodiment, it is described stress be any other type known in the art stress.
In another embodiment, these active every kind of letters for all strengthening neurotransmitter mediation that phosphatide synthesizes are stimulated Number transduction, so as to improve memory, intelligence and other cognitive functions.Phosphatide is stimulated to synthesize above-mentioned active every kind of and its above-mentioned As a result the every kind of independent embodiment for all representing the present invention in.
In one embodiment, the individual of method of the invention is the mankind.In another embodiment, the individual is Women.In another embodiment, the individual is male.In another embodiment, the individual is the women of gestation. In another embodiment, the individual is the women of lactation.In another embodiment, the individual is baby (infant). In another embodiment, the individual is baby (baby).In another embodiment, the individual is child.Another In embodiment, the individual is children.In another embodiment, the individual is underage child.In another embodiment In, the individual is adult.In another embodiment, the individual is the elderly (aging adult).In another implementation In scheme, " old age " refers to any embodiment listed above.Every kind of possibility represents the independent implementation of the present invention Scheme.
In another embodiment, " baby " refers to individual of the age below 6 months.In another embodiment, should Term refers to individual of the age below 5 months.In another embodiment, which refers to of the age below 4 months Body.In another embodiment, which refers to individual of the age below 3 months.In another embodiment, which is Refer to individual of the age below 2 months.In another embodiment, which refers to individual of the age below 1.5 months. In another embodiment, which refers to individual of the age below 1 month.In another embodiment, which refers to year Individual of the age below 10 weeks.In another embodiment, which refers to individual of the age below 9 weeks.In another implementation In scheme, which refers to individual of the age below 7 weeks.In another embodiment, which refers to the age below 6 weeks Individual.In another embodiment, which refers to individual of the age below 5 weeks.Every kind of possibility represents the present invention's One independent embodiment.
In another embodiment, " baby " refers to individual of the age below 1 years old.In another embodiment, the art Language refers to individual of the age below 18 months.In another embodiment, which refers to of the age below 6 months Body.In another embodiment, which refers to individual of the age below 7 months.In another embodiment, which is Refer to individual of the age below 8 months.In another embodiment, which refers to individual of the age below 9 months.Another In one embodiment, which refers to individual of the age below 10 months.In another embodiment, which refers to the age Individual below 11 months.In another embodiment, which refers to individual of the age below 13 months.In another reality Apply in scheme, which refers to individual of the age below 14 months.In another embodiment, which refers to the age 16 The individual of less than a month.In another embodiment, which refers to individual of the age below 20 months.In another embodiment party In case, which refers to individual of the age below 2 years old.In another embodiment, which refers to sucking individual. In another embodiment, which refers to wean but the individual in above-mentioned the range of age.Every kind of possibility represents The independent embodiment of the present invention.
In another embodiment, " child " refers to the individual of 1-2 Sui.In another embodiment, which refers to 6-24 months big individuals.In another embodiment, which refers to 8-24 months big individuals.In another embodiment In, which refers to 10-24 months big individuals.In another embodiment, which refers to 13-24 months big individuals. In another embodiment, which refers to 14-24 months big individuals.In another embodiment, which refers to 16-24 A month big individual.In another embodiment, which refers to 18-24 months big individuals.In another embodiment, should Term refers to 12-18 months big individuals.In another embodiment, which refers to 13-18 months big individuals.Another In embodiment, which refers to 15-18 months big individuals.In another embodiment, which refers to 12-20 months big Individual.In another embodiment, which refers to 14-20 months big individuals.In another embodiment, which is Finger not yet weans, but the individual big less than 20 months.In another embodiment, which refers to not yet wean, but less than 24 A month big individual.Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, " children " refer to individual of the age in under-18s.In another embodiment, the art Language refers to individual of the age below 17 years old.In another embodiment, which refers to individual of the age below 16 years old. In another embodiment, which refers to individual of the age below 15 years old.In another embodiment, which refers to the age Individual below 14 years old.In another embodiment, which refers to individual of the age below 13 years old.In another embodiment party In case, which refers to individual of the age below 12 years old.In another embodiment, which refers to the age below 11 years old Individual.In another embodiment, which refers to individual of the age below 10 years old.In another embodiment, the art Language refers to individual of the age below 9 years old.In another embodiment, which refers to individual of the age below 8 years old.Another In one embodiment, which refers to individual of the age below 7 years old.
In another embodiment, " underage child " refers to individual of the age below 7 years old.In another embodiment, The term refers to individual of the age below 6 years old.In another embodiment, which refers to individual of the age below 5 years old. In another embodiment, which refers to individual of the age below 4 years old.In another embodiment, which refers to year Individual of the age below 3.5 years old.In another embodiment, which refers to individual of the age below 3 years old.In another implementation In scheme, which refers to individual of the age below 2.5 years old.Every kind of possibility represents the independent embodiment party of the present invention Case.
In other embodiments, " adult " refers to the individual for exceeding one of the child age upper limit listed above. In another embodiment, which refers to the individual for exceeding one of underage child upper age limit listed above.Every kind of possibility Represent the independent embodiment of the present invention.
In the another embodiment of the method and composition of the present invention, before omega-fatty acid, ω -6 aliphatic acid, its metabolism Body or the composition of the present invention play one of effect listed herein by improving phosphatide synthesis.In another embodiment, There is the effect and do not increase phosphatide synthesis.Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, method and composition of the invention includes uridine source.In another embodiment, this hair Bright method and composition includes choline source.In another embodiment, " source ", which refers to improve in blood flow or tissue, it is expected chemical combination The compound of the concentration of thing (uridine, choline etc.).In another embodiment, " source " referred to by the individual tissue or enzyme generation Thank to the compound for desired compound.In another embodiment, " source " refers to the change that desired compound is metabolized as by target cell Compound.In another embodiment, the uridine source is cytidine, it is converted into uridine by human liver.In another embodiment In, the uridine source is the phosphoric acid of cytidine 5 '.In another embodiment, the uridine source is the diphosphonic acid of cytidine 5 '.Another In embodiment, the uridine source is the triphosphoric acid of cytidine 5 '.In another embodiment, the uridine source is known in the art Any other cytidine-phosphate.In another embodiment, the uridine source is CDP-choline.In another embodiment, it is described Uridine source is known in the art any other uridine source.Every kind of uridine source represents the independent embodiment of the present invention. Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, the uridine phosphate used in method of the invention is the phosphoric acid of uridine 5 '.In another reality Apply in scheme, the uridine phosphate is the diphosphonic acid of uridine 5 '.In another embodiment, the uridine phosphate is three phosphorus of uridine 5 ' Acid.In another embodiment, the uridine phosphate is any other uridine phosphate known in the art.Every kind of possibility represents The independent embodiment of the present invention.
In other embodiments, except uridine in itself in addition to uridine based compound as uridine source or uridine precursor. In other embodiments, these are food or diet product such as algae, uridine salt such as uridine phosphate, acylated urine rich in uridine Glycosides etc..In another embodiment, the acyl derivative or its mixture of uridine, such as United States Patent (USP) 5,470,838 is also administered Disclosed in those.Every kind of uridine precursor represents the independent embodiment of the present invention.
In another embodiment, method of the invention further includes administration choline.In another embodiment, it is of the invention Method further includes administration choline salt.In another embodiment, method of the invention further includes the chemical combination that administration is metabolized as choline Thing.In another embodiment, method of the invention further includes administration choline source.In another embodiment, above-mentionedization is administered One of compound increases the influence that ω -3 or ω -6 aliphatic acid and/or uridine synthesize membrane phospholipid.As (embodiment) provides herein , choline and ω -3 or ω -6 aliphatic acid is administered and shows water to phosphatide, synapsin and synaptic membrane in neuron and brain tissue Flat and memory, intelligence and cognitive function and nervous function unexpected increase.
In another embodiment, any method and composition of the invention includes administration omega-fatty acid and choline. In another embodiment, any method and composition of the invention includes administration omega-fatty acid and choline salt.Another In embodiment, any method and composition of the invention includes administration ω -6 aliphatic acid and choline.In another embodiment In, any method and composition of the invention includes administration ω -6 aliphatic acid and choline salt.
In another embodiment, any method and composition of the invention includes being administered comprising omega-fatty acid, urine The composition of glycosides and choline.In another embodiment, any method and composition of the invention includes being administered including ω -3 The composition of aliphatic acid, uridine and choline salt.In another embodiment, any method and composition of the invention includes giving Composition of the pack containing ω -6 aliphatic acid, uridine and choline.In another embodiment, any method and composition of the invention Include the composition of administration ω -6 aliphatic acid, uridine and choline salt.
In another embodiment, any method and composition of the invention includes administration ω -6 aliphatic acid and ω -3 fat Fat acid.In another embodiment, any method and composition of the invention includes administration ω -6 aliphatic acid, omega-fatty acid And uridine.In another embodiment, any method and composition of the invention includes administration ω -6 aliphatic acid, ω -3 fat Acid and choline.In another embodiment, any method and composition of the invention includes administration ω -6 aliphatic acid, ω -3 fat Fat acid and choline salt.In another embodiment, any method and composition of the invention include administration ω -6 aliphatic acid, Omega-fatty acid, uridine and choline.In another embodiment, any method and composition of the invention includes administration ω -6 Aliphatic acid, omega-fatty acid, uridine and choline salt.
In another embodiment, method and composition of the invention includes anti-inflammatory polyunsaturated fatty acid.In another reality Apply in scheme, include two kinds of different omega-fatty acids.In another embodiment, one of described two omega-fatty acids are anti- Scorching polyunsaturated fatty acid.In another embodiment, one of described two omega-fatty acids are DHA.In another embodiment In, one of described two omega-fatty acids are EPA.In another embodiment, described two omega-fatty acids are EPA and DHA.
In another embodiment, the ratio of described two omega-fatty acids is 0.05: 1.In another embodiment, institute Ratio is stated as 0.1: 1.In another embodiment, the ratio is 0.15: 1.In another embodiment, the ratio is 0.2∶1.In another embodiment, the ratio is 0.3: 1.In another embodiment, the ratio is 0.4: 1.Another In one embodiment, the ratio is 0.5: 1.In another embodiment, the ratio is 0.6: 1.In another embodiment In, the ratio is 0.7: 1.In another embodiment, the ratio is 0.8: 1.In another embodiment, the ratio For 0.9: 1.In another embodiment, the ratio is 1: 1.In another embodiment, DHA and EPA is included in above-mentioned ratio In one of example (DHA: EPA).In another embodiment, DHA and EPA is included in one of aforementioned proportion (EPA: DHA).
In another embodiment, method and composition of the invention includes two kinds of different ω -6 aliphatic acid.
In another embodiment, the ratio of omega-fatty acid and ω -6 aliphatic acid is in method of the invention or composition 1∶1.In another embodiment, the ratio is 1.5: 1.In another embodiment, the ratio is 2: 1.In another reality Apply in scheme, the ratio is 3: 1.In another embodiment, the ratio is 4: 1.In another embodiment, the ratio Example is 5: 1.In another embodiment, the ratio is 6: 1.In another embodiment, the ratio is 8: 1.Another In embodiment, the ratio is 10: 1.In another embodiment, the ratio is 12: 1.In another embodiment, institute Ratio is stated as 15: 1.In another embodiment, the ratio is 20: 1.In another embodiment, the ratio is 30: 1. In another embodiment, the ratio is 40: 1.In another embodiment, the ratio is 50: 1.In another embodiment party In case, the ratio is 60: 1.In another embodiment, the ratio is 80: 1.In another embodiment, the ratio For 100: 1.
Every kind of combination of omega-fatty acid, ω -6 aliphatic acid, uridine, choline and/or choline salt represents one of the present invention Independent embodiment.Every kind of combination of different omega-fatty acids represents the independent embodiment of the present invention.It is different ω -6 aliphatic acid every kind of combination represent the present invention an independent embodiment.One of every kind of proportional representation present invention Independent embodiment.
In another embodiment, the choline source is lecithin.In another embodiment, the choline source is lecithin Fat.In another embodiment, the choline source is acetylcholine.In another embodiment, the choline source is two phosphorus of born of the same parents Choline (citicholine) or α-glyceryl phosphoryl choline.In another embodiment, the choline source is CDP-choline.Another In one embodiment, the choline source is any other choline source known in the art.Every kind of choline source represents the one of the present invention A independent embodiment.
In another embodiment, the choline salt is sulfonate, such as：Long alkyl chain sulfonate.In another embodiment In, the choline salt is choline chloride.In another embodiment, the choline salt is choline bitartrate.In another implementation In scheme, the choline salt is choline citrate.In another embodiment, the choline salt is choline tartrate.Another In embodiment, the choline salt is iron choline citrate complex.In another embodiment, the choline source is this area Any other known choline salt.Every kind of choline salt represents the independent embodiment of the present invention.
In another embodiment, the present invention is provided to treat the composition of paediatrics neurological disorder, the composition by Arbitrary composition composition disclosed in the method for the present invention.Every kind of composition represents the independent embodiment of the present invention.
In another embodiment, the composition that the present invention is provided to increase intelligence, the composition is by the present invention's Arbitrary composition composition disclosed in method.Every kind of composition represents the independent embodiment of the present invention.
In another embodiment, method and composition of the invention is even having no lack of omega-fatty acid or ω -6 fat Their effect is played in the individual of acid.In another embodiment, method and composition of the invention uses pharmacological dose Polyunsaturated fatty acid.In another embodiment, using therapeutic dose.In another embodiment, the pharmacology agent Amount is higher than what is normally taken in from the diet rich in polyunsaturated fatty acid.In another embodiment, by the way that pharmacology is administered The polyunsaturated fatty acid and/or uridine of dosage improve the film water having no lack of in the individual of polyunsaturated fatty acid and put down.Another In embodiment, it is of the invention the result shows that, polyunsaturated fatty acid plays biochemical action in brain, so as to support pharmacology agent The purposes of the polyunsaturated fatty acid of amount.Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, the dosage of the omega-fatty acid included in method and composition of the invention is in about 400- The scope of 2000mg/ days.In another embodiment, scope of the dosage on about 500-2000mg/.In another embodiment party In case, the scope is about 600-2000mg/ days.In another embodiment, the scope is about 800-2000mg/ days. In another embodiment, the scope is about 1000-2000mg/ days.In another embodiment, the scope is about 1200- 2000mg/ days.In another embodiment, the scope is about 1500-2000mg/ days.In another embodiment, the model Enclose is about 400-3000mg/ days.In another embodiment, scope of the dosage on about 500-3000mg/.In another reality Apply in scheme, the scope is about 600-3000mg/ days.In another embodiment, the scope is about 800-3000mg/ Day.In another embodiment, the scope is about 1000-3000mg/ days.In another embodiment, the scope is about 1200-3000mg/ days.In another embodiment, the scope is about 1500-3000mg/ days.In another embodiment, The scope is about 2000-3000mg/ days.In another embodiment, the scope is about 400-4000mg/ days.Another In embodiment, scope of the dosage on about 500-4000mg/.In another embodiment, the scope is about 600- 4000mg/ days.In another embodiment, the scope is about 800-4000mg/ days.In another embodiment, the model Enclose is about 1000-4000mg/ days.In another embodiment, the scope is about 1200-4000mg/ days.In another embodiment party In case, the scope is about 1500-4000mg/ days.In another embodiment, the scope is about 2000-4000mg/ days. In another embodiment, the scope is about 3000-4000mg/ days.In another embodiment, the scope is about 400- 1000mg/ days.In another embodiment, the scope is about 500-1000mg/ days.In another embodiment, the model Enclose is about 600-1000mg/ days.In another embodiment, the scope is about 800-100mg/ days.
In another embodiment, the dosage of omega-fatty acid is at least 400mg/ days.In another embodiment, it is described Dosage is at least 500mg/ days.In another embodiment, the dosage is at least 600mg/ days.In another embodiment, The dosage is at least 700mg/ days.In another embodiment, the dosage is at least 800mg/ days.In another embodiment In, the dosage is at least 900mg/ days.In another embodiment, the dosage is at least 1g/ days.In another embodiment In, the dosage is at least 1200mg/ days.In another embodiment, the dosage is at least 1.5g/ days.In another implementation In scheme, the dosage is at least 2g/ days.
In another embodiment, the dosage of omega-fatty acid is 5-50mg/kg/ days.In another embodiment, it is described Dosage is 2-100mg/kg/ days.In another embodiment, the dosage is 7-50mg/kg/ days.In another embodiment, The dosage is 10-50mg/kg/ days.In another embodiment, the dosage is 15-50mg/kg/ days.In another embodiment party In case, the dosage is 20-50mg/kg/ days.In another embodiment, the dosage is 30-50mg/kg/ days.Another In embodiment, the dosage is 5-30mg/kg/ days.In another embodiment, the dosage is 7-30mg/kg/ days. In another embodiment, the dosage is 10-30mg/kg/ days.In another embodiment, the dosage is 15-30mg/kg/ Day.In another embodiment, the dosage is about 5mg/kg/ days.In another embodiment, the dosage is about 7mg/ Kg/ days.In another embodiment, the dosage is about 10mg/kg/ days.In another embodiment, the dosage is about 15mg/kg/ days.In another embodiment, the dosage is about 20mg/kg/ days.In another embodiment, the dosage It is about 30mg/kg/ days.In another embodiment, the dosage is about 40mg/kg/ days.In another embodiment, it is described Dosage is about 50mg/kg/ days.In another embodiment, the dosage is at least 5mg/kg/ days.In another embodiment, The dosage is at least 6mg/kg/ days.In another embodiment, the dosage is at least 8mg/kg/ days.In another embodiment party In case, the dosage is at least 10mg/kg/ days.In another embodiment, the dosage is at least 15mg/kg/ days.Another In one embodiment, the dosage is at least 20mg/kg/ days.In another embodiment, the dosage is at least 30mg/kg/ Day.In another embodiment, the dosage is at least 40mg/kg/ days.In another embodiment, the dosage is at least 50mg/kg/ days.In another embodiment, the dosage is at least 70mg/kg/ days.In another embodiment, above-mentioned dose One of amount is administered to baby.In another embodiment, one of above-mentioned dosage is administered to baby.In another embodiment, on One of dosage is stated to be administered to child.Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, the pregnant special dosage of women is given to meet its needs.In another embodiment In, which is about 200-2000mg/ days.In another embodiment, which is about 400-1700mg/ days.In another reality Apply in scheme, which is about 600-1500mg/ days.In another embodiment, which is about 800-1300mg/ days. In another embodiment, which is about 200-3000mg/ days.In another embodiment, which is about 400-3000mg/ Day.In another embodiment, which is about 600-3000mg/ days.In another embodiment, which is about 800- 3000mg/ days.In another embodiment, which is about 1000-3000mg/ days.In another embodiment, which is About 2000-3000mg/ days.In another embodiment, the dosage of pregnant women is about 1000 mg/ days.In another embodiment party In case, the dosage is about 1500mg/ days.In another embodiment, the dosage is about 2000mg/ days.In another implementation In scheme, the dosage is about 3000mg/ days.
In another embodiment, the special dosage of high cholesterol individual is given to meet its needs.In another embodiment party In case, the scope of the dosage of high cholesterol individual on about 200-4000mg/.
In another embodiment, scope of the dosage of high cholesterol individual on about 400-3500mg/.
In another embodiment, scope of the dosage of high cholesterol individual on about 600-3000mg/.
In another embodiment, scope of the dosage of high cholesterol individual on about 1000-2500mg/.
In another embodiment, scope of the dosage of high cholesterol individual on about 1500-2300mg/.
In another embodiment, the dosage of high cholesterol individual is about 2000mg/ days.
In the another embodiment of the method and composition of the present invention, DHA is included by one of above-mentioned dosage.In another reality Apply in scheme, the dosage of DHA is 1-50mg/kg/ days.In another embodiment, the dosage of DHA is 400-1000mg/ days. In another embodiment, EPA is included 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/ days.Every kind of dosage represents the independent reality of the present invention Apply scheme.
In other embodiments, the dosage of ω -6 aliphatic acid included in the method and composition of the present invention is the above Any dosage of the omega-fatty acid referred to.In another embodiment, arachidonic acid is included by one of above-mentioned dosage.Another In one embodiment, arachidonic dosage is 1-50mg/kg/ days.In another embodiment, arachidonic dosage For 400-1000mg/ days.Every kind of dosage represents the independent embodiment of the present invention.
In another embodiment, eicosahexaenoic acid (EPA) is administered together with another ω -3 or ω -6 aliphatic acid. In another embodiment, EPA was added with the dosage of about 200mg/ days.In another embodiment, the dosage is 100- 300mg/ days.In another embodiment, which is 150-250mg/ days.In another embodiment, which is 170- 230mg/ days.In another embodiment, which is 100-1000mg/ days.In another embodiment, which is 150- 800mg/ days.In another embodiment, which is 200-600mg/ days.In another embodiment, which is 300- 500mg/ days.In another embodiment, the dosage is about 300mg/ days.In another embodiment, the dosage is about 400mg/ days.In another embodiment, the dosage is about 500mg/ days.In another embodiment, the dosage is about 600mg/ days.In another embodiment, the dosage is about 800mg/ days.In another embodiment, the dosage is about 1000mg/ days.
In another embodiment, the dosage of EPA is 1-12mg/kg/ days.In another embodiment, the dosage is 1.5-12mg/kg/ day.In another embodiment, the dosage is 2-12mg/kg/ days.In another embodiment, it is described Dosage is 3-12mg/kg/ days.In another embodiment, the dosage is 4-12mg/kg/ days.In another embodiment, The dosage is 5-12mg/kg/ days.In another embodiment, the dosage is 6-12mg/kg/ days.In another embodiment In, the dosage is 8-12mg/kg/ days.In another embodiment, the dosage is 1-8mg/kg/ days.In another embodiment party In case, the dosage is 1.5-8mg/kg/ days.In another embodiment, the dosage is 3-8mg/kg/ days.In another reality Apply in scheme, the dosage is 4-8mg/kg/ days.In another embodiment, the dosage is about 1mg/kg/ days.Another In embodiment, the dosage is about 1.5mg/kg/ days.In another embodiment, the dosage is about 2mg/kg/ days. In another embodiment, the dosage is about 3mg/kg/ days.In another embodiment, the dosage is about 4mg/kg/ days. In another embodiment, the dosage is about 6mg/kg/ days.In another embodiment, the dosage is about 8mg/kg/ Day.In another embodiment, the dosage is about 10mg/kg/ days.In another embodiment, the dosage is about 12mg/ Kg/ days.In another embodiment, one of above-mentioned dosage is administered to baby.In another embodiment, one of above-mentioned dosage to Baby is administered.In another embodiment, one of above-mentioned dosage is administered to child.Every kind of possibility represents one of the present invention solely Vertical embodiment.
In another embodiment, the EPA of higher doses is administered to the women of gestation.In another embodiment, it is described Dosage is about 1200mg/ days.In another embodiment, the dosage is about 1500mg/ days.In another embodiment, institute It is about 1800mg/ days to state dosage.In another embodiment, the dosage is about 2000mg/ days.In another embodiment, The dosage is about 2500mg/ days.In another embodiment, the dosage is about 3000mg/ days.In another embodiment In, the dosage is 500-3000mg/ days.In another embodiment, the dosage is 800-3000mg/ days.In another reality Apply in scheme, the dosage is 1000-3000mg/ days.In another embodiment, the dosage is 1500-3000mg/ days. In another embodiment, the dosage is 2000-3000mg/ days.In another embodiment, the dosage is 500- 2000mg/ days.In another embodiment, the dosage is 800-2000mg/ days.In another embodiment, the dosage For 1000-2000mg/ days.In another embodiment, the dosage is 1500-2000mg/ days.
Every kind of dosage of omega-fatty acid, ω -6 aliphatic acid or other EPA represents the independent implementation of the present invention Scheme.
In another embodiment, the dosage of the uridine included in method and composition of the invention was on 10-500mg/ Between (including end value).In another embodiment, the dosage is 20-500mg/ days.In another embodiment, described dose Measure as 30-500mg/ days.In another embodiment, the dosage is 50-500mg/ days.In another embodiment, it is described Dosage is 100-500mg/ days.In another embodiment, the dosage is 150-500mg/ days.In another embodiment, The dosage is 200-500mg/ days.In another embodiment, the dosage is 300-500mg/ days.In another embodiment In, the dosage of uridine is between 10-400mg/ days.In another embodiment, the dosage is 20-400mg/ days.Another In embodiment, the dosage is 30-400mg/ days.In another embodiment, the dosage is 50-400mg/ days.Another In one embodiment, the dosage is 100-400mg/ days.In another embodiment, the dosage is 150-400mg/ days. In another embodiment, the dosage is 200-400mg/ days.In another embodiment, the dosage of uridine is in 10- Between 300mg/ days.In another embodiment, the dosage is 20-300mg/ days.In another embodiment, the dosage For 30-300mg/ days.In another embodiment, the dosage is 50-300mg/ days.In another embodiment, described dose Measure as 100-300mg/ days.In another embodiment, the dosage is 150-300mg/ days.In another embodiment, institute Dosage is stated as 200-300mg/ days.In another embodiment, the dosage is about 50mg/ days.In another embodiment, institute It is about 70mg/ days to state dosage.In another embodiment, the dosage is about 100mg/ days.In another embodiment, it is described Dosage is about 150mg/ days.In another embodiment, the dosage is about 200mg/ days.In another embodiment, it is described Dosage is about 300mg/ days.In another embodiment, the dosage is about 400mg/ days.In another embodiment, it is described Dosage is about 500mg/ days.
In another embodiment, the dosage of uridine is 0.1-6mg/kg/ days.In another embodiment, the dosage For 0.2-6mg/kg/ days.In another embodiment, the dosage is 0.3-6mg/kg/ days.In another embodiment, institute Dosage is stated as 0.5-6mg/kg/ days.In another embodiment, the dosage is 1-6mg/kg/ days.In another embodiment In, the dosage is 1.5-6mg/kg/ days.In another embodiment, the dosage is 2-6mg/kg/ days.In another implementation In scheme, the dosage is 3-6mg/kg/ days.In another embodiment, the dosage is 0.1-3mg/kg/ days.Another In embodiment, the dosage is 0.15-3mg/kg/ days.In another embodiment, the dosage is 0.2-3mg/kg/ days. In another embodiment, the dosage is 0.3-3mg/kg/ days.In another embodiment, the dosage is 0.5-3mg/ Kg/ days.In another embodiment, the dosage is 0.8-3mg/kg/ days.In another embodiment, the dosage is 1- 3mg/kg/ days.In another embodiment, the dosage is about 0.1mg/kg/ days.In another embodiment, the dosage It is about 0.15mg/kg/ days.In another embodiment, the dosage is about 0.2mg/kg/ days.In another embodiment, institute It is about 0.3mg/kg/ days to state dosage.In another embodiment, the dosage is about 0.4mg/kg/ days.In another embodiment In, the dosage is about 0.6mg/kg/ days.In another embodiment, the dosage is about 0.8mg/kg/ days.In another reality Apply in scheme, the dosage is about 1mg/kg/ days.In another embodiment, the dosage is about 1.5mg/kg/ days.Another In one embodiment, the dosage is about 2mg/kg/ days.In another embodiment, the dosage is about 3mg/kg/ days. In another embodiment, the dosage is about 4mg/kg/ days.In another embodiment, the dosage is about 6mg/kg/ days. In another embodiment, one of above-mentioned dosage is administered to baby.In another embodiment, one of above-mentioned dosage is given to baby Medicine.In another embodiment, one of above-mentioned dosage is administered to child.Every kind of possibility represents the independent reality of the present invention Apply scheme.
Every kind of uridine dosage represents the independent embodiment of the present invention.
In another embodiment, the dosage of the choline included in method and composition of the invention was on 100mg-10g/ Between (including end value).In another embodiment, the dosage is 1g-3g.In another embodiment, the dosage is 150mg-8g.In another embodiment, the dosage is 200mg-6g.In another embodiment, the dosage is 300mg-5g.In another embodiment, the dosage is 400mg-4.5g.In another embodiment, the dosage is 500mg-4g.In another embodiment, the dosage is 600mg-4g.In another embodiment, the dosage is 800mg-3.5g.In another embodiment, the dosage is 1.2g-3g.In another embodiment, the dosage is 1.5g-2.5g.In another embodiment, the dosage is about 0.5g.In another embodiment, the dosage is about 0.7g.In another embodiment, the dosage is about 1g.In another embodiment, the dosage is about 1.2g.Another In embodiment, the dosage is about 1.5g.In another embodiment, the dosage is about 2g.In another embodiment, The dosage is about 2.5g.In another embodiment, the dosage is about 3g.In another embodiment, the dosage is About 4g.
In another embodiment, the dosage of choline is 1-100mg/kg/ days.In another embodiment, the dosage For 2-100mg/kg/ days.In another embodiment, the dosage is 3-100mg/kg/ days.In another embodiment, institute Dosage is stated as 5-100mg/kg/ days.In another embodiment, the dosage is 8-100mg/kg/ days.In another embodiment In, the dosage is 10-100mg/kg/ days.In another embodiment, the dosage is 20-100mg/kg/ days.Another In embodiment, the dosage is 30-100mg/kg/ days.In another embodiment, the dosage is 50-100mg/kg/ Day.In another embodiment, the dosage is 1-50mg/kg/ days.In another embodiment, the dosage is 1.5- 50mg/kg/ days.In another embodiment, the dosage is 2-50mg/kg/ days.In another embodiment, the dosage For 3-50mg/kg/ days.In another embodiment, the dosage is 5-50mg/kg/ days.In another embodiment, it is described Dosage is 8-50mg/kg/ days.In another embodiment, the dosage is 10-50mg/kg/ days.In another embodiment, The dosage is about 1mg/kg/ days.In another embodiment, the dosage is about 1.5mg/kg/ days.In another embodiment In, the dosage is about 2mg/kg/ days.In another embodiment, the dosage is about 3mg/kg/ days.In another embodiment party In case, the dosage is about 5mg/kg/ days.In another embodiment, the dosage is about 7mg/kg/ days.In another implementation In scheme, the dosage is about 10mg/kg/ days.In another embodiment, the dosage is about 15mg/kg/ days.Another In embodiment, the dosage is about 20mg/kg/ days.In another embodiment, the dosage is about 30mg/kg/ days. In another embodiment, the dosage is about 40mg/kg/ days.In another embodiment, the dosage is about 50mg/kg/ Day.In another embodiment, the dosage is about 60mg/kg/ days.In another embodiment, the dosage is about 80mg/ Kg/ days.In another embodiment, the dosage is about 100mg/kg/ days.In another embodiment, one of above-mentioned dosage It is administered to baby.In another embodiment, one of above-mentioned dosage is administered to baby.In another embodiment, above-mentioned dosage One of to child be administered.Every kind of possibility represents the independent embodiment of the present invention.
Every kind of in above-mentioned dosage is the amount of choline equivalent；Therefore, compound choline is (such as：Choline chloride or winestone Sour choline) actual dose will correspondingly higher.
Every kind of choline dosage represents the independent embodiment of the present invention.
In another embodiment, composition of the invention is by long term administration.In another embodiment, " long-term " refers to Administration at least 1 week.In another embodiment, which refers to administration at least 2 weeks.In another embodiment, phase time It is limited at least 10 days.In another embodiment, which is at least 3 weeks.In another embodiment, the time limit It is at least 4 weeks.In another embodiment, which is at least 5 weeks.In another embodiment, which is At least 6 weeks.In another embodiment, which is at least two moon.In another embodiment, which is At least three moon.In another embodiment, which is at least four moon.In another embodiment, the time limit For at least six moon.In another embodiment, which is at least six moon.In another embodiment, phase time It is limited at least 1 year.In another embodiment, which is at least 2 years.In another embodiment, the time limit It is at least 3 years.In another embodiment, which is at least 5 years.In another embodiment, which is At least 10 years.
In another embodiment, which is 1 week.In another embodiment, which refers to administration 2 weeks. In another embodiment, which is 10 days.In another embodiment, which is 3 weeks.In another implementation In scheme, which is 4 weeks.In another embodiment, which is 5 weeks.In another embodiment, this when Between the time limit be 6 weeks.In another embodiment, which is 2 months.In another embodiment, which is 3 A month.In another embodiment, which is 4 months.In another embodiment, which is 6 months. In another embodiment, which is 6 months.In another embodiment, which is 1 year.In another implementation In scheme, which is 2 years.In another embodiment, which is 3 years.In another embodiment, this when Between the time limit be 5 years.In another embodiment, which is 10 years,
In another embodiment, the administration of the polyunsaturated fatty acid component of the present composition continues above-mentioned phase time One of limit.In another embodiment, the administration of ω -3 components of the present composition continues one of above-mentioned time limit.Another In one embodiment, the administration of ω -6 components of the present composition continues one of above-mentioned time limit.In another embodiment In, the administration of the uridine component of the present composition continues one of above-mentioned time limit.In another embodiment, of the present invention group The administration of the choline or choline salt component of compound continues one of above-mentioned time limit.
Every kind of time limit represents the independent embodiment of the present invention.
In another embodiment, " contact " refer to by the present invention composition directly to it is described individual or brain cell to Medicine.In another embodiment, " contact " refers to the composition of the present invention being administered indirectly to the individual or brain cell.Cause This, in another embodiment, the method for the present invention includes such method, wherein the individual connects with compound or composition Touch, the compound or composition is metabolized as ω -3 or ω -6 aliphatic acid in cerebrospinal fluid, blood flow etc., afterwards the ω -3 or Any other active transport process or passive that ω -6 aliphatic acid is circulated in vivo by diffusion or compound known in the art Transport process is contacted with the brain cell.In another embodiment, the compound is metabolized as ω -3 or ω -6 by target cell Aliphatic acid.Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, the derivative of ω -3 or ω -6 aliphatic acid is used in method and composition of the invention. In another embodiment, the derivative is ω -6 derivative of fatty acid gamma-Linolenic acids.In another embodiment, it is described Derivative is any other derivative of ω -3 or ω -6 aliphatic acid known in the art.Every kind of derivative represents the one of the present invention A independent embodiment.
In another embodiment, the present invention provides the side of the nerve cell of increase individual or the neural process branch of brain cell Method, it is included to the individual administration omega-fatty acid or its metabolic precursor thereof, wherein the omega-fatty acid or its metabolic precursor thereof Synthesis of the nerve cell to phosphatide is improved, so as to increase its neural process branch.In another embodiment, the present invention provides Increase individual nerve cell or brain cell neural process branch method, it include to it is described individual be administered ω -6 aliphatic acid or Its metabolic precursor thereof, wherein ω -6 aliphatic acid or its metabolic precursor thereof increase synthesis of the nerve cell to phosphatide, so as to increase Add the neural process branch of nerve cell.In another embodiment, the object of this method is developmental brain or its nerve cell. In another embodiment, the object is to have not been diagnosed as the adult with any cognition or neurological disorder.Every kind of possibility Represent the independent embodiment of the present invention.
In another embodiment, the present invention provides the side of the nerve cell of increase individual or the neural process branch of brain cell Method, it includes including (a) uridine, its acyl derivative, uridine phosphate or CDP-choline to the individual administration；ω -3 (b) The composition of aliphatic acid or its metabolic precursor thereof, wherein the composition increases synthesis of the nerve cell to phosphatide, so as to increase Add its neural process branch.In another embodiment, the present invention provides the nerve cell of increase individual or the neural process of brain cell The method of branch, it includes including (a) uridine, its acyl derivative, uridine phosphate or CDP-choline to the individual administration；With (b) ω -6 aliphatic acid or the composition of its metabolic precursor thereof, wherein the composition increases synthesis of the nerve cell to phosphatide, So as to increase the neural process branch of nerve cell.In another embodiment, the object of this method is developmental brain or its god Through cell.In another embodiment, the object is to have not been diagnosed as the adult with any cognition or neurological disorder.It is every kind of Possibility represents the independent embodiment of the present invention.
In another embodiment, the present invention provides the nerve cell of increase individual or the neural process of brain cell to outgrowth Method, it include to it is described individual administration includes (a) uridine, its acyl derivative, uridine phosphate or CDP-choline；(b) The composition of omega-fatty acid or its metabolic precursor thereof, wherein the composition increases synthesis of the nerve cell to phosphatide, from And increase its neural process to outgrowth.In another embodiment, the present invention provides the nerve cell or brain cell of increase individual Method from neural process to outgrowth, it include to it is described individual administration comprising (a) uridine, its acyl derivative, uridine phosphate Or CDP-choline；ω -6 aliphatic acid or the composition of its metabolic precursor thereof, wherein the composition increase the nerve cell (b) Synthesis to phosphatide, so as to increase the nerve cell of individual or the neural process of brain cell to outgrowth.In another embodiment, The object of this method is developmental brain or its nerve cell.In another embodiment, the object is to have not been diagnosed as suffering from Any cognition or the adult of neurological disorder.Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, the present invention provides the neural process for increasing nerve cell to the method for outgrowth, it includes To the individual administration omega-fatty acid or its metabolic precursor thereof, wherein the omega-fatty acid or its metabolic precursor thereof increase the god Synthesis through cell to phosphatide, so as to increase its neural process to outgrowth.In another embodiment, the present invention provides increase The nerve cell of body or method from the neural process of brain cell to outgrowth, it include to individual administration ω -6 aliphatic acid or its Metabolic precursor thereof, wherein ω -6 aliphatic acid or its metabolic precursor thereof increase synthesis of the nerve cell to phosphatide, so as to increase The nerve cell of individual or the neural process of brain cell are to outgrowth.In another embodiment, the object of this method is in development Brain or its nerve cell.In another embodiment, the object is had not been diagnosed as with any cognition or neurological disorder Adult.Every kind of possibility represents the independent embodiment of the present invention.
In another embodiment, the present invention provides a kind of kit, and it includes used in the method for implementing the present invention Compound or composition.
In another embodiment, " pharmaceutical composition " refers to dietary supplements.In another embodiment, which is Refer to infant formala.In another embodiment, which refers to processed baby food.In another embodiment, The term refers to nutritional supplement.In another embodiment, which refers to any classification for being rich in omega-fatty acid Food.In another embodiment, which refers to the food for being rich in ω -6 aliphatic acid.In another embodiment, the art Language refers to the food for being rich in uridine.In another embodiment, which refers to the food for being rich in choline.In another implementation In scheme, which refers to the food for being rich in choline salt.
In another embodiment, " food " refers to food.In another embodiment, which refers to beverage. In another embodiment, which refers to powdered drink mixtures.In another embodiment, the term refer to using food as Preparation, functional food, dietary supplements or the nutraceutical on basis.
In another embodiment, if food can be dry form, including：Liquid, suspension, powder, semisolid and solid Body.Semisolid is intended to include ice milk (custards), dessert pudding, concentrated cream, mousse, ice cream, yoghourt and sugaring Gelatin (sweetened gelatin).Specific embodiment is not limited to, solid form can be prepared as the rod similar to energy stick Shape, sheet, cooky, biscuit, dough (pasta) or puffing material such as puffed rice or rice cake sample food.Some embodiments will Individual is asked to dissolve snack food, suspend or be hydrated again.
Each type of pharmaceutical composition represents the independent embodiment of the present invention.
In another embodiment, the present invention relates to ω -3 or ω -6 aliphatic acid and/or its analog, derivative, isomery Body, metabolin, pharmaceutically acceptable salt, medicine, hydrate, the purposes of N- oxides or combinations thereof.Therefore, in another reality Apply in scheme, the method for the present invention includes the analog of administration polyunsaturated fatty acid.In another embodiment, it is of the invention Method includes the derivative of administration polyunsaturated fatty acid.In another embodiment, it is more not the method for the present invention includes administration The isomers of saturated fatty acid.In another embodiment, the method for the present invention includes the metabolism of administration polyunsaturated fatty acid Thing.In another embodiment, the method for the present invention includes the pharmaceutically acceptable salt of administration polyunsaturated fatty acid.Another In embodiment, the method for the present invention includes the medicine of administration polyunsaturated fatty acid.In another embodiment, it is of the invention Method includes the hydrate of administration polyunsaturated fatty acid.In another embodiment, it is more not the method for the present invention includes administration The N- oxides of saturated fatty acid.In another embodiment, the method for the present invention includes the class of administration polyunsaturated fatty acid Like any combination of thing, derivative, isomers, metabolin, pharmaceutically acceptable salt, medicine, hydrate or N- oxides.
In the another embodiment of the method and composition of the present invention, polyunsaturated fatty acid is given as triglycerides Medicine.
In another embodiment, term " isomers " includes, but in another embodiment, is not limited to optical isomer And the like, constitutional isomer and the like, rotamer and the like etc..
In another embodiment, present invention additionally comprises polyunsaturated fatty acid derivative.Term " derivative " include but It is not limited to ether derivant, acid derivative, amide derivatives, ester derivant etc..In addition, present invention additionally comprises polyunsaturated fatty acid The hydrate of compound." hydrate " includes but not limited to semihydrate, monohydrate, dihydrate, trihydrate etc. to term.
Present invention additionally comprises the metabolin of polyunsaturated fatty acid compound.Term " metabolin " referred to by metabolism or generation Any material that journey of apologizing for having done sth. wrong is generated from another material.
Present invention additionally comprises the medicine of polyunsaturated fatty acid compound.Term " medicine " refers to be suitable for pharmaceutical use Composition (pharmaceutical composition), as defined herein.
In addition, the present invention include polyunsaturated fatty acid compound defined herein pure (Z)-and (E)-isomers and its Mixture, and pure (RR, SS)-and (RS, SR)-enantiomer pair and its mixture.
Pharmaceutical composition and medication
In another embodiment, the pharmaceutical composition containing polyunsaturated fatty acid and/or uridine can pass through ability Field technique personnel's any known method is for example parenteral, by carcinoma, transmucosal, it is percutaneous, intramuscular, intravenous, intracutaneous, subcutaneous, It is administered in peritonaeum, in intra-ventricle, encephalic, intravaginal or tumour to individual.
In the another embodiment of the method and composition of the present invention, described pharmaceutical composition is administered orally, therefore matches somebody with somebody It is made as being suitable for the form being administered orally, i.e.,：Solid or liquid preparation.Suitable solid orally ingestible include tablet, capsule, Pill, granule, bolus etc..Suitable liquid oral medicine includes solution, supensoid agent, dispersant, emulsion, finish etc.. In another embodiment of the present invention, active ingredient is formulated in capsule.According to the embodiment, composition of the invention Inert carrier or diluent, hard gelatin capsule are also included in addition to reactive compound.
In another embodiment, described pharmaceutical composition through intravenous, intra-arterial, intramuscular injection liquid preparation come to Medicine.Suitable liquid preparation includes solution, supensoid agent, dispersant, emulsion, finish etc..In another embodiment, the medicine Compositions intravenous administration, therefore it is formulated as being suitable for the form of intravenous administration.In another embodiment, the medicine Composition intraarterial delivery, therefore it is formulated as being suitable for the form of intraarterial delivery.In another embodiment, the medicine group Compound intramuscular administration, therefore it is formulated as being suitable for the form of intramuscular administration.
In another embodiment, described pharmaceutical composition is partly administered to body surface, therefore is formulated as being suitable for office The form of portion's administration.In another embodiment, suitable topical formulations include gelling agent, ointment, emulsion, lotion, drops Deng.
In another embodiment, described pharmaceutical composition is administered as suppository, such as：Rectal suppository or urethral suppositories. In another embodiment, described pharmaceutical composition is administered by being subcutaneously implanted for piller (pellet).In another implementation In scheme, the piller provides the controlled release of polyunsaturated fatty acid and/or uridine within a period of time.
In another embodiment, the reactive compound delivers in vesica such as liposome.
In other embodiments, the carrier or diluent used in method of the invention includes but not limited to：Natural gum, form sediment Powder is (such as：Cornstarch, pregelatinized starch), sugar (such as：Lactose, mannitol, sucrose, glucose), cellulosic material (such as：Crystallite Cellulose), acrylate (such as：Polymethacrylates), calcium carbonate, magnesia, talcum or its mixture.
In other embodiments, the pharmaceutically acceptable carrier of liquid preparation be aqueous solution or non-aqueous solution, suspension, Lotion or oil.The example of nonaqueous solvents is propane diols, polyethylene glycol and injectable organic ester such as ethyl oleate.Aqueous carrier includes Water, alcohol/aqueous solution, lotion or suspension, including brine and buffer medium.The example of oil is animal oil, vegetable oil or synthesis come The oil in source, such as：Peanut oil, soybean oil, olive oil, sunflower oil, cod-liver oil, other sea hydrobionts are oily or from milk or eggs Lipid.
In another embodiment, parenteral carrier (being used for subcutaneous, intravenous, intra-arterial or intramuscular injection) includes chlorination Sodium solution, woods lattice glucose, glucose and sodium chloride, lactated Ringer's solution and expressed oi.Intravenous vehicles include liquid and The replenishers of nutritional supplement, electrolyte replenisher such as based on woods lattice glucose.Example is sterile liquid Ru Shui and oil, is added Or it is added without surfactant and other pharmaceutically acceptable assistant agents.In general, water, brine, glucose solution and correlation Sugar juice and polyalcohol such as propane diols or polyethylene glycol are preferable liquid-carriers, especially for injectable solutions Speech.The example of oil is the oil of animal oil, vegetable oil or synthesis source, such as：Peanut oil, soybean oil, olive oil, sunflower oil, Cod-liver oil, other sea hydrobionts oil or the lipid from milk or egg.
In other embodiments, the composition also includes adhesive (such as：Gum arabic, cornstarch, gelatin, Carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl cellulose, povidone), disintegrant (such as：Corn forms sediment Powder, farina, alginic acid, silica, Ac-Di-Sol, Crospovidone, guar gum, starch glycolic Sodium), the buffer of various pH and ionic strength (such as：Tris-HCl, acetate, phosphate), prevent the additive of adsorption Such as albumin or gelatin, detergent (such as：Polysorbas20, Tween 80, polyoxypropylene F68 (Pluronic F68), bile salt), egg White enzyme inhibitor, surfactant are (such as：Lauryl sodium sulfate), penetration enhancer, cosolvent (such as：Glycerine, polyethylene are sweet Oil), antioxidant (such as：Ascorbic acid, sodium metasulfite, Butylated Hydroxyanisole), stabilizer (such as：Hydroxypropyl cellulose, hydroxypropyl first Base cellulose), tackifier (such as：Carbomer, cataloid, ethyl cellulose, guar gum), sweetener (such as：A Sipa Smooth, citric acid), preservative (such as：Thimerosal, benzylalcohol, parabens), lubricant (such as：Stearic acid, magnesium stearate, poly- second two Alcohol, lauryl sodium sulfate), glidant (such as：Cataloid), plasticizer (such as：Ethyl phthalate, lemon triethylenetetraminehexaacetic acid Ester), emulsifying agent (such as：Carbomer, hydroxypropyl cellulose, lauryl sodium sulfate), polymer coating agent (such as：Poloxamer or Moor Lip river sand amine), coating agent and film forming agent (such as：Ethyl cellulose, acrylate, polymethacrylates) and/or assistant agent.It is above-mentioned An every kind of independent embodiment for representing the present invention in excipient.
In another embodiment, provided herein is pharmaceutical composition be controlled release composition, i.e.,：Wherein polyunsaturated fat The composition of a period of time release of acid and/or uridine upon administration.The composition of controlled release composition or sustained release is included in Lipophilic depots are (such as：Aliphatic acid, wax, oil) in preparation.In another embodiment, the composition is immediate release composition, I.e.：The composition that wherein whole polyunsaturated fatty acids and/or uridine release immediately upon administration.
In another embodiment, described pharmaceutical composition delivers in controlled release system.Such as：It can be used intravenous defeated The reagent is administered in note, implantable osmotic pump, transdermal patch, liposome or other administering modes.In one embodiment, can make It is (above-mentioned referring to Langer with pumping；Sefton, CRCCrit.Ref.Biomed.Eng.14：201(1987)；Buchwald et al., Surgery 88：507(1980)；Saudek et al., N.Engl.J.Med.321：574(1989).In another embodiment, High molecular material can be used；Such as used in microballoon or implant.In yet another embodiment, controlled release system is placed in treatment Near target such as brain, a part for whole-body dose is so only needed (see, 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, the composition further include by active material incorporation high-molecular compound such as polylactic acid, Among or on the particulate preparation of polyglycolic acid, hydrogel etc., or mix to liposome, micro emulsion, protomere, single or multiple lift On vesica, blood shadow or spherical.) as composition will influence physical state, solubility, stability, in vivo release Speed and internal clearance rate.
Present invention additionally comprises with polymer (such as：Poloxamer or pool Lip river sand amine) coating particulate composition and with for The compound of the antibody coupling of tissue-specific receptors, ligand or antigen or the chemical combination with the ligand coupling of tissue-specific receptors Thing.
Present invention additionally comprises by the water-soluble polymer such as copolymer of polyethylene glycol, polyethylene glycol and polypropylene glycol, Carboxymethyl cellulose, glucan, polyvinyl alcohol, polyvinylpyrrolidone or polyproline covalent attachment modification compound. It is known with corresponding unmodified compound phase ratio, the half-life period of the compound of modification after intravenous injection in blood is notable Longer (Abuchowski et al., 1981；Newmark et al., 1982 and Katre et al., 1987).Such modification can also improve Compound solubility in aqueous, eliminate aggregation, enhancing compound physical and chemical stability and substantially reduce exempting from for compound Epidemic focus and reactivity.Therefore, such polymer-change is administered by dosage less than unmodified compound or more low frequency Compound adduct may obtain desired Biological acdtivity in vivo.
By mix, pelletize or tabletting method to prepare the preparation of the pharmaceutical composition comprising active component in this area be ripe Know.The active therapeutic ingredient is usually mixed with excipient pharmaceutically acceptable and compatible with the active ingredient.For mouth Clothes administration, by derivative such as salt, ester, N- oxides etc. that polyunsaturated fatty acid and/or uridine or its physiology are resistant to with In the purpose conventional additives such as carrier, stabilizer or inert diluent mix, and be converted into by conventional method it is appropriate Form of medication such as tablet, coated tablet, hard-gelatin capsules or Gelseal, aqueous pharmaceutical, alcoholic solution agent or oil solution Agent.For parenteral, derivative such as salt, ester, the N- oxygen that polyunsaturated fatty acid and/or uridine or its physiology are resistant to Compound etc. is converted into solution, supensoid agent or emulsion, if it is desired, then with for the conventional and suitable material such as hydrotropy of the purpose Agent or other materials convert together.
In another embodiment, active component is formulated into the combination as neutral pharmaceutically acceptable salt form Thing.Pharmaceutically acceptable salt includes and inorganic acid such as hydrochloric acid or phosphoric acid or organic acid such as acetic acid, oxalic acid, tartaric acid, mandelic acid Deng the acid-addition salts (being formed with the free amine group of polypeptide or antibody molecule) of formation.The salt formed from free carboxy could also be from The inorganic basis such as hydroxide of sodium, potassium, ammonium, calcium or iron and organic base for example isopropylamine, trimethylamine, 2- ethyl amido alcohols, Histidine, procaine etc..
Every kind of independent implementation for representing the present invention in above-mentioned additive, excipient, preparation and medication Scheme.
EXPERIMENTAL DETAILS
Embodiment 1
Phosphatide is improved with omega-fatty acid processing PC-12 cells to synthesize
Material and experimental method
Reagent
Obtained from Perkin-Elmer (Boston, MA)14The choline chloride of C flag.From Biomol (Plymouth Meeting, PA) obtain DHA, oleic acid or palmitic acid.Obtained from AmershamBiosciences Corp (Piscataway, NJ) 14C- choline.
Cell culture
PC-12 cells are maintained in+10% hyclone (FBS) of Dahl Burke Improved Eagle Medium (DMEM). To be tested, by cell growth in 35 millimeters of (mm) culture dishes of quintuplicate collagen bed board.Cell is being contained 28 μM When culture 18 is small in the DMEM without serum of +/- 5 micromole (μM) DHA of choline, oleic acid or palmitic acid (hr).Then containing With 0.5 micromicrocurie (μ Ci)/ml's in the DMEM without serum of 10 micromole (μM) choline14When C- choline mark 2.5 is small.
Mark phosphatide quantifies
With tissue homogenizer (Polytron PT 10-35, Kinematica AG, Switzerland) by cell 100 It is homogenized in the ice-cold deionized water of volume；Then by the equal portions of 1ml and 3ml chloroforms+carbinol mixture (2: 1 volume/volume) Mixing, is acutely vortexed 30 seconds.After when cooled on ice 1 is small, by mixture successively with 3ml chloroforms+carbinol mixture (2: 1 volumes/ Volume) and 1ml it is ice-cold deionized water mixing.Mixture is acutely vortexed, is subsequently placed in cold room overnight when small (18).Pass through Centrifugation (10 minutes, 4 DEG C；1000g) the organic phase (lower floor) and water phase (upper strata) of separating mixture.By the upper of an equal portions (2ml) Layer is mutually used to measure CDP-choline (seeing below), and 0.1-0.4ml lower floors equal parts are dried in vacuo, and is analyzed for phosphatide.It is logical Measurement phosphorus is crossed to measure the total phospholipids content in remaining 0.1ml lower floors equal parts.By remaining 0.4ml lower floors equal parts 40 Replicated in μ l methanol, use silica G plates (Adsorbosil Plus-1, Alltech) and carry out thin-layered chromatography, flowing The mutually system to be made of chloroform/ethanol/triethylamine/water (30: 34: 30: 8).With 0.1% diphenyl hexatriene in petroleum ether In solution to after spraying on plate, differentiate corresponding band under ultraviolet lamp with phosphatide standard items.By each phosphatide classification (PC, PE, SM, PS and PI) band scraped from plate, be extracted into 1ml methanol；It is dried in vacuo and is used to measure phosphorus content.By with it is every What secondary measure carried out together uses KH2PO4Standard curve comparative measurements total phosphorus content.0.5ml 4.5% is added into each sample HClO4/ 27%H2SO4And by each test tube when 180 DEG C of heating 3 are small.After being cooled to room temperature, 5ml colour reagents are added (respectively For 10: 1 dilute solution containing 2.5mg/ml ammonium molybdates, 8.2mg/ml sodium acetates and 100mg/ml ascorbic acid), by test tube When culture 2 is small at 37 DEG C.With the trap of spectrophotometer measurement 820nm.Phosphorus content is multiplied by 25 and obtains phosphatide quality.
Statistical analysis
Data are examined to be analyzed through one-way analysis of variance (variance analysis), then Si Shi t.
As a result
For the influence that synthesize to phosphatide of evaluation omega-fatty acid, when preculture 18 is small presence or absence of under by DHA after, general PC-12 cells with14The choline culture of C flag.Then the incorporation marked in phosphatide is measured.Be not belonging to omega-fatty acid oleic acid and Palmitic acid is used as negative control.By with DHA precultures, improve to the synthesis conspicuousness of phosphatidyl choline (PC), but oleic acid or Palmitic acid not effect, (Fig. 1) proved such as the incorporation increase marked in PC.Therefore, handled and improved with omega-fatty acid Cellular phospholipid synthesizes.
Embodiment 2
Omega-fatty acid improves the synthesis of a variety of phosphatide with dosage-dependent manner
The stimulation synthesized for further characterization omega-fatty acid to phosphatide, PC-12 is pre-processed with the DHA of various dose Cell, and the choline of mark is exposed to, as described in Example 1, then measure in phosphatide14The incorporation of C flag.It is pre- with DHA Processing improves the synthesis (Fig. 2) of phosphatide.The increase of synthesis is dose-dependent.Therefore, omega-fatty acid is with dose-dependant Property mode stimulates phosphatide to synthesize.
Embodiment 3
Phosphatide is improved with ω -6 fatty acid treatment SHSY-5Y cells to synthesize
Material and experimental method
Cell culture
SHSY-5Y cells grow to close be paved with 35mm culture dishes in DMEM+10%FBS.By cell containing When culture 18 is small in the DMEM+1%FBS without serum of the +/- 10 μM of DHA of 30 μM of choline, arachidonic acid or palmitic acid.So Afterwards by cell marking, quantitative mark phosphatide as described in Example 1.
The preparation of DHA-BSA compounds
It is 100 micromoles that DHA, which is dissolved in ethanol to concentration, is freezed at -80 DEG C with 10 microlitres of equal portions.For each reality Test, an equal portions be diluted to 10 micromoles in ethanol, it would be desirable to the final solution in the medium of volume with it is isometric BSA solution (1gm/ml) mixes.
As a result
Next research ω -6 aliphatic acid is to human neuroblastoma cell --- phosphatide synthesizes in SHSY-5Y cells Influence.In this embodiment, arachidonic acid (a kind of ω -6 aliphatic acid) improves phosphatide synthesis, but DHA or palmitic acid are without this Act on (Fig. 3 A).
Embodiment 4
ω -6 aliphatic acid improves the synthesis of a variety of phosphatide with dosage-dependent manner
The influence that arachidonic acid synthesizes phosphatide in SHSY-5Y cells is further characterized, as described in Example 2 Omega-fatty acid and PC-12 cells are such.Arachidonic acid under a series of dosage with dosage-dependent manner improve total phospholipids, The synthesis of PC and phosphatidyl-ethanolamine, as seen by for DHA (Fig. 3 B).Therefore, ω -6 aliphatic acid is with dosage-dependent manner Stimulate the synthesis of a variety of phosphatide.
Embodiment 5
Polyunsaturated fatty acid is administered and improves cephalin level, and adding uridine causes further collaboration to improve
Material and experimental method
Diet
Reference standard diet (table 4) is by 16% protein rodent diet (Harlan of Teklad Global Teklad, Madison, WI) composition, it contains 0.1% choline chloride (CC), and corresponding daily dose is 50mg/kg/ days.UMP With 0.5%UMP2Na+The form of w/w provides, and adds in control diet, is also prepared by Harlan Teklad, corresponding In 240mg/kg/ days UMP.The dosage of DHA is 300mg/kg/ days, is that 5% gum arabic of 200 microlitres of (mcL)/days is molten Liquid, the group without receiving DHA only receive carrier (5% gum arabic).DHA is carried by Nu-Chek Prep (Elysian, MN) For UMP is provided by Numico (Wagenigen, NL).
Significant changes of weight is not all shown for any group during the experiment.
4. reference standard diet of table
The collection of brain
Gerbil jird is anaesthetized with ketamine and xylazine (80 and 10mg/kg weight, peritonaeum in), liquid nitrogen is immersed on its head In 2 minutes, then break end and put to death.Rapid (30 seconds) brain is taken out with rongeur immediately and is stored in -80 DEG C.
The measurement of cephalin
The brain hemisphere of freezing is weighed, with tissue homogenizer (Polytron PT 10-35, KinematicaAG, Switzerland) it is homogenized in the ice-cold deionized water of 100 volumes, is then analyzed as described in Example 1.
DNA and protein determination
Measure protein in full brain homogenate samples so as to using dihomocinchonine acid reagent (PerkinElmer, Norwalk, CT, USA).The measurement of DNA by measure transmitting of the sample in fluorescence photometer in the presence of bisbenzimidazole at 460nm come into OK, bisbenzimidazole is a kind of fluorescent dye (American Hoechst for being known as Hoechst H 33258 Corporation), its maximum excitation wavelength with 356nm, and maximum emission wavelength is 458nm when being combined with DNA.
As a result
The gerbil jird that weight is 80-100g is divided into 4 groups, every group 8, the enriching substance described in table 1 is administered：
1. treatment group of table
After 4 weeks, animal is put to death, measure 1 is except decerebellation and the total phospholipids and PC, phosphatidyl-ethanolamine of the brain hemisphere of brain stem (PE), the content of sphingomyelins (SM), phosphatidylinositols (PI) and phosphatidylserine (PS).Omega-fatty acid (DHA) makes total phosphorus Lipid level improves to conspicuousness the level (Fig. 4 and table 2 and 3) higher than control group.The combination of DHA and UMP causes concertedness Further improve (26%) (i.e.：Higher than observed in DHA groups (12%) and UMP groups (5%) elevated and).For each phosphorus Fat observed similar result (table 2 and table 3).The value of phosphatide is whether normalized to amount (Fig. 4 A and the table of protein 2) or the amount (Fig. 4 B and table 3) to DNA, it all observed statistical conspicuousness.
Table 2：The influence of DHA, UMP or two kinds of processing to cephalin level, phospholipid level are standardized to protein level. Data representation is the +/- standard error of mean of average value (SEM).Statistical analysis is examined using two-way analysis of variance and Tukey. “*" represent P ＜ 0.05 compared with the control；“**"-P ＜ 0.01；“***"-P ＜ 0.001.
Table 3：The influence of DHA, UMP or two kinds of processing to cephalin level, phospholipid level are standardized to DNA level.System Count credit analysis/data representation such as table 2.
These results confirm above example as a result, showing that omega-fatty acid and ω -6 aliphatic acid improve cephalin Synthesis and cephalin are horizontal, have both improved total phosphorus lipid level or have improved the level of single phosphatide.These results further demonstrate that, more Unrighted acid causes further to cooperate with raising with the combination of uridine.In addition, these results indicate that polyunsaturated fatty acid Stimulation to phosphatide synthesis is general phenomenon, is not limited to specific phosphatide or experimental model.
Form four kinds of structure phosphatide (these four phosphatide of a large amount of cell membranes in brain：PC, PE, PS and sphingomyelins) improve ratio Example approximately equal, these four compounds are every kind of all to improve about 20%.Therefore, the ratio of four kinds of structure phosphatide in film is maintained.Phase Ying Di, film quality are improved without destroying normal membrane structure and function.These results confirm what is obtained from previous embodiment Data, further evidence is provided for the composition for improved and enhancing brain function of the present invention.
Embodiment 6
Brain CDP-choline level is reduced to gerbil jird administration omega-fatty acid and improves cephalin level
Material and experimental method
CDP-choline determination method
The upper strata (water) of equal portions (2ml) is mutually dried in vacuo, replicates and injects in HPLC.Dry sample is in 100-200 μ Replicate in l water and analyzed by HPLC on anion-exchange column (AlltechHypersil APS-2,5mm, 250X4.6mm). Buffer A (the H of CDP-choline linear gradient3PO4, 1.75mM, pH 2.9) and B (NaH2PO2, 500mM, pH 4.5) and elution, The linear gradient is from 0 to 100%B in 30 minutes.Using the system, CDP-choline and 40 minutes in constant gradient system Time in material such as UMP points of proximally co-elute open.The retention time of CDP-choline is 9.5 minutes.In each experiment knot Shu Houhe rinsed pillar to remove the nucleotide of reservation every several days with buffer B.Each nucleotide peak UV absorption is 280 Detected at nm, by being identified compared with the position of true standard product and by adding nucleotide standard items into sample.
As a result
For influence of the measure administration polyunsaturated fatty acid to CDP-choline level, measure in previous embodiment in animal Brain CDP-choline is horizontal.Administration DHA and/or UMP reduces CDP-choline horizontal (Fig. 5 A) and CDP- ethanol amine level (Fig. 5 B). DHA makes CDP-choline is horizontal to reduce by 26% (compared with only receiving the group of carrier of control diet and DHA), in the sand of UMP- processing 21% (compared with only receiving the group of carrier of the diet containing UMP and DHA) (being all P ＜ 0.05) is reduced in mouse.Dual factors side Difference analysis finds that DHA has the [F (1,28)=31.7 that has a significant impact；P ＜ 0.001].
In another study, add UMP into standard diet and do not improved at the same time with DHA processing conspicuousnesses in brain PC, PE and PI are horizontal, are respectively increased 13%, 29% and 48% (table 5A).Administration DHA improves this without UMP also conspicuousness A little phosphatide level (being respectively increased 22%, 20% and 52%) in brain and sphingomyelin levels (improving 24%).UMP+DHA makes Whole phosphatide improve, the sum which improves caused by being more than UMP or DHA individually.
Then, it have studied the time-histories of these raisings.After handling 1 week, UMP does not produce the influence of conspicuousness, and UMP+DHA Brain PC (21%) and PS (38%) is set to have slight but conspicuousness raising.Handled 3 weeks with UMP+DHA and cause all 5 kinds of phosphatide Conspicuousness improves (21-48%), and single UMP causes raising (table 5B) that is smaller but still being conspicuousness.
Table 5：The influence of UMP and/or polyunsaturated fatty acid to cephalin level
Therefore, under these conditions, be administered influence of the polyunsaturated fatty acid to cephalin be attributable to CDP-choline to The conversion increase of PC and related phosphatide.
Embodiment 7
Omega-fatty acid is administered to gerbil jird and/or uridine improves synapsin level
Material and experimental method
The horizontal determination method of synapsin
Synapsin is measured with slot blot method and immunoblotting.For immunoblotting, by brain homogenate thing etc. Part mixes with 2X KFL sample loading buffers, boils 5 minutes, then carries out gel electrophoresis.It is loaded the protein of equivalent and uses SDS- PAGE (4-20%；Bio-Rad, Hercules, CA, USA) separation.Then by Protein transfer to pvdf membrane (Immobilon-P, Millipore, Billerica, MA, USA).With 4% skimmed milk power (Varnation, Glendale, CA, USA) remaining binding site is closed 30 minutes in Tris buffered salines-tween (TBST).2X KFL sample loading buffers are such as Lower preparation：Mix 3.76ml 1M TRIS, pH 6.8；20% lauryl sodium sulfate of 6ml；6ml glycerine；1.5ml sulfydryl second Alcohol；1% bromophenol blues of 2ml and 10.74ml water.
For slot blot method, by two sets of equal portions (18-21 μ l from brain homogenate thing in deionized water；Containing 20 μ g eggs White matter) use slot blot microfilter device [Minifold (R) II Slot BlotSystem (SCR 072/0)；Schleicher ＆ Schuell, Inc., Keene, NH, USA] by the direct trace of vacuum filter in polyvinylidene fluoride film (Immobilon-P, Millipore, Billerica, MA, USA) on.Remaining binding site with 4% skimmed milk power (Varnation, Glendale, CA, USA) closed 30 minutes in TBST.Then by film (from slot blot method and immunoblotting) in TBST buffer solutions Cleaning 5 times, immerses containing important antibody (the anti-NF-70 of mouse, rabbit-anti-NF-M, the anti-PSD-95 of mouse and the anti-cynapse fusion of mouse Albumen -1) TBST solution in.Overnight incubation and with after TBST buffer solution for cleaning 5 times, by trace and appropriate connection peroxidating When the secondary antibody culture 1 of thing enzyme is small.Then trace is cleaned 5 times in TBST buffer solutions, uses ECL systems (Amersham Biosciences, Piscataway, NJ, USA) and Kodak X-AR egative films detect and the protein-antibody complexes that develop.Make Will with the SupervistaS-12 scanners (UMAX Technologies, Freemont, CA, USA) equipped with transparency adapter Film digitization.Public Domain NIH Image program relative immunity reactivity bands are used by optical densitometric method.Absorbance Area under the curve is standardized as the percentage of the absorbance that control group produces in identical trace.Protein level is expressed as pair According to these the percentage in animal.
As a result
Measure the brain level of 4 kinds of synapsins in the animal for receiving the UMP and DHA measured described in embodiment 5.Processing 3 or 4 Zhou Hou, neural process nerve fibril albumen NF-70 and NF-M increase 43% (P ＜ 0.01) or 102% (P ＜ 0.001) respectively With 19% (P ＜ 0.05) or 48% (P ＜ 0.01) (Fig. 6).Postsynaptic density albumen PSD-95 and vesicle protein cynapse fusion egg In vain -1 level increase 38% and 41% (being all P ＜ 0.001) after 3 weeks, increased after 1 week 35% (P ＜ 0.01) or 25% (P ＜ 0.05) (Fig. 7).
These results further prove, polyunsaturated fatty acid is administered and uridine improves the amount of synaptic membrane.These improve with Those observed in phospholipid level are similar, show that synaptic levels raise in brain.
Embodiment 8
It is horizontal that DHA, EPA and AA improve cephalin
Material and experimental method
To adult gerbil jird administration reference standard diet (table 4), contain or not contain 0.5%UMP and/or 300mg/kg/ days DHA, EPA or AA.The group drug administration carrier (5% gum arabic) of DHA is not received.
As a result
Administration UMP and/or the polyunsaturated fatty acid gerbil jird of 3 weeks is put to death, measures the level of various cephalins.Such as table 6 Shown, DHA, EPA and AA improve phospholipid level.
Table 6：It is horizontal that the cephalin after polyunsaturated fatty acid and/or uridine is administered
Embodiment 9
Omega-fatty acid and uridine improve the number of adult and developmental gerbil jird and the dendritic spines in rat brain
In two weeks, normal adult gerbil jird control diet is given daily or is supplemented with UMP (240mg uridines/kg) and DHA The diet of (gavage, 300mg/kg).After treatment, by animal sacrificed by decapitation, with carbocyanine film tracer DiI (C18) 3 (" DiI, " Molecular Probes, Eugene, OR) fixed hippocampal slices are dyed.Sea is obtained from two-photon microfilm The image of horse neuron.In the animal of DHA+UMP is received, dendritic spines density (per unit length in hippocampus CA1 cone neurone Dendron in spine number) improve to conspicuousness and (improve 27%, p=.001 compared with the control；(Fig. 8).
In another study, make gestation rat freely consumed before childbirth 10 days, lactation when freely consume 20 days Control diet containing choline or be supplemented with UMP forms uridine the diet, every group of half also connect by gavage daily By DHA or its dilution.Then young rat is put to death, checks brain section to measure the number of hippocampus dendritic spines.Single UMP and individually DHA all improve the level of dendritic spines number, and both combinations cause to further improve (table 7).
Table 7：The raising of dendritic spines number in developmental animal after UMP and DHA is administered
Embodiment 10
DHA and UMP improves study
Material and experimental method
Gerbil jird can freely obtain food and water until on the day of experiment test, in that day, be stayed overnight when small to its fasting 17 first, Then food is provided from 11AM to 6PM.Gerbil jird started from 4 weeks before 3 monthly ages, Behavioral training dietary supplementations have UMP mouse grain and/ Or 300mg/kg DHA (every group of n=8), until training terminates.Animal is operated daily first, continues 4 days, so that they It is accustomed to Conventional contact.Then them was familiar with labyrinth in 4 days again, this by by food grain be placed in labyrinth arm everywhere and allow 3 Minute is found to carry out.Gerbil jird receives 1 experiment/day, every time between experiment by all surface with 10% ethanol disinfection.Training package Include for all experiments, food grain is placed in identical two labyrinths arm distal end.Gerbil jird is placed in labyrinth center, it is allowed to 2 points Clock finds food grain.When gerbil jird be again introduced into equipped with food grain and previously in test to cross labyrinth arm in when, occur Working memory error.When gerbil jird, which enters, is not charged with the labyrinth arm of food grain in previous test, reference memory mistake occurs.Record The percentage of the food grain found.
As a result
To measure the influence of uridine and/or DHA to study, to the animal of diet of the animal administration containing uridine and/or DHA And recall tests are carried out to it.DHA and UMP improves the percentage (Fig. 9) for the animal that can complete task.
Embodiment 11
The cephalin being administered to gestation and lactation mother in DHA and UMP raising offsprings is horizontal
As described in example 9 above, to gestation and lactation rat administration DHA and/or uridine.20 days after birth, place Dead rat, obtains brain sample, measures phosphatide.Being administered alone DHA makes PC, PI, PE and sphingomyelins of each cell (DNA) in brain (SM) it has been respectively increased 36%, 166%, 38% and 78%.The effect of DHA is significantly expanded to the 66% of control by UMP, 210%, 68% and 99% (table 8).These improve the raising for being more than and being observed in adults.When being normalized to protein, obtain Similar result (table 9).Therefore, the phosphatide in offspring can be improved to gestation and lactation mother administration DHA and/or uridine It is horizontal.
Table 8：The average phospholipid level (nmol/mg protein) of the 20th day after young rat birth.Compared with the control：*P ＜ .05,**P ＜ .001.Value in bracket is raising percentage compared with the control.
Table 9：The average phospholipid level (nmol/ micrograms of DNA) of the 20th day after young rat birth.Compared with the control：*P ＜ .05,** P ＜ .001.Value in bracket is raising percentage compared with the control.
Embodiment 12
Omega-fatty acid improves the lipid synthesis in the neuron in Short-term Culture thing
Material and experimental method
Hippocampal cell is cultivated 3 weeks in Neutrobasal plus B27 culture mediums, to reaching full maturity.It is real The same day is tested, by cell and DMEM+ choline cultures, adds or be added without DHA.Add14C- choline, by cell be further cultured for 2 it is small when, such as Extract and measure what is newly formed described in embodiment 114The PC of C flag.
As a result
For influences of the measure DHA to phosphatide in the neuron in Short-term Culture thing, neuron is pre-processed with DHA+ choline.With Only the cell (" control ") of administration choline is compared, and DHA makes the synthesis of phosphatide improve (Figure 10 more than 2 times；P=0.04).These knots Fruit confirms that DHA improves the phospholipid level in brain cell and nerve cell.

Claims (11)

  1. (1. a) docosahexaenoic acid；(b) uridine；Choline preparing nerve cell or brain cell for improve individual (c) Dendritic spines amount medicine in purposes, wherein the dosage of the uridine is 10-500mg uridines/day, and the choline Dosage is 100mg-10g/ days.
  2. 2. the purposes of claim 1, wherein women of the individual for gestation.
  3. 3. the purposes of claim 1, wherein the docosahexaenoic acid is by improving nerve cell or brain cell to phosphatide Synthesize to improve the amount of the phosphatide.
  4. 4. the purposes of claim 3, wherein the phosphatide is phosphatidyl choline, phosphatidyl-ethanolamine, phosphatidylinositols, phosphatidyl Serine or sphingomyelins.
  5. 5. the purposes of claim 1, wherein the choline is choline salt.
  6. 6. the purposes of claim 5, wherein the choline salt is choline chloride, choline bitartrate, choline citrate or winestone Sour choline.
  7. 7. the purposes of claim 1, wherein the medicine is nutritional supplement.
  8. 8. the purposes of claim 1, wherein the uridine be the phosphoric acid (UMP) of uridine -5 '-one, uridine -5 '-diphosphonic acid (UDP) or Uridine -5 '-triphosphoric acid (UTP).
  9. 9. the purposes of claim 1, wherein the uridine is the phosphoric acid (UMP) of uridine -5 '-one.
  10. 10. the purposes of claim 1, wherein (a) is docosahexaenoic acid, (b) is the disodium hydrogen phosphate (UMP of uridine -5 '-one 2Na+), and (c) is choline chloride.
  11. 11. the purposes of claim 1, wherein the content of the choline is 200mg to about 6g choline salts.
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 CN101495490A (en) 2009-07-29
CN101495490B true 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)

Families Citing this family (6)

* 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
US20140316003A1 (en) * 2011-10-21 2014-10-23 Omthera Pharmaceuticals, Inc. Methods and compositions for treating or preventing attention deficit hyperactivity disorder
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
US20190125721A1 (en) * 2016-05-04 2019-05-02 Neurotrope Bioscience, Inc. Methods and compositions for treatment of rett syndrome
AU2017289278A1 (en) * 2016-06-27 2019-01-17 Ohio State Innovation Foundation Liponucleotide-based therapy for ARDS

Family Cites Families (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

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Simopoulos et al..Workshop on the essentiality of and Recommended Dietary Intakes for Omega-6 and Omega-3 Fatty Acids.《Journal of the American College of Nutrition》.1999,第18卷(第5期),487-489. *
Wayne S. Fenton, M.D.，et al..A Placebo-Controlled Trial of Omega-3 Fatty Acid.《Am J Psychiatry》.2001,第158卷(第12期),2071–2074. *

Also Published As

Publication number Publication date
CN101506218A (en) 2009-08-12
CN101495490A (en) 2009-07-29

Similar Documents

Publication Publication Date Title
US10736912B2 (en) Compositions containing PUFA and/or uridine and methods of use thereof
CN101495490B (en) Composition and its application method containing polyunsaturated fatty acid and/or uridine
CN104721203A (en) Glycerophospholipids for the improvement of cognitive functions
CN106902104A (en) Method for treating neurotrosis
CN106535881A (en) Compositions and methods to promote bone formation
RU2429851C2 (en) Compositions containing pufa and/or uridine, and methods of application thereof
AU2012203650B2 (en) Compositions containing PUFA 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
CN117618448A (en) Composition for improving memory, preparation and preparation method thereof
AU2014274585A1 (en) Compositions containing pufa and/or uridine 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