CN104367587B - Application of the nicotinamide mononucleotide after rush cerebral ischemia is prepared in nerve regneration drug - Google Patents
Application of the nicotinamide mononucleotide after rush cerebral ischemia is prepared in nerve regneration drug Download PDFInfo
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
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Abstract
The present invention relates to pharmaceutical technology fields.The present invention provides application of the nicotinamide mononucleotide after rush cerebral ischemia is prepared in nerve regneration drug.Nicotinamide mononucleotide of the present invention can be used as active pharmaceutical ingredient and pharmaceutically acceptable auxiliary material to be prepared into pharmaceutical composition.Since nicotinamide mononucleotide compound is body Endogenous protective substances in itself, available data is not yet reported for work its adverse reaction, therefore safe as drug or health products, treats window width.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to nicotinamide mononucleotide prepare promote nerve regneration drug or
Application in health food.
Background technology
Cerebral arterial thrombosis is a kind of common disease for seriously endangering human health, and disability rate is very high.Cerebral apoplexy is survived
Person often leaves different degrees of dysfunction, seriously affects the quality of life of patient, and heavy burden is brought to society and family.
The study found that case fatality rate and disability rate can effectively be reduced by carrying out scientific and rational intervention to cerebral stroke at acute period correlative factor.
Traditional view is thought, after cerebral ischemia generation,
Due to ischemic necrosis neuron be not resilient or regenerated because nerve exist only in embryonic period, embryonic phase and
Birth early stage.But recent researches are found in the olfactory bulb of adults, hippocampus and telocoele there are a large amount of neural stem cell,
These stem cells can break up neuroblast in life process, this is found to be nervous system injury and disease brings new control
Treatment theory.Neural stem cell can be divided into the various nerve cells such as neuron, Deiter's cells, this mistake under incentive condition
Journey is regulated and controled by endogenous and extrinsic factor.
According to the record of state food and drug administration, currently on the market without refreshing for promoting after cerebral ischemia
Through regenerated drug.
Nicotinamide mononucleotide（Nicotinamide mononucleotide, abbreviation NMN）It is a kind of existing interior in vivo
Property substance in source can carry out iii vitro chemical synthesis at present.It has now been found that it plays the role of reducing blood glucose（Referring to document：
Yoshino J,et al.,Nicotinamide mononucleotide,a key NAD(+)intermediate,treats
the pathophysiology of diet-and age-induced diabetes in mice,Cell
Metab.2011Oct5;14(4):528-36.）.Whether Neural Stem Cells can be promoted for nicotinamide mononucleotide
Break up and migrate, improve nervous function, improve survival, quality of life aspect there is not yet document report.
Invention content
The purpose of the present invention is to provide the new applications of nicotinamide mononucleotide, that is, provide nicotinamide mononucleotide and preparing
Promote the application in nerve regneration drug or health food..
The present inventor passes through lot of experiments, surprisingly finds：Nicotinamide mononucleotide, which has, promotes nerve regneration to make
With, and the functional of the cranial nerve caused by ischemic can be effectively improved.The present invention is hindered using intraluminal middle cerebral artery occlusion in rats
It is disconnected to prepare cerebral ischemic model, further inquired into this compound of nicotinamide mononucleotide in 7-14 days after ischemic it is neural again
Raw influence.
The present invention provides nicotinamide mononucleotide answering in the drug or health food that promote nerve regneration is prepared
With.
Invention further provides nicotinamide mononucleotide prepare promote cerebral ischemia after nerve regneration drug or guarantor
Application in health food.
Nicotinamide mononucleotide of the present invention is the nicotinamide mononucleotide of this field routine, is existed in human body
Endogenous material, can also artificial synthesized or for direct gained purchased in market commodity.The chemistry of the nicotinamide mononucleotide
Structural formula is as shown in formula I：
Nicotinamide mononucleotide of the present invention can be used as active pharmaceutical ingredient and pharmaceutically acceptable auxiliary material to prepare
Into pharmaceutical composition.Wherein, the active pharmaceutical ingredient nicotinamide mononucleotide is the aforementioned nicotinamide mononucleotide of the present invention.
Wherein described pharmaceutically acceptable auxiliary material refers to the excipient substance of art of pharmacy routine.The pharmaceutically acceptable auxiliary material
Including：Diluent, excipient, adhesive, filler and one or more of agent of bursting apart, the excipient substance further include flavor
Substance.Wherein described excipient is preferably water；Described adhesive is preferably：Cellulose derivative, gelatin or polyethylene pyrrole
Pyrrolidone；The filler is preferably starch, and the disintegrant is preferably：Calcium carbonate or sodium bicarbonate.The flavor substances
Matter refers to the substance that taste or flavor for improvement pharmaceutical composition add, and the flavor substance preferably includes various fragrance
Agent, essence and/or sweetener.
Wherein the dosage form of described pharmaceutical composition is this field regular dosage form.The dosage form of described pharmaceutical composition is given according to it
The ingredient of medicine approach or excipient substance, is preferably comprised：Tablet, pulvis, capsule, parenteral solution, drops or transdermal gel preparation.
The administration route of wherein described pharmaceutical composition is preferably comprised：Oral medication, drug administration by injection, mucosal drug delivery or saturating
Skin is administered.The mode of wherein described drug administration by injection is preferably comprised：Intraperitoneal injection, be subcutaneously injected, intravenous injection, intramuscular injection or
It is injected in lymph node.
In described pharmaceutical composition, the content of nicotinamide mononucleotide is preferably 0.1%~99.9%, and content is preferably
It is 0.5~99.9%, the percentage is mass percent.
The individual of described pharmaceutical composition treatment is preferably human or animal, and the dosage of described pharmaceutical composition is preferable
Ground is 1~1000mg/ kg body weights/day, and specifically used amount can suitably be adjusted according to age, state of an illness of Different Individual etc.
It is whole.
For the present invention in addition to special instruction, the percentage is all mass percent.
On the basis of common knowledge of the art, above-mentioned each optimum condition can be combined arbitrarily to get each preferable reality of the present invention
Example.The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is：
1st, the present invention provides nicotinamide mononucleotides（NMN）The drug of nerve regneration after promotion cerebral ischemia is prepared
Or the application in health food.The compound can effectively facilitate more neural stem cell to ripe neural cellular differentiation,
Nervous function damage caused by improving brain diseases, makes up the nerve cell lost in above-mentioned lysis, is substantially improved
Memory function is practised, is of great significance to neurological impairments recovery.
2nd, nicotinamide mononucleotide administration route type is compared with horn of plenty, according to different dosage forms can by oral, injection or
The approach such as person's mucosal drug delivery are applied to the individual for the treatment of.
3rd, nicotinamide mononucleotide compound is body Endogenous protective substances in itself, and available data is not yet reported for work, and its is bad
Reaction, thus it is safe as drug or health products, treat window width.
Description of the drawings
Hippocampal dentate areas of the Fig. 1 to give nicotinamide mononucleotide group mouse after cerebral ischemic model group and cerebral ischemia
BrdU/DCX Positive Cell Counts figures；
Wherein A dyes schematic diagram for Double immune fluorescent；B is statistical chart；BrdU/DCX positive cells are newborn migration
Neuron（Arrow logo）.
Hippocampal dentate areas of the Fig. 2 to give nicotinamide mononucleotide group mouse after cerebral ischemic model group and cerebral ischemia
BrdU/NeuN Positive Cell Counts figures；
Wherein A dyes schematic diagram for Double immune fluorescent；B is statistical chart；BrdU/NeuN positive cells are newborn maturation
Neuron（Arrow logo）.
14 day learning and memory functions of the Fig. 3 to give nicotinamide mononucleotide group mouse after cerebral ischemic model group and cerebral ischemia
Comparison diagram；
Wherein A is water maze laboratory schematic diagram；B is escapes latent experiment statistics figure；C is the long-distance statistical chart in path.
Fig. 4 is proliferative conditions of the in vitro culture neural stem cell after control drug and nicotinamide mononucleotide is given；
Wherein A is immunofluorescence dyeing schematic diagram；B is statistical chart.
Specific embodiment
In conjunction with embodiment and attached drawing, the present invention is described in detail, but the implementation of the present invention is not limited only to this.
The reagents and materials used in the present invention are commercially available or can be prepared by literature method.Tool is not specified in the following example
The experimental method of concrete conditions in the establishment of a specific crime, usually according to normal condition or according to the normal condition proposed by manufacturer.
Embodiment 1
It is blocked using mouse brain middle arteries and prepares brain damage model, model preparation process is as follows：By mouse（C57BL/6J,
It is purchased from Shanghai Si Laike experimental animals Co., Ltd）Anesthesia（4% chloraldurate, 0.1ml/10g, intraperitoneal injection）Implement brain soldier afterwards
Middle operation（1. mouse selects 5-0 monofilament nylon sutures, the final diameter on top is 0.150~0.200mm.Veutro neck is hit exactly
Notch, further blunt separation sternohyoideus, breastbone papillary muscle and omohyoid, exposure right carotid（CCA）With
Right side external carotid artery（ECA）.2. the proximal end of CCA and the section start of external carotid artery 3-0 suture ligatures.3. internal carotid（ICA）
It is relaxed and ligatured with 3-0 sutures, and determine that it does not have branch to be tied.4. it under arteria carotis communis bifurcated at 3mm, is relaxed with 6-0 sutures
Ligation, to mark the position of arteriotomy and prevent bleeding.5. the position for the 6-0 sutures that are near at hand at arteriotomy.⑥
Bolt line is carefully injected to encephalic, and the depth of insertion is counted from crotch, mouse 9-11mm.At this point, slight resistance shows bolt line
Top have been located in the proximal end of arteria cerebri anterior, blocking the origin of artery and posterior communicating artery in ipsilateral cerebral.）Cerebral apoplexy 2
Hour takes out tether wires Reperfu- sion.
Nicotinamide mononucleotide is injected intraperitoneally in administration group（NMN）（It is purchased from Sigma Co., USA）500mg/kg/day (physiology
Saline) successive administration 9 days；Continuous 9 days of control group injection normal saline.All animals were injected intraperitoneally at the 3rd~5 day
5- bromodeoxyuridines nucleosides (5-bromodeoxyuridine, Brdu are purchased from Sigma companies) 300mg/kg, in the 9th day through more
Polyformaldehyde heart perfusion takes brain to cook frozen section and carries out immunohistochemical staining after fixing.
Newborn neuron proliferation apoptosis uses 5- bromodeoxyuridine nucleosides antibody（BrdU is purchased from Abcam companies）With double skins
Quality antibody（Doublecortin is purchased from Santa Cruz companies）Carry out Double immunofluorescence detection；Newborn maturation nerve
Member uses 5- bromodeoxyuridine nucleosides antibody（BrdU is purchased from Abcam companies）With neuronal glutamate transporter antibody（neuron
NeuN is purchased from Millipore companies）Carry out Double immunofluorescence detection.The detection method of Double immunofluorescence can refer to：Pei
Wang,Chao-Yu Miao,et al.Induction of autophagy contributes to the
neuroprotection of nicotinamide phosphoribosyltransferase in cerebral
ischemic stroke,Autophagy8:1,1–11;January1,2012。
As shown in Figure 1, nicotinamide mononucleotide（NMN）Newborn migration neuron number can be effectively increased.Such as Fig. 2 institutes
Show, nicotinamide mononucleotide（NMN）The ripe neuronal quantity of new life in mouse post-stroke hippocampus DG areas can be significantly improved.These
As a result illustrate that nicotinamide mononucleotide can promote the nerve regneration after ischemic on animal cerebral ischemic model.
Embodiment 2
It is blocked using mouse brain middle arteries and prepares brain damage model, model preparation process is the same as embodiment 1.
Nicotinamide mononucleotide is injected intraperitoneally in administration group（NMN）（It is purchased from Sigma Co., USA）500mg/kg/day (physiology
Saline) successive administration 9 days；Continuous 9 days of control group injection normal saline.
After 14 days, the learning and memory function of two groups of mouse is evaluated using Morris water maze laboratories.Morris water
Maze experiment step is as follows：(1) mouse is faced into pool wall into the water, is put into East, West, South, North four direction at random and is used as
Beginning position.Record mouse finds the time of underwater platform（Second）Path length with finding platform（Rice）.It is preceding several times train in,
If mouse found the time of underwater platform more than 60 seconds, guiding mouse is needed to find platform and be placed on stopping on platform
10 seconds.(2) mouse is fetched, dry after be placed under incandescent lamp and dry, put back in cage.Training 4 times daily of every mouse, are instructed twice
It is 15~20 minutes to practice time interval, continuous training 5 days.Record escapes latent time with escaping path length and uniting to it
Meter analysis.
As shown in figure 3, nicotinamide mononucleotide（NMN）The learning and memory function after focal cerebral ischemia can effectively be enhanced, said
The bright drug plays the role of promoting nerve regeneratl.
Embodiment 3
Using the neural stem cell of in vitro culture, control group gives physiological saline, nicotinamide mononucleotide（NMN is purchased from
Sigma companies）Administration, dosage are 300 μM.
The neural stem cell process of in vitro culture is as follows：Take pregnant mouse（Pregnant 14-15 days age）Cervical dislocation is put to death, after cleaning,
It takes out tire mouse and detaches brain tissue, under a dissecting microscope, peel meninx and blood vessel off, and cut brain.With microsurgical scissors, cut
Broken brain tissue, and 2ml Accutase digestive ferments are added dropwise, cell incubator is put into, is digested 15-20 minutes.After digestion, add
Enter isometric nerve stem cell culture medium and terminate digestion.After the filtration of 200 mesh nylon wires, 1000 revs/min of centrifugations are after ten minutes
Supernatant is abandoned, collects cell.After cell is resuspended, it is inoculated in nerve stem cell culture medium.37 DEG C are put into, 5% carbon dioxide incubator
In, it cultivates 5-7 days.The cell clone of non-adherent growth is collected by centrifugation, fully piping and druming forms it into individual cells.Secondary culture 4-
Monoclonal nerve ball can be obtained within 7 days.
As shown in figure 4, nicotinamide mononucleotide（NMN）The proliferation of mouse neural stem cells can effectively be enhanced, illustrate the medicine
Object plays the role of promoting nerve regeneratl.
The preferred embodiment of the invention is illustrated above, but the invention be not limited to it is described
Embodiment, those skilled in the art can also make various equivalent under the premise of without prejudice to the invention spirit
Modification or replacement, these equivalent modifications or replacement are all contained in the application claim limited range.
Claims (1)
1. application of the nicotinamide mononucleotide after promotion cerebral ischemia is prepared in the drug or health food of nerve regneration, described
Nerve regneration refers to effectively facilitate more neural stem cell to ripe neural cellular differentiation after promoting cerebral ischemia, improves brain diseases
Caused nervous function damage makes up the nerve cell lost in above-mentioned lysis, promotes learning and memory function.
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| US11787830B2 (en) | 2021-05-27 | 2023-10-17 | Metro International Biotech, Llc | Crystalline solids of nicotinic acid mononucleotide and esters thereof and methods of making and use |
| US11878027B2 (en) | 2015-08-05 | 2024-01-23 | Metro International Biotech, Llc | Nicotinamide mononucleotide derivatives and their uses |
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| CN105030807B (en) * | 2015-07-13 | 2018-11-06 | 中国人民解放军第二军医大学 | Niacinamide ribose is preparing the application in treating Imaging in Patients with Cerebral Ischemia Disease drug |
| GB2542881B (en) | 2015-10-02 | 2020-01-01 | Carr Andrew | Crystal forms of ß-nicotinamide mononucleotide |
| CN107412247A (en) * | 2016-05-23 | 2017-12-01 | 上海风劲生物医药科技有限公司 | Application of the nicotinamide mononucleotide in prevention or treatment cerebral hemorrhage medicine is prepared |
| US11040996B2 (en) | 2016-07-30 | 2021-06-22 | Bontac Bio-Engineering(Shenzhen) Co., Ltd | Method for preparing nicotinamide mononucleotide (NMN) |
| US11634690B2 (en) | 2017-01-31 | 2023-04-25 | Oriental Yeast Co., Ltd. | Agent for accelerating growth of pluripotent stem cells |
| AU2019214858B2 (en) | 2018-01-30 | 2023-02-02 | Metro International Biotech, Llc | Nicotinamide riboside analogs, pharmaceutical compositions, and uses thereof |
| EP3770250A4 (en) * | 2018-03-22 | 2021-11-24 | Oriental Yeast Co., Ltd. | Differentiation promoter for pluripotent stem cells |
| US10618927B1 (en) | 2019-03-22 | 2020-04-14 | Metro International Biotech, Llc | Compositions and methods for modulation of nicotinamide adenine dinucleotide |
| US11939348B2 (en) | 2019-03-22 | 2024-03-26 | Metro International Biotech, Llc | Compositions comprising a phosphorus derivative of nicotinamide riboside and methods for modulation of nicotinamide adenine dinucleotide |
| CN111759877A (en) * | 2020-07-02 | 2020-10-13 | 深圳市旷逸生物科技有限公司 | NMN-containing pharmaceutical composition for improving intelligence and strengthening brain |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101601679A (en) * | 2009-03-17 | 2009-12-16 | 中国人民解放军第二军医大学 | A kind of application of nicotinamide mononucleotide. |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101601679A (en) * | 2009-03-17 | 2009-12-16 | 中国人民解放军第二军医大学 | A kind of application of nicotinamide mononucleotide. |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11878027B2 (en) | 2015-08-05 | 2024-01-23 | Metro International Biotech, Llc | Nicotinamide mononucleotide derivatives and their uses |
| US11787830B2 (en) | 2021-05-27 | 2023-10-17 | Metro International Biotech, Llc | Crystalline solids of nicotinic acid mononucleotide and esters thereof and methods of making and use |
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