CN1814276A - Nerve-protection function of thymosin beta 10 - Google Patents
Nerve-protection function of thymosin beta 10 Download PDFInfo
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- CN1814276A CN1814276A CN 200510005030 CN200510005030A CN1814276A CN 1814276 A CN1814276 A CN 1814276A CN 200510005030 CN200510005030 CN 200510005030 CN 200510005030 A CN200510005030 A CN 200510005030A CN 1814276 A CN1814276 A CN 1814276A
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Abstract
The invention supplies a drug compound containing thymosin beta-10 or its usable salt or its biology function ramification to cure kinds of nerve damage. The invention also could be used to cure physical property nerve damage. And it could be used to prevent and cure brain tissue and nervous tissue damage like Parkinson's disease, Alzheimer disease, and so on.
Description
Technical field
The present invention relates to a kind of active small molecular polypeptide with neuroprotective cell and the effect of treatment neural tissue injury: extrasin beta-10, its pharmaceutical composition can be used for treating the brain injury that a variety of causes causes, spinal cord injury and peripheral nerve injury.
Background
Nervous system comprises central nervous system's (brain, spinal cord) and peripheral nervous system (peripheral nerve tissue).Nervous system injury can be caused by multiple factor: (1) physical damnification, directly cause the nervous tissue infringement of damage location, the cranial nerve tissue injury or the spinal cord injury that cause as wound; (2) ischemia temporarily or permanently or the anoxia of partial nerve system are fastened the cranial nerve tissue injury that plug causes as apoplexy or brain; (3) contact neurotoxin, as be used for the treatment of the chemicals of cancer or be used for the treatment of two deoxidation born of the same parents of AIDS sweet; (4) chronic metabolic disease, the peripheral nerve injury that causes as diabetes or renal dysfunction; (5) neurodegenerative diseases comprises parkinson disease, Alzheimer disease etc.The neurocyte of one or more types can involve in impaired nervous tissue.
Protection after the nerve injury is one of severe challenge of facing of neuroscientists with repairing always.Through effort for many years, many researchs are verified, and nervous system has plasticity, not only show as various to external world stimulations and have intensive compensatory and adaptive capacity, the more important thing is to have the ability that the damage back is repaired or rebuild on structure and function.The realization of this process had both needed to start some gene regulation program of neurocyte self, needed quite complicated local environment and condition again.In recent years, along with the discovery of nerve growth factor and the application of nervous tissue's stem cell transplantation, brought hope for to a certain extent the treatment nerve injury.
Nerve growth factor (NGF) and neurotrophin (NT) play an important role in neurocyte and glial cell are reached maturity, and the damage of neurocyte and glial cell is had the certain protection effect.Utilize the gene transfection technology that the neurotrophic factor related gene is imported mammalian cell strain, be transplanted in the brain then, or utilize neurocyte and glial cell in the reverse transcription virus gene carrier direct infection brain, make these cells that pass through genetic modifications in the local expression associated protein, thereby reach the purpose of treatment central nervous system injury.The structural remodeling of the success that neural pluripotent stem cell in-vitro separation is cultivated after for nervous system injury provides probability, and the stem cell of transplanting can break up in host becomes corresponding neurocyte and glial cell with the realization injury repairing.Although these methods help to help injured nerve cells regeneration and repair theoretically, also there is a big difference apart from practical application.Because it is found that,, use the nervous tissue after these methods are difficult to the reparation damage separately because the reparation of injured nerve cell and regeneration are very complicated processes.Still exist the safety problem except transgenic technology at present, damage the injured nerve cell and the damaged local tissue hypoxia ischemia that cause, make injured nerve cells and transplant after nervous tissue be difficult to survival.
Purpose of the present invention just provides a kind ofly promptly to be had the neuroprotective cell, promote the nervous cell regenerating reparation, has the active small molecular polypeptide that promotes the neovascularization effect again; extrasin beta-10; its pharmaceutical composition can be used for treating the brain injury that a variety of causes causes, spinal cord injury and peripheral nerve injury.
Description of drawings
Fig. 1 extrasin beta-10 is to the protection of rat retina neurocyte.Matched group is undressed rat retina neurocyte.At experimental group, the extrasin beta-10 with variable concentrations carries out protectiveness pretreatment one hour to the rat retina neurocyte earlier.Add hydrogen peroxide then in experimental group and matched group neuronal cell cultures liquid, making the final concentration of hydrogen peroxide in culture fluid is 100 μ M, and experimental group and matched group neurocyte were cultivated 24 hours at 37 ℃.Adopt the MTT analytic process, with the oxidation resistance of neurocyte and time-to-live as index, observe extrasin beta-10 to the rat retina protecting neuron from acute.The result shows: compare with matched group, retina nerve cell death quantity obviously reduces after the pretreatment of extrasin beta-10 protectiveness, and this protective effect is strengthened along with the increase of extrasin beta-10 concentration.
Description of the invention
The present invention originates in existing discovering, participates in the growth course of cranial nerve tissue at the early stage extrasin beta-10 of embryo.We discover recently, even after growing up, still contain abundant extrasin beta-10 in cerebral tissue and the peripheral nervous tissue.We imagine this micromolecule polypeptide and probably the growth of neurocyte are had certain effect; therefore under the situation that neurocyte sustains damage; this micromolecule polypeptide has the neuroprotective cell probably, promotes the function that nervous cell regenerating and damage back nervous tissue repair.In further experiment, we as neural cell model, cause neural cell injury with hydrogen peroxide with the retinal neuronal cell of isolated culture, observe extrasin beta-10 to protecting neuron from acute.Experimental result shows: compare with matched group, extrasin beta-10 can stimulate the motion of human umbilical vein's endotheliocyte and epidermis cell specifically.Cell movement plays an important role in wound healing.Newborn blood capillary promptly begins to obtain employment, and already present venule sprouts and to the wound growth, need cell movement; The basal layer cell of the epithelium broken ends of fractured bone moves the covering wound surface to wound surface around damaged, needs cell movement.Extrasin beta-10 can promote cell migration, therefore has the effect of quickening wound healing.
The present invention has determined that further thymosin beta 10 can promote effectively that in vivo vascular endothelial cell moves, and promotes vascularization, promotes tissue regeneration and wound healing.Chick chorioallantoic membrane (CAM) vascularization result of the test shows, extrasin beta-10 promote angiopoietic effect with as the effect of the epithelical cell growth factor of positive control quite or better.Actin is a cell intensive amount rich in protein, is cytoskeletal protein, and it can participate in the various kinds of cell functional activity by the conversion of monomer and polymer form, as cell movement, cellular contraction, absorption, secretion, dna replication dna, cell division or the like.Extrasin beta-10 can be incorporated on the actin monomer, come the functional status of modulate actin by the polymerization that suppresses actin, quicken cell function activities such as cell movement, cell division, not only showing as various to external world stimulations has intensive compensatory and adaptive capacity, the more important thing is to have the ability of repairing or rebuilding after anti-damage and the damage on structure and function.
Therefore, the invention provides a kind of extrasin beta-10 or its acceptable salts or its physiological function derivative that contains effective dose, and the formulated pharmaceutical composition with protection and the effect of treatment neural tissue injury of applicable carrier.The effect of this treatment and neuroprotective cell is based on us and finds in experiment, and 1) under extraneous harmful factor stimulated, extrasin beta-10 had protective effect to neurocyte itself.2) extrasin beta-10 also has the effect that promotes that new vessels growth and cell move.Therefore, in neural tissue injury's repair process, extrasin beta-10 also can promote the growth of injured nerve tissue local new vessels in the neuroprotective cell, improve the hypoxic-ischemic environment, promotes nervous cell regenerating, repair in trauma.
The nervous system injury that the present invention can be used for preventing and treat a variety of causes to cause comprises the damage of central nervous system's (brain, spinal cord) and peripheral nervous system (peripheral nerve tissue comprises): (1) physical damnification, directly cause the neural tissue injury of damage location, the cranial nerve tissue injury or the spinal cord injury that cause as wound; (2) ischemia temporarily or permanently or the anoxia of partial nerve system are fastened the cranial nerve tissue injury that plug causes as apoplexy or brain; (3) contact neurotoxin, as be used for the treatment of the chemicals of cancer or be used for the treatment of two deoxidation born of the same parents of AIDS sweet; (4) chronic metabolic disease, the peripheral nerve injury that causes as diabetes or renal dysfunction; (5) neurodegenerative diseases and old and feeble cerebral tissue and the neural tissue injury that causes comprise parkinson disease, Alzheimer disease etc.(6) the cranial nerve cell dysfunction and cause neural abalienation symptom etc.
The extrasin beta-10 that the present invention describes is the polypeptide composition that has in the normal human.Therefore, use highly purified extrasin beta-10 safety, reliable.In embodiment of the present invention, extrasin beta-10 can be a separation and Extraction from histiocyte, can be that direct chemical is synthetic, also can be artificial expression.In addition, any have the bioactive substance that can bring out or stimulate body tissue, cell to produce extrasin beta-10 and all belong to category of the present invention.
This to nervous system injury and disease prevention, treatment and protective effect be not limited only to extrasin beta-10; a plurality of allotype bodies that also should comprise extrasin beta-10; as extrasin beta 4, extrasin beta 9, extrasin beta 11, thymosin, extrasin beta 13, extrasin beta 14, extrasin beta 15; thymosin beta 16 and the above-mentioned LKKTET that contains, the allotype body and the oxidized form thereof of LKKTNT aminoacid sequence.
The present invention also can share with other drug in the neural nerve injury process of treatment a variety of causes in addition.As the somatomedin (PDGF) that in treatment, adds nerve growth factor (NGF), neurotrophin (NT), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), MNGF (MNGF), insulin like growth factor (IGF-1), platelet source, epidermal growth factor (EGF), transforming growth factor (TGF-β), VEGF (VEGF) etc., all be included in the present invention.
Pharmaceutical composition of the present invention can be an injecta composition, is used for intravenous, intraperitoneal, intramuscular or subcutaneous injection.The example of preparation injecta composition comprises the oxidation type extrasin beta-10 or derivatives thereof of effective dose and the fluid matrix mixing manufacture of aequum is formed that the example of this substrate comprises water or normal saline, wherein also can add other beneficiating ingredient or adjuvant.
Pharmaceutical composition of the present invention can be solid dosage forms compositionss such as oral capsule, tablet, powder, comprises the oxidation type extrasin beta-10 or derivatives thereof dry powder of effective dose and the pharmaceutic adjuvant mixing manufacture of aequum are formed.Pharmaceutical composition of the present invention can also be the oral liquid compositions.The example of preparation oral liquid compositions comprises the oxidation type extrasin beta-10 or derivatives thereof of effective dose and the fluid matrix mixing manufacture of aequum is formed that the example of this substrate comprises water or normal saline, wherein also can add other beneficiating ingredient or adjuvant.
In this article, " carrier " is meant substrate or the adjuvant that contains active oxidation type extrasin beta-10, is used for serving as delivery system.In the present invention, " delivery system " refers to active oxidation type extrasin beta-10 to be the body of passing the human or animal when pharmaceutical composition (medicament preparation or dosage form) when being used.Therefore term " delivery system " comprises the substrate or the adjuvant of the form of ownership that common pharmaceutical composition can use, as solid, semisolid and fluid composition.Special relevant compositions is, for example, ointment, hydrophilic ointment, emulsifiable paste, paste, frost, gel, hydrogel, solution, emulsion, suspension, washing liquid, liniment, shampoo, soap agent, paste, spray, powder, thin film, bedding and padding, application, binder, plaster etc.
Topical application pharmaceutical composition of the present invention preferably contains the ointment or the frost of active component.When making ointment, active component can use paraffinic base or water miscibility ointment base, perhaps, makes the cream that active component contains water bloom base.The example of external type compositionss such as preparation masking liquid, ointment comprises mixing with additive aequum effective dose.These additives are selected from the substrate commonly used or the adjuvant of external used medicine or cosmetics usually, for example vaseline, liquid paraffin, lanoline, stearic acid list glyceride, Polyethylene Glycol, hexadecanol, glycerol, second alcohol and water etc.
If desired, the water of frost can comprise, for example, the polyhydric alcohol of 30%W/W at least promptly contains the alcohol of two or more bases, as propylene glycol, fourth-1, and 3-glycol, mannitol, sorbitol, glycerol and Polyethylene Glycol and their mixture.Topical preparation can increase or reduce contained active component as required.
The present invention can also use with the mode that may command discharges intermixture.Herein " may command release intermixture " is meant any complex.This complex can be used for slowly discharging the efficient oxidation type extrasin beta-10 composition that comprises wherein.This complex contains biological effective components can be solid shape, infiltrative, and half shape admittedly is colloidality or aqueous.
Embodiment
Retinal neuronal cell protection experiment
After the rat retina neurocyte was separated the Mus body, the certain hour of can surviving in culture fluid carried out the normal metabolic activity.At first, with the extrasin beta-10 of variable concentrations the experimental group neurocyte being carried out protectiveness pretreatment one hour, is matched group with undressed neurocyte.Add hydrogen peroxide then in experimental group and matched group neuronal cell cultures liquid, making the final concentration of hydrogen peroxide in culture fluid is 100 μ M, and experimental group and matched group neurocyte were cultivated 24 hours at 37 ℃.Adopt MTT and TUNEL analytic process, with the oxidation resistance of neurocyte and time-to-live as index, observe extrasin beta-10 to the rat retina protecting neuron from acute.The result shows: compare obvious minimizing with matched group through the dead quantity of the pretreated retinal neuronal cell of extrasin beta-10 protectiveness; extrasin beta-10 has the effect of the nerve cell death that significant protection causes by peroxidating, and (Fig. 1) strengthened in this protective effect along with the increase of concentration.
Embodiment 2
Promote the blood vessel hyperplasia experiment
Extrasin beta-10 adopts chick chorioallantoic membrane (CAM) experiment to detect to the facilitation of angiogenesis, open a 1cm2 left and right sides window hatching on 7 days the fertilization Embryo Gallus domesticus eggshell, with the chemosynthesis extrasin beta-10 albumen application of sample of variable concentrations on the sterilization filter paper, and be positioned over CAM, continue down for 37 ℃ to cultivate 48 hours at the constant temperature and humidity incubator then, observe the angiogenic growth situation.This experiment is the test contrast with the normal saline, phorbol myristate acetate (PMA) 0.5 microgram/positive contrast of 10 microlitres.The measuring result shows that extrasin beta-10 albumen application of sample group chick chorioallantoic membrane angiogenic growth is obviously vigorous, and caliber is thick and branch is many, is lobate distribution.With normal saline group angiogenic growth degree in contrast, the blood vessel hyperplasia degree of extrasin beta-10 5 micrograms/10 microlitres significantly increases than normal saline group, and the blood vessel hyperplasia degree of 10 micrograms/10 microlitres and PMA positive controls blood vessel hyperplasia degree are quite or slightly many.This experimental result shows that extrasin beta-10 has the effect of obvious promotion blood vessel hyperplasia.
Embodiment 3
The protein content of extrasin beta-10 in the nervous tissue
Tissue and organs and tissues specimen are all fixed through 10% neutral formalin, dehydration, routine paraffin wax embedding, the thick serial section of 4 μ m.Make specificity extrasin beta-10 antibody mediated immunity group labelling.See the expression of Fig. 2 extrasin beta-10 in nervous tissue.In cerebral tissue, compare with other cell, visible a large amount of extrasin beta-10 protein expressions in the cranial nerve cell, it is painted that endochylema is dark brown Huang, also can see the pale brown color positive signal (Fig. 2 A) of small quantities of particles shape in the karyon of part cell.In addition, can see the abundant extrasin beta-10 albumen of content in peripheral nervous tissue such as the coat of the stomach flesh layer nerve tract, connective tissue is not then seen extrasin beta-10 albumen (Fig. 2 B) around coat of the stomach flesh layer and the nervous tissue.
Claims (10)
1 one kinds are used for the treatment of the nerve injury pharmaceutical composition of (comprising brain injury, spinal cord injury and peripheral nerve injury), contain the extrasin beta-10 of effective dose, its biological activity variant or salt and its acceptable pharmaceutical carrier.
2 is described according to claim 1, and extrasin beta-10 is meant whole aminoacid sequences of extrasin beta-10, also can be partial amino-acid series or its variant and oxidized form, and main being meant has the amino acid fragment of LKKTET.
3 is described according to claim 2, and extrasin beta-10 can be nature extraction, chemosynthesis or artificial the expression.
4 is described according to claim 1, and the present invention also comprises a plurality of allotype bodies of extrasin beta-10.These allotype bodies contain LKKTET or LKKTNT aminoacid sequence, as extrasin beta 4, extrasin beta 9, extrasin beta 11, thymosin, extrasin beta 13, extrasin beta 15, thymosin beta 16, and the variant and the oxidized form of these allotype bodies.
5 is described according to claim 1, and the present invention can be used for treating various nerve injury, comprises central nervous system and diseases in peripheral nerve system.As because various brain injury, spinal cord injury and the peripheral nerve injury that the various diseases ischemia, the anoxia that cause cause.
6 is described according to claim 1, and the present invention also can be used for treating various physical property nerve injury.The brain injury, spinal cord injury and the peripheral nerve injury that cause as mechanical damage, wound, traffic accident etc.
7 is described according to claim 1, neurodegenerative diseases and old and feeble cerebral tissue and the neural tissue injury that causes that the present invention also can be used for preventing and treat a variety of causes to cause comprise parkinson disease, Alzheimer disease etc. and cranial nerve cell dysfunction and the neural abalienation symptom that causes etc.
8 is described according to claim 1, and its pharmaceutical composition also can share with other drug, and as nerve growth factor (NGF), neurotrophin (NT) etc., and other has various somatomedin, cytokine and other factor of regulating the extrasin beta-10 generation.
9 is described according to claim 1, and pharmaceutically useful carrier can be solid dosage forms compositionss such as oral capsule, tablet, powder in its pharmaceutical composition, can also be injecta composition, is used for intravenous, intraperitoneal, intramuscular or subcutaneous injection.
10 is described according to claim 1, and pharmaceutically useful carrier comprises the substrate or the adjuvant of the form of ownership that common pharmaceutical composition can use in its pharmaceutical composition, as solid, semisolid and fluid composition.Special relevant compositions is, for example, ointment, hydrophilic ointment, emulsifiable paste, paste, frost, gel, hydrogel, solution, emulsion, suspension, washing liquid, liniment, shampoo, soap agent, paste, spray, powder, thin film, bedding and padding, application, binder, plaster etc.
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| CN 200510005030 CN1814276A (en) | 2005-01-31 | 2005-01-31 | Nerve-protection function of thymosin beta 10 |
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| CN 200510005030 CN1814276A (en) | 2005-01-31 | 2005-01-31 | Nerve-protection function of thymosin beta 10 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104744583A (en) * | 2015-04-16 | 2015-07-01 | 中国农业科学院特产研究所 | Tbeta10 recombinant protein of cornu cervi of sika deer and preparation method and application thereof |
| CN109593860A (en) * | 2019-02-12 | 2019-04-09 | 山东大学齐鲁医院 | Application of the TMSB10 in diagnosis and treatment glioma |
| WO2021129897A1 (en) | 2019-12-26 | 2021-07-01 | Centro Nacional De Biopreparados | Protein-based pharmaceutical composition with neuroprotective, immunomodulating, anti-inflammatory and antimicrobial activity |
-
2005
- 2005-01-31 CN CN 200510005030 patent/CN1814276A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104744583A (en) * | 2015-04-16 | 2015-07-01 | 中国农业科学院特产研究所 | Tbeta10 recombinant protein of cornu cervi of sika deer and preparation method and application thereof |
| CN109593860A (en) * | 2019-02-12 | 2019-04-09 | 山东大学齐鲁医院 | Application of the TMSB10 in diagnosis and treatment glioma |
| WO2021129897A1 (en) | 2019-12-26 | 2021-07-01 | Centro Nacional De Biopreparados | Protein-based pharmaceutical composition with neuroprotective, immunomodulating, anti-inflammatory and antimicrobial activity |
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