CN102218051A - Application of sodium valproate in preparation of medicament for treating or improving optic nerve pathological changes of glaucoma - Google Patents
Application of sodium valproate in preparation of medicament for treating or improving optic nerve pathological changes of glaucoma Download PDFInfo
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Abstract
The invention belongs to the field of pharmacy, and relates to application of sodium valproate in preparation of medicaments for treating or improving optic nerve pathological changes of glaucoma. The in-vitro cell culture experiment and in-vivo animal experiment indicate that sodium valproate with certain concentration can promote retina ganglionic cells (RGCs) cultured in vitro to survive and enhance the extension capacity of the axon, and can lower the expression of proapoptotic gene BAX and promote the RGCs to survive under the conditions of chronic high intraocular pressure, thereby relieving the damage of RGCs. The experiments prove that the sodium valproate can protect the RGCs in the aspects of multiple pathogeneses of glaucoma optic nerve pathological changes, and further more, can be used as an active ingredient for preaprating medicaments for treating glaucoma optic nerve pathological changes, especially medicaments for protecting RGCs. The invention has important application value and favorable social and economic benefits in clinical treatment of glaucoma.
Description
Technical field
The invention belongs to pharmaceutical field, relate to the new purposes of sodium valproate in pharmacy, be specifically related to sodium valproate in preparation treatment or improve purposes in the medicine of glaucomatous optic neuropathy.
Background technology
Glaucoma is that (retinal ganglion cell, RGC) the gradually capable property regression of apoptosis and aixs cylinder thereof is the optic neuropathy of feature to a class, is to be only second to cataractous world's second largest diseases causing blindness with retinal ganglial cells.The whole world had 6,680 ten thousand primary glaucoma patients and about 6,000,000 patients with secondary glaucoma approximately in 2000, and wherein about 6,700,000 patients are because of the glaucoma blinding; Expect the year two thousand twenty, the U.S. will have three million peoples of surpassing to suffer from glaucoma, and at least 8 ten thousand people can be final therefore blind.In China, the blindness patient reaches 5,200,000 in 9,400,000 glaucoma patients, and blind rate almost approaches cataract.Therefore, the glaucoma control is the key areas of China and world ophthalmology research always, has very important society, economic implications.
Studies show that the pathologic basis of glaucoma retina, optic nerve injury is RGCs death; The degeneration that the development of mitigate the disease to a certain extent of simple reduction intraocular pressure but can not be contained Secondary cases RGCs death and aixs cylinder thereof.The existing pathogenesis complexity that studies confirm that glaucoma RGCs death and axonal degeneration thereof, be the final final result of multiple pathogenic link comprehensive functions such as neuron, neurogliocyte and ophthalmic microenvironment, mainly comprise: the glutamic acid excitatory toxicity that the mechanical damage that high intraocular pressure causes, glutamic acid over loading cause, tumor necrosis factor release, oxidative stress, Developmental and Metabolic Disorder, neurotrophic factor are deprived, glial cell activation etc.Present treatment means clinically; comprise intraocular pressure lowering or neuroprotective; often can only be at a kind of death of attempting to delay RGCs in above-mentioned numerous paathogenic factors; little can be simultaneously with two or more medicine or methods that cause the links of RGCs death as the treatment target spot, so clinical efficacy is limited.Clinical practice need be sought at glaucomatous complicated pathogenesis, and the medicine that can work to a plurality of target spots simultaneously makes the therapeutic effect of remarkable lifting glaucoma retina, optic nerve injury.
(Sodium Valproate is a clinical convulsion and an antiepileptic line medicine VPA) to sodium valproate, and extensive use is nearly 40 years, is mainly used in the treatment of epilepsy, amphicheirality's mental disorder, can see through blood brain barrier rapidly, and curative effect determines that safety is good.Have not yet to see the effect that relevant sodium valproate can cause multiple pathogenesis, raising protection retinal ganglial cells and the aixs cylinder thereof of glaucoma RGCs death by the intervention of a plurality of treatment target spot, especially improve or treat the report of glaucomatous optic neuropathy.
Summary of the invention
The objective of the invention is to overcome the defective and the deficiency of prior art, the new purposes of sodium valproate (VPA) in pharmacy is provided, be specifically related to sodium valproate in preparation treatment or improve purposes in the medicine of glaucomatous optic neuropathy;
More specifically, the invention provides sodium valproate in preparation treatment or improve purposes, the particularly sodium valproate purposes in the medicine of preparation protection glaucoma retinal ganglial cells in the medicine of glaucoma retina, optic nerve injury.
Glaucoma of the present invention is a primary open angle glaucoma, normal tension glaucoma (low-critical glaucoma).
Sodium valproate of the present invention (commercially available) belongs to I class hdac inhibitor, is the very little short-chain fatty acid of a kind of molecular weight, and its chemical name is a valproate, and molecular formula is: C
8H
15NaO
2, molecular weight is: 166.20, have the molecular structure of formula I:
（Ⅰ） 。
The present invention is a subjects with the former generation SD rat retinal ganglion cell and the chronic high intraocular pressure SD rat model of In vitro culture, the effect of sodium valproate to the quantity of the former generation retinal ganglial cells (RGCs) of In vitro culture and aixs cylinder length thereof, the speed of growth observed in research, and to the redemption effect of chronic high intraocular pressure rat RGCs; Experimental result shows: (1) described sodium valproate can promote survival and the axon growth thereof of the former generation RGCs of adult SD rats of In vitro culture; Add VPA and cultivated the back the 3rd, 7 day, RGCs quantity is respectively 402 ± 63 and 389 ± 47, and significantly more than matched group (P＜0.01), aixs cylinder average length (μ m) is 68.4 ± 13.1(P＜0.01), 114.6 ± 23.5 (P＜0.01); Average axon growth speed is 18.6 ± 5.2(P＜0.01); (2) VPA can improve the albumen and the mRNA expression raising of gene relevant with cell survival among the former generation RGCs of In vitro culture, comprises Bcl-2, survivin, catenin and hsp70 etc.; (3) interior or intraperitoneal injection VPA or PBS(matched group of chronic high intraocular pressure SD rat animal model vitreous chamber) the 1st, 2,3,8 weeks of back adopt the method row retina of the retrograde labelling of fluorogolds to spread the RGCs quantity of sheets counting survival, the result shows, the cell quantity that presents complete circle or oval green fluorescence on the sheet of VPA injection group retina shop increases, the fluorescence fragment of irregular form is less, the aixs cylinder profile phase is to complete, quantity increases, difference significantly (P＜0.01) during with the 3rd and 8 weeks; (4) behind chronic high intraocular pressure SD rat glass intracavity or the intraperitoneal injection VPA, trophic factors BDNF, cell survival related gene bcl-2, catenin and survivin and the α-synuclein proteic expression relevant with reducing the glutamic acid excitatory toxicity improve 6.3-7.9,2.6-3.7,2.1-4.2,3.4-5.6,3.1-3.8 doubly than PBS injection group respectively in the retina; (5) behind chronic high intraocular pressure SD rat glass intracavity or the intraperitoneal injection VPA, significantly reduce inflammatory factor TNF-alpha content in the retina; The TNF-alpha content is 486.2 ± 12.4ng/mg in the PBS group, and the VPA group is 194.7 ± 8.6 ng/mg, and difference has statistical significance (P＜0.01); (6) behind chronic high intraocular pressure SD rat glass intracavity or the intraperitoneal injection VPA, significantly suppress the retinal gliocytes transition that high intraocular pressure causes and activate, activated marker protein OX42 of glial cell and GFAP descend at intraretinal content (P＜0.01).
Experimental result shows, but described sodium valproate is direct regulation and control RGCs high expressing cell survival genes bcl-2, catenin, SURVIVIN and hsp70 not only, reducing BAX expresses, promote RGCs survival and axon elongation, can also be by the release of the glutamic acid excitatory toxicity in antagonism or the intervention glaucomatous optic neuropathy pathogenesis, glial cell transition activation, inflammatory factor TNF-α, the links such as minimizing of trophic factors BDNF are improved microenvironment and are saved RGCs.The carrying out property regression of high intraocular pressure RGCs of delaying chronic and aixs cylinder thereof; Described sodium valproate can be used as active ingredient preparation treatment glaucomatous optic neuropathy medicine, the particularly medicine of preparation protection RGCs; Sodium valproate of the present invention also can be used for preparing the medicine that promotes the retinal ganglial cells axon elongation, the medicine that suppresses the glaucomatous optic neuropathy process activated medicine of mesoglia cells transition and reduce retina glutamic acid excitatory toxicity.
Another object of the present invention, a kind of glaucoma retina, optic nerve protection agent are provided, it is active constituents of medicine that described protective agent adopts the sodium valproate of safe and effective amount, necessary adjuvant on the pharmaceutics in addition, make multiple dosage forms such as conventional tablet, enteric coatel tablets, slow releasing tablet, syrup, spray capsule, injection, gel, ointment, solution, suspension, that its route of administration can adopt is oral, intravenous injection, local eye drip or be coated with eye, intracameral injection, vitreous body intracavitary administration or through the implant sustained-release administration; Described protective agent can with one or more intraocular pressure lowering medicines simultaneously or give successively, or with one or more optic nerve protection agent simultaneously or give successively.
The present invention has confirmed the protective effect of described VPA to RGCs by cell culture experiments in vitro and two aspects of interior animal experiment respectively; Nearly 40 years of described VPA extensive use clinically, all clear and definite to the safety and the pharmacokinetics of human body, need not clinical verification, and can see through blood brain barrier rapidly, and be difficult for degraded, nontoxic.The invention provides the new purposes of VPA in glaucoma optic nerve protection field, described VPA can remove to protect retinal ganglial cells at a plurality of pathogenesis of glaucomatous optic neuropathy simultaneously, and effective.VPA of the present invention will produce important use to the glaucoma clinical treatment and be worth and favorable social and economic benefits the protective effect of RGCs, will benefit vast glaucoma patient.
Description of drawings
Fig. 1 is that the former generation RGC of In vitro culture added behind the variable concentrations VPA the 3rd, 7 day, the quantitative analysis of RGC quantity and aixs cylinder length, wherein, A: add behind the variable concentrations VPA the 3rd day RGC quantity and aixs cylinder length, B: add behind the variable concentrations VPA the 7th day RGC quantity and aixs cylinder length.
Fig. 2 is that Western blot and Real-time PCR method detect behind the former generation RGC that 100 μ M VPA add In vitro culture the 3rd day, and the albumen of Bcl-2, survivin, catenin, HSP70 and BAX and mRNA express.
After Fig. 3 is chronic high intraocular pressure rat vitreous chamber or abdominal cavity VPA injection, the survival of retinal ganglial cells, wherein, A is the retrograde labelling retinal ganglial cells of fluorogold, B is the quantitative analysis of 1,2,3,4 all retina ganglionic cells survivals between each group.
Fig. 4 is the expression of survival associated protein; VPA is after 3 days in the vitreous chamber injection, and Western detects survival relevant β-catenin, bcl-2 and the expression of survivin is obviously raised.
Fig. 5 shows that VPA significantly improves chronic high intraocular pressure retina microenvironment, and wherein, A:VPA improves chronic high intraocular pressure retina α-synuclein expression; B: under the VPA effect, the protein expression level of BDNF obviously improves, and GFAP and OX-42 significantly reduce; After C:Elisa method detection VPA is expelled to normal or chronic high intraocular pressure rat vitreous chamber, the content of inflammatory factor TNF-α in the retina.
The specific embodiment
Below in conjunction with instantiation the present invention is elaborated.Experimental technique described in the following embodiment if no special instructions, is conventional method.
One, material and method
1, medicine: sodium valproate (VPA), sigma company product.
2, animal: laboratory animal is provided for use by healthy SD rat (being provided by Chinese Academy of Sciences's Shanghai Experimental Animal Center), and is male, and in Mus 8 weeks of age, body weight 180～200g raises the animal center in the court.
3, main material and reagent: hyclone (Gibco company product), bovine serum albumin (BSA, Sigma company product), Neurobasal culture medium and B27(Gibco company product), papain and ovomucin (Sigma company product), reorganization neurotrophic factor BDNF and CNNF(Invitrogen company product), basic fibroblast growth factor bFGF(Invitrogen company product), glutamine (Sigma company product), the OX-42 monoclonal antibody, the survivin monoclonal antibody, the Bcl-2 monoclonal antibody is available from Chemicon company, the GFAP polyclonal antibody is available from Neomarker company, and the catenin monoclonal antibody is available from R﹠amp; D company.
4, SD rat retinal ganglion cell purification is cultivated
SD rat eye conventional treatment, get retina and put into the graduated centrifuge tube that fills PBS, PBS washes 3 times, add 37 ℃ of digestion of the long-pending papain digestion liquid of monoploid after 30 minutes, add and contain ovomucin (2mg/ml), DNase(0.004%) and solution BSA(1mg/ml), blow and beat into cell suspension, centrifugal 800rpm/5min, solution is centrifugal again after washing through ovomucin (10mg/ml) with BSA(10mg/ml) for cell precipitation, and 0.1% BSA that adds phosphoric acid buffer makes cell suspension; Then cell suspension is joined in the culture bottle of OX-41 bag quilt, place 30min under the room temperature,, all contact with the position of culture bottle bag quilt to guarantee all cells every 10min wave and culture bottle gently; Careful absorption does not stick to the cell in the culture bottle, joins in the centrifuge tube of OX-7 bag quilt, hatch 30min under the room temperature after, wash centrifuge tube gently 5 times with 3ml PBS, with Neurobasal culture medium flushing adherent cell, after 800rpm/5min is centrifugal, collect the RGC cell of purification again; Resuspended with the Neurobasal culture medium, by (500/cm2) be inoculated in the 6 porocyte culture plates in 5000cells/ hole; RGC is with containing glutamine (1mM), B27(1:50), BDNF(50ng/ml), cultivates in Neurobasal born of the same parents' culture medium CNTF(50ng/ml), 37 ℃, 5%CO2 incubator.
5, HDACi is to the effect of the RGC cell of In vitro culture
VPA concentration is respectively: 1uM, and 10 uM, 50uM, 100uM, 1mM, the RGC of purification add the VPA of above-mentioned variable concentrations respectively in culture medium after former being commissioned to train foster 24 hours, and PBS is as negative control.Quantity, length (5 cell measurements are chosen in each visual field) in the form, quantity and the aixs cylinder that add back 24h, 48h, 72h, 5d, the observation of 7d inverted phase contrast microscope and record RGC; Westernblot expresses with albumen and mRNA that the Real-time PCR method detects gene Bcl-2, survivin relevant with cell survival among the RGCs.
The result shows:
1, VPA promotes the RGCs survival and the axon growth thereof of In vitro culture
As shown in Figure 1, when adding concentration in the culture medium when being the VPA of 1 μ M or 10 μ M, ganglion cell's quantity and aixs cylinder length are not seen significant difference (P〉0.05) in experimental group and the blank group.When the concentration that adds is 50 μ M, 100 μ M or 1mM, ganglion cell's quantity of surviving significantly increases, and axon growth speed is fast, and length increases, and is similar when adding TSA.Effect is the most obvious when wherein being 100 μ M with concentration.Observed in the 3rd day and the 7th day, and in culture medium, added 100 μ M VPA time cell quantities and be respectively 402 ± 63(n=24, P＜0.01) and 389 ± 47(n=24, P＜0.01); Aixs cylinder average length (μ m) is 68.4 ± 13.1(P＜0.01), 114.6 ± 23.5 (P＜0.01); Average axon growth speed is 18.6 ± 5.2(P＜0.01).
2, VPA improves protein B cl-2 relevant with survival among the In vitro culture RGCs and survivin expression
As shown in Figure 2, the Bcl-2 relevant among the RGCs when adopting Western blot and real-time method to detect to add in the culture medium 24h, 48h behind the VPA, 72h with survival with 7d, the albumen of survivin, catenin, hsp70 and BAX and mRNA express, the result shows, VPA can improve the albumen and the mRNA expression of survival genes respectively, reduces the BAX gene and the protein expression that promote apoptosis.
Above-mentioned experimental result shows, certain density VPA can promote the RGCs survival of In vitro culture, also can improve simultaneously the extension ability of its aixs cylinder, it is relevant that its mechanism may directly raise the gene and the protein expression of being correlated with cell survival with VPA, as Bcl-2, survivin, catenin.
One, material and method
1, medicine: sodium valproate (VPA), sigma company product.
2, animal: laboratory animal is provided for use by healthy SD rat (being provided by Chinese Academy of Sciences's Shanghai Experimental Animal Center), and is male, and in Mus 8 weeks of age, body weight 180～200g raises in the court's animal center (illumination 12 hours, dark 12 hours).
3, main material and reagent
Fluorogold: Invitrogen company product.
OX-42 monoclonal antibody, survivin monoclonal antibody are available from Chemicon company, and Bcl-2 monoclonal antibody, GFAP polyclonal antibody are available from Neomarker company, and α-synuclein and catenin monoclonal antibody are available from R﹠amp; D company.
TNF-alpha immunization integrated enzyme reaction test kit (Elisa) is an Invitrogen company product.
Two, experimental technique
1, high intraocular pressure Animal Model Making of SD rat chronic and grouping
Rat is sooner or later respectively surveyed intraocular pressure once, 1 week of continuous measurement before setting up model.After the 10% chloral hydrate intraperitoneal anesthesia rat ventricumbent position is fixed on the operating-table, the capable eye topical anesthesia of 0.4% times of promise happiness eye liquid, left eye is an experimental eye, right eye is the contrast eye.Corneoscleral junction 1-2mm place cuts off bulbar conjunctiva apart from the top, and passivity is separated fascia, and a shallow-layer vein is respectively arranged on rat eye temporo side and the temporo, is Y-shaped, and traveling is comparatively straight.Gently with vein separation and the ligation of 9-0 atraumatic suture.Open so that nearly corneoscleral junction section blood vessel is angry, corneoscleral junction section blood flow far away disappears, and does not have hemorrhage sign as the ligation success simultaneously.The contrast eye only separates episcleral veins, does not do ligation.Postoperative is sewed up conjunctiva continuously with 8-0 not damaged medical suture, but eyes are coated with enlightening sieve eye ointment, treats to put back in the cage after rat revives.Immediate postoperative, postoperative 30 min, l h, 12 h, l d, 1 wk, 2 wk, 4 wk, 8 wk measure respectively and respectively organize intraocular pressure, and Measuring Time is respectively 10 o'clock of the morning and 4 o'clock of afternoon.And the topical manifestations of observing the art eye.The rat intraocular pressure is measured with TONO-PEN, and every eye records 6 meansigma methodss (each meansigma methods is the mean of 4 intraocular pressure readings) at least, when the credibility interval of these numerical value 〉=95%, promptly is used for statistical analysis as valid data.
60 rats choosing successfully modeling are divided into 4 groups at random: vitreous chamber injection VPA group, lumbar injection VPA group, vitreous chamber injection PBS group and intraperitoneal injection of saline group (0.9% sodium chloride), every group of 15 rats.
2, rat vitreous chamber injection
The SD rat is weighed, and medication is anaesthetized in the back and step is the same.Eyes drip U.S. Dolly with abundant mydriasis, and a times promise happiness eye drip is done anterior corneal surface anesthesia.Place the plastic ring of the about 4-5mm of a diameter then at anterior corneal surface, in circle, splash into an amount of 1% sodium carboxymethyl cellulose simulation preset lens.Then under operating microscope direct-view outside corneoscleral junction 1mm directly micro sample adding appliance is thrust vitreous body in the place, about 2-3mm that advances in the vitreous chamber of syringe needle below crystal does not touch crystal as far as possible.Selection is looked the vitreous chamber position at nipple temporo side 2 disc diameter places and is injected 2 μ l liquid.Slowly withdraw from micro-sample injector then, on scleral surface, stay the dereism tunnel of aperture size.Postoperative is coated with eyes with 0.1% chlorotetracycline eye ointment, to protect from infection and bitot's patches.Observing the rats breathing situation revives to it.
3, dosage
The dosage of VPA vitreous chamber administration: VPA is diluted to the solution that final concentration is 0.1mM with PBS, and every eye injection volume is 2ul, and being equivalent to the crude drug amount is the 0.34ug/ eye, is administered once weekly.The PBS of every eye injection of matched group equal volume, weekly.
VPA intraperitoneal administration dosage: VPA is diluted to the solution that final concentration is 100g/L (10%) with normal saline, and every 1ml contains crude drug 0.1g.By the every 100g body weight of rat 300ul(30mg) intraperitoneal injection, once a day, be equivalent to crude drug amount 300mg/kg.d; Matched group: per weight gives the normal saline with the VPA equal volume, once a day.Finish until experiment.
4, the retrograde labelling rat RGC of fluorogold
Get normal and chronic high intraocular pressure animal respectively, anesthesia is the same.Rat is fixed on the stereotaxic instrument, and routine disinfection, processing expose skull sagittal suture and lambdoid suture, and 30 % hydrogen peroxide are smeared periosteum, identification Bregma point.According to Paxinos rat brain stereotaxic atlas, be zero point with the Bregma point, after move 6. 3 ± 0. 2mm, 1. 40 ± 0. 2mm is opened on the side, degree of depth 3.50mm location, the bone hole of making 2 about 1mm of diameter respectively with electric dental engine.Draw fluorogold (150mg/ml, solvent are dimethylformamide) with 10 μ L microsyringes, slowly inject the bilateral superior colliculus, 5 μ L are injected in every hole, and let the acupuncture needle remain at a certain point 10min.Fascia and skin are sewed up in layering.But enlightening sieve eye ointment is smeared in the wound.Art finishes and continues to feed.
5, full retina shop sheet and RGCs counting
Rat anesthesia and heart perfusion method are ditto described.Take out eyeball, cut off anterior ocular segment, remove vitreous body, put into behind the 4 % paraformaldehydes fixedly 1h, move to 0.01MPBS again, the ophthalmology microscope separates retina, does the otch of 4 places perpendicular to optic disc in retinal periphery, makes it be divided into four quadrants that size is close substantially, retinal nerve fibre layer is faced up, be tiled on the microscope slide, 75 % buffering glycerol mounting is observed under from the retina edge to the average distance fluorescence microscope of looking nipple in each quadrant and is taken pictures.,, the RGCs of labelling in each visual field is counted apart from looking each picked at random visual field, about 1/ 6,1/ 2,5/ 6 places of nipple at each quadrant, ask the meansigma methods of RGCs density (individual/mm for 12 visuals field
2).
6, the ELISA method detects and respectively organizes TNF-alpha content in the retina, western blot method detects respectively organizes retina BDNF, Bcl-2, survivin, catenin and α-synuclein expression, and glial cell activates the expression of specificity marker thing ox-42 and GFAP.
Three experimental results show
1, as shown in Figure 3, vitreous chamber or intraperitoneal injection VPA have significant protective effect to chronic high intraocular pressure retinal ganglial cells; Vitreous chamber and intraperitoneal injection VPA do not see significant difference to the protective effect of chronic high intraocular pressure retinal ganglial cells, but the dosage of vitreous chamber administration is littler than intraperitoneal administration dosage; Compare with PBS injection group, the cell quantity that presents complete circle or oval green fluorescence on the sheet of rat retina shop behind the application VPA increases, and the fluorescence fragment of irregular form is less, and the aixs cylinder profile phase is to complete, quantity increases, difference significantly (p＜0.01) during with the 3rd week.
2, VPA raises among the RGCs expression with survival related gene B cl-2, survivin and catenin.The result as shown in Figure 3, behind vitreous chamber or the lumbar injection VPA, albumen bcl-2, survivin relevant with retinal ganglial cells survival and the expression of catenin are obviously raised, and are respectively 1.7,2.4 and 3.8 times of matched group.
3, VPA significantly improves chronic high intraocular pressure retina microenvironment, helps the retinal ganglial cells survival.
As shown in Figure 5, behind vitreous chamber or the lumbar injection VPA, the proteic up-regulated of retina α-synuclein, this protein expression improves can reduce the glutamic acid excitatory toxicity, alleviates the damage (shown in Fig. 5 A) to retinal ganglial cells; Secondly, compare than matched group, VPA group activated mark OX--42 of glial cell and GFAP express and reduce, and the transition that prompting VPA can suppress chronic high intraocular pressure retinal gliocytes activates; Retina BDNF expressed significantly rising of also generation after Westernblot detected VPA; In addition, play an important role in chronic high intraocular pressure ganglionic cell damage because of inflammatory factor TNF-α.Further research VPA is to the influence of retina TNF-alpha expression; whether also can from this angle performance protection ganglion cell's effect, the result shows that TNF-α average content in normal retina is 30.4 ± 5.7 ng/mg albumen if inquiring into VPA; significantly raise during high intraocular pressure, be about normal 16 times.VPA has no significant effect (p＞0.05) (shown in Fig. 5 C) to normal retina TNF-alpha expression, but can significantly reduce TNF-alpha content in the high intraocular pressure retina.
Above-mentioned experimental result shows, during chronic high intraocular pressure, VPA can reduce the expression of short apoptogene BAX by raising the expression of survival genes Bcl-2, survivin, catenin and hsp70 among the RGCs, promotes the RGCs survival; Simultaneously, the damage that VPA also can the retina microenvironment alleviates RGCs when improving chronic high intraocular pressure, comprising: VPA improves the expression of α-synuclein, reduces retina glutamic acid excitatory toxicity; VPA reduces the release of chronic high intraocular pressure retinitis inflammation factor TNF-α, improves the expression of nutrition BDNF; Suppress the retinal gliocytes transition and activate, thus protection RGCs.
Claims (9)
1. sodium valproate is in preparation treatment or improve purposes in the medicine of glaucomatous optic neuropathy; Described sodium valproate has the structure of formula I,
（Ⅰ） 。
2. sodium valproate promotes purposes in the medicine of retinal ganglial cells axon elongation in preparation.
3. by the described purposes of claim 1, it is characterized in that described medicine is to suppress the activated medicine of glaucomatous optic neuropathy process mesoglia cells transition.
4. by the described purposes of claim 1, it is characterized in that described medicine is the medicine that reduces retina glutamic acid excitatory toxicity.
5. a glaucoma retina, optic nerve protection agent is characterized in that, described protective agent is that adjuvant necessary on active constituents of medicine and the pharmaceutics is formed by the sodium valproate of the claim 1 of safe and effective amount.
6. by the described glaucoma retina of claim 5, optic nerve protection agent, it is characterized in that described protectant dosage form is conventional tablet, enteric coatel tablets, slow releasing tablet, syrup, spray capsule, injection, gel, ointment, solution or suspension.
7. press claim 5 or 6 described glaucoma retinas, optic nerve protection agent; it is characterized in that that described protective agent adopts is oral, intravenous injection, local eye drip or be coated with eye, intracameral injection, vitreous body intracavitary administration or through implant sustained-release administration administration.
8. press claim 5 or 6 described glaucoma retinas, optic nerve protection agent, it is characterized in that, described protective agent and one or more intraocular pressure lowering medicines while or administration successively.
9. press claim 5 or 6 described glaucoma retinas, optic nerve protection agent, it is characterized in that, described protective agent and one or more optic nerve protection agent while or administration successively.
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