CN102258518A - Application of huperzine A to preparation of medicament for treating glaucoma and/or ischemia-induced optic nerve damage - Google Patents
Application of huperzine A to preparation of medicament for treating glaucoma and/or ischemia-induced optic nerve damage Download PDFInfo
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- CN102258518A CN102258518A CN201010185040XA CN201010185040A CN102258518A CN 102258518 A CN102258518 A CN 102258518A CN 201010185040X A CN201010185040X A CN 201010185040XA CN 201010185040 A CN201010185040 A CN 201010185040A CN 102258518 A CN102258518 A CN 102258518A
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Abstract
The invention relates to the technical field of medicaments, in particular to application of (-)-huperzine A, a lycopodium alkaloid active monomer component which is separated from Chinese folk herb huperzia serrata, to preparation of a medicament for treating glaucoma and/or ischemia-induced optic nerve damage. The compound huperzine A disclosed by the invention has a structural formula which is shown in the specification. Experiments prove that the huperzine A has obvious miosis and ocular tension reduction effects on a glaucoma animal model and an obvious protection effect on expression of proteins of ischemia or ocular hypertension-induced animal retinopathy and apoptosis inflammation and is expected to be developed into a new medicament for treating the glaucoma and/or ischemia-induced optic nerve damage. The structural formula of the (-)-huperzine A is shown in the specification.
Description
Technical field
The present invention relates to medical technical field, relate to a kind of lycopods alkaloid effective monomer component that is separated to from folks of china medical herbs Herba Lycopodii serrati (HuperziaSerrata)---huperzine A ((-)-huperzineA) purposes the medicine of the optic nerve injury that preparation treatment glaucoma and/or ischemia bring out.
Background technology
Glaucoma is common clinically oculopathy, and main reveal any symptoms is that the intraocular pressure rising causes carrying out property optic nerve lesion and defect of visual field, finally can cause losing one's sight.Treating glaucomatous main means is medicine, laser and operation, and its Chinese medicine control intraocular pressure is most important, most basic treatment means, has the effect that can not be substituted.It is a lot of to be used for glaucomatous medicine now, and cholinomimetic, adrenoreceptor blocker, prostaglandin etc. are arranged.Cholinomimetic mainly by strengthening cholinergic function, shrinks the corpus ciliare longitudinal muscle, and tractive scleral spur and trabecular reticulum make the trabecular reticulum mesh open the promotion ah outflow.These above-mentioned glaucoma treatment drug mains will reduce intraocular pressure by following two kinds of mechanism: reduce aqueous humor and generate; Perhaps promote aqueous humor to discharge, finally reach the purpose of control intraocular pressure.Therefore, seek effectively that control intraocular pressure, safety are good, the persistent medicine of drug action still is the main direction of current glaucoma treatment.
Yet, because glaucoma is that a class is the oculopathy of common trait with specificity optic nerve lesion and defect of visual field, its optic nerve lesion cutter system really is still not fully aware of at present, and the intraocular pressure of some glaucoma patient and not obvious rising, a lot of in recent years scholars think that glaucoma is the nerve retrograde affection that the multi-pathogenesis too many levels brings out.Therefore, the research of treatment glaucoma medicine not only should get down to the reduction intraocular pressure, increases the eye blood flow, more should be conceived to optic nerve protection.Optic nerve protection was suggested in the mid-90 in 20th century, and it is similar to nervus centralis protection, promptly by the intervention of medicine or other method, those was not sustained damage as yet or the optic element that only is subjected to the part damage is survived or prolonged the time-to-live.Optic nerve protection is more suitable for the disease of slowly losing in retinal neuronal cell; therefore wherein significant to the glaucoma optic nerve lesion, research also becomes emerging and hot fields in current glaucoma treatment and other retinal diseases gradually to the protection of optic nerve.Study verifiedly, the Chinese and western drugs with function of protecting optic nerve can obviously improve the apoptosis and the inflammatory reaction of optic element, performance retina function of protecting optic nerve.Therefore, reduce the glaucoma treatment medicine of intraocular pressure symptomatic treatment with traditional passing through and compare, the medicine of research retina function of protecting optic nerve then acts on the generation and the evolution of disease by target, be direct purpose with treatment retina optic nerve.The collaborative performance of this effect and reducing iop function, and then blocking-up or slow down the optic nerve injury that former paathogenic factor causes, will provide for the treatment of these ophthalmology difficult miscellaneous diseases of glaucoma new may.
Huperzine A is a kind of efficient, high selectivity, reversible cholinesterase inhibitor, by the efficient inhibition to acetylcholinesterase, increases the level of acetylcholine, thereby strengthens cholinergic function.Yet, do not have the bibliographical information huperzine A to bring into play the glaucoma treatment effect at present by its cholinergic and non-cholinergic protective effect.
Summary of the invention
Main purpose of the present invention is to provide the purposes of Chinese herbal medicine active component huperzine A in the medicine of the optic nerve injury that preparation treatment glaucoma and/or ischemia bring out.
Described huperzine A is for bringing into play the chemical compound of therapeutic effect by reducing intraocular pressure.
Described huperzine A is the chemical compound that reduces intraocular pressure performance therapeutic effect by miosis function.
Described ischemia is the optic nerve ischemia under high intraocular pressure or the non-high intraocular pressure situation.
Described huperzine A is to have the chemical compound that optic nerve injury is had protective effect.
Described huperzine A is to have the chemical compound that improves retina cell apoptosis, retina cell inflammatory phenomena.
Another object of the present invention provides a kind of pharmaceutical composition for the treatment of the optic nerve injury that glaucoma and/or ischemia bring out, and it comprises the huperzine A and the acceptable accessories for the treatment of effective dose.
The present invention confirms that first huperzine A can significantly dwindle glaucoma animal model pupil, reduces glaucoma animal model intraocular pressure, and the unconventionality expression that can obviously improve retina injury that ischemia or high intraocular pressure bring out and apoptosis, inflammation associated protein is expressed.Described huperzine A, chemical name is: (5R, 9R, 11E)-and 5-amino-11-ethylidene-5,6,9,10-tetrahydrochysene-7-methyl-5,9-methylene ring cycloocta-(b) pyridine-2 (1H) ketone; Chemical structural formula is as follows:
Huperzine A
(-)-Huperzine?A
Described huperzine A can commercial sources obtain, and also can prepare by phytochemistry extraction or complete synthesis mode.
According to the present invention, the huperzine A of the optic nerve injury effective dose that treatment glaucoma and/or ischemia can be brought out and any adjuvant of pharmaceutically permission are made pharmaceutical composition.Described pharmaceutical composition can be used by eye drip, oral, parenteral, suction-type spraying or by the mode of implanted reservoir.
In addition, the present invention also provides a kind of pharmaceutical preparation for the treatment of the optic nerve injury that glaucoma and/or ischemia bring out, and it comprises the huperzine A for the treatment of effective dose.Described preparation can be any one dosage form pharmaceutically, includes but not limited to water solublity eye drop, gel-type eye drop, eye ointment, tablet, capsule, pill, injection etc.
The invention discloses the purposes of huperzine A in the medicine of the optic nerve injury that preparation treatment glaucoma and/or ischemia bring out.Prove first by the zoopery means, huperzine A can significantly dwindle glaucoma animal model pupil, reduce glaucoma animal model intraocular pressure, retina injury that ischemia or high intraocular pressure bring out and apoptosis, inflammation correlative protein expression can be improved simultaneously, the medicine of the optic nerve injury that treatment glaucoma and/or ischemia bring out can be used to prepare.
Description of drawings
Fig. 1 is the reducing iop of huperzine A to the chronic glaucoma rat.Wherein,
##P＜0.01 is than sham operated rats,
*P＜0.01 is than model group.
Fig. 2 is myosis (A) and intraocular pressure lowering (B) effect of huperzine A to the chronic glaucoma rabbit.Wherein,
#P＜0.05,
##P＜0.01 is than normal self-controlled group,
*P＜0.05,
*P＜0.01 is than model group.
Fig. 3 brings out the protective effect of rat retina damage to ischemia or high intraocular pressure for huperzine A.
Fig. 4 is the effect of huperzine A to urgency/chronic glaucoma rat retina apoptosis and inflammation correlative protein expression.Wherein,
*P＜0.05,
*P＜0.01 is than model group.
The specific embodiment
Embodiment 1: huperzine A is to the reducing iop of chronic glaucoma rat
Purpose and principle: induce the chronic glaucoma rat model with the scleral veins ligating methods.Electricity coagulates to get rid of after scleral veins causes aqueous humor to generate and is obstructed, and forms chronic high Intraocular Pressure Model, and the high intraocular pressure of simulation glaucoma is to nerve cell damage such as papilla of optic nerve.Can estimate the reducing iop and the retina function of protecting optic nerve of anti-glaucoma medicine by this model.
Method: after adopting pentobarbital sodium 30mg/kg intravenous injection anesthetized rat, be fixed on the experiment operating-table, last palpebra inferior is done the threading traction, the art eye gives 1% tetracaine angle conjunctival surface anesthesia, cut off bulbar conjunctiva along the top corneoscleral junction, passivity is separated fascia, scleral veins in the exposure, gently with vein separation and burn to iron and close 3 scleral veins of right eye, tailing edge burns and irons the place of closing and cut short blood vessel.Post surgery treatment: with 10-0 not damaged medical suture interrupted suture conjunctiva, the operation eye is coated with chlortetracycline eye ointment, intravenous injection antibiotic.Intraocular pressure raises after the operation modeling, and intraocular pressure continues steadily after the week.
Laboratory animal be divided into sham operated rats, scleral veins burn close high Intraocular Pressure Model group, scleral veins burns and closes+huperzine A administration group.After operation modeling one all intraocular pressures are stable, carry out the administration of huperzine A eye drip.Model group gives the corresponding solvent contrast.0.5,1,2,3,4,6,8 hours different group varieties of intraocular pressure after the mensuration administration.
Result and evaluation: compare with high Intraocular Pressure Model group, huperzine A administration group can significantly reduce the intraocular pressure (Fig. 1) of chronic glaucoma rat.
Embodiment 2: huperzine A is to the myosis and the reducing iop of chronic glaucoma rabbit model
Purpose and principle: induce the chronic glaucoma rabbit model with the Chymetin injection.Induce to the back room of lagophthalmos by the injection Chymetin, the Suspensory ligament of Chymetin hydrolysis crystal forms fragment retardance trabecular reticulum, causes aqueous humor generation back to discharge and is obstructed, thereby form high intraocular pressure.Can estimate the myosis and the reducing iop of anti-glaucoma medicine and retina function of protecting optic nerve by this model.
Method: the high Intraocular Pressure Model of rabbit, anesthesia, myosis, entry needle passes the Chymetin that pupil inserts the 500U/ml of back room injection 0.2ml, the needle point swing is beneficial to Chymetin and is uniformly distributed in back room, the pin of injection was kept somewhere 2 minutes at least, and pin carefully shifts out and avoids Chymetin damage cornea then.20ml physiology water for injection cleans cornea, and conjunctiva etc. are located.The high intraocular pressure in one week back is continual and steady.
Laboratory animal is divided into Chymetin back room injection model group, Chymetin back room injection+huperzine A administration group.The modeling that undergos surgery of every treated animal right eye, left eye is as own control.After operation modeling one all intraocular pressures are stable, carry out the administration of huperzine A eye drip.Model group gives the corresponding solvent contrast.0.5,1,2,3,4,6,8 hours different group varieties of intraocular pressure after the mensuration administration.
Result and evaluation: compare with high Intraocular Pressure Model group, the huperzine A administration is obviously dwindled chronic glaucoma rabbit pupil and is reduced the glaucoma lagophthalmos and press (Fig. 2).
Embodiment 3: huperzine A brings out the protective effect of rat retina damage to ischemia or high intraocular pressure
Purpose and principle: adopt enhancing perfusion to induce rat acute glaucoma model or bilateral ligation to bring out the global brain ischemia model, detect the degree of impairment of ganglia retinae and the protective effect of huperzine A with crystal violet (Cresyl Violet acetate) and HE method.The acute glaucoma model forms high Intraocular Pressure Model at short notice, high intraocular pressure compressing optic nerve, and the build-up of pressure damage model is simulated retinal ischemia when the glaucoma acute attack at short notice, causes the damage to retina and optic nerve.Bilateral neck total ligation causing rat whole brain ischemia comprises retinal ischemia.
Method:
Enhancing perfusion is induced rat glaucoma model: the SD rat is used 30mg/kg pentobarbital sodium injecting anesthetic, and the anesthesia of 1% tetracaine eye table is fixed on rat head on the operating board, exposes right eye.When the 5 number sword-shaped needles that head end shutoff and needle body have a side opening thrust cornea direction of travel be corner of the eyes angle Zi nearly nasal side to offside corner of the eyes angle, the normal saline bottle that slowly raises then, investigate the lasting pressure time of rising 136cm be 1 hour to amphiblestroid degree of injury.Pressurization slowly reduces pressure, the antibiotic eye drip after finishing.
The bilateral ligation model: the animal random packet, performed the operation the same day, chloral hydrate anesthesia, the cervical region median incision separates bilateral common carotid arteries and ligation.Sew up the incision afterwards.In the whole common carotid artery ligation process, rat temperature maintains about 37 degrees centigrade, and operation finishes the pneumoretroperitoneum injection and replenishes normal saline.Postoperative intramuscular injection penicillin.
Rat retina section and HE dyeing: frozen section adopts the rat to excessive anesthesia of heart perfusion to fix, and the bilateral eyeball of complete taking-up rat is soaked in to take out after 24 hours in 4% the paraformaldehyde and is placed in 30% the sucrose solution O.C.T. embedding, 15 μ m section.Paraffin section adopts the rat to excessive anesthesia of heart perfusion to fix, and changes in the fixative then and fixes, back dehydration, saturatingization, waxdip, embedding, 3～5 μ m section.Paraffin section de-waxing, haematoxylin dyeing 5 minutes, washing, 1% acidic alcohol differentiation 30 seconds, 1% ammonia returns indigo plant, and distilled water is given a baby a bath on the third day after its birth inferior, Yihong dyeing, the gradient ethanol dehydration, dimethylbenzene is transparent, medium-sized gummy mounting, optical microscope is observed down.
Pharmaceutical intervention: in the high Intraocular Pressure Model of acute glaucoma, huperzine A gives eye drops after pressurization finished in 1 hour, and animal pattern is put to death after 48 hours, separates eyeball, carries out the retina section after fixing, and observes huperzine A to amphiblestroid protective effect.In the bilateral ligation model, huperzine A group successive administration was put to death after 1 month, separated eyeball, carried out the retina section after fixing, and observed huperzine A to amphiblestroid protective effect.
Result and evaluation: compare with acute high intraocular pressure mouse model group, huperzine A administration group has significant protective effect (Fig. 3) to retina injury.
Embodiment 4: huperzine A brings out the effect of rat retina apoptosis/inflammation correlative protein expression to acute high intraocular pressure
Purpose and principle: use acute high intraocular pressure glaucoma model, observe after the pharmaceutical intervention effect to apoptosis or inflammation correlative protein expression.This model is by the aqueous humor pressurization, causes retinal ischemia, and then causes retina injury.Protein expression adopts Western blot method.What Western Blot adopted is polyacrylamide gel electrophoresis, and detected material is a protein, and " probe " is antibody, and " colour developing " resists with two of labelling.Through PAGE isolating protein example, to transfer on the solid phase carrier (for example cellulose nitrate film), solid phase carrier is with non-covalent bond form adsorbed proteins, and can keep the polypeptide type and the biologic activity thereof of electrophoretic separation constant.With the protein on the solid phase carrier or polypeptide as antigen, play immunoreation with corresponding antibody, react with enzyme or isotope-labeled second antibody, colour developing of process substrate or autoradiography are with the protein ingredient of the specific destination gene expression of detection electrophoretic separation again.
Method: sacrificed by decapitation rat, under cryogenic conditions, separate fresh retina, each retina adds the lysate of 70 μ l, ultrasonication, centrifugal, get supernatant, do standard curve with the bovine serum albumin standard substance, be diluted to identical protein concentration and mix with 2 * sds gel sample loading buffer equal-volume, boiling water boiled 10 minutes, got suitable volume sample and went up sample.Electrophoretic condition is: concentrate glue 80V constant voltage, and 35 minutes, separation gel 120V, 100 minutes, after celluloid changes film, milk sealing 0.5-1 hour, corresponding one anti-4 ℃ of overnight incubation, PBST rinsing 3 times, two anti-incubated at room 2 hours, PBST rinsing 3 times, the colour developing of ECL PLUS test kit, imaging.
Huperzine A gives eye drops after pressurization finished in 1 hour, animal pattern is put to death after 48 hours, peels off eyeball, separates retina, the preparation protein sample is observed the improvement effect of huperzine A to apoptosis and inflammation correlative protein expression with above-mentioned determining the protein quantity method.
Result and evaluation: compare with the glaucoma model group, the huperzine A administration can obviously reduce inflammation associated protein GFAP, increases apoptosis regulatory protein Akt and expresses (Fig. 4).
Claims (9)
1. the purposes of the following chemical compound huperzine A of structural formula in the medicine of the optic nerve injury that preparation treatment glaucoma and/or ischemia bring out,
2. purposes according to claim 1 is characterized in that, described huperzine A is for bringing into play the chemical compound of therapeutic effect by reducing intraocular pressure.
3. purposes according to claim 2 is characterized in that, described huperzine A is the chemical compound that reduces intraocular pressure performance therapeutic effect by miosis function.
4. purposes according to claim 1 is characterized in that, described ischemia is the optic nerve ischemia under high intraocular pressure or the non-high intraocular pressure situation.
5. purposes according to claim 1 is characterized in that, described huperzine A is to have the chemical compound that optic nerve injury is had protective effect.
6. purposes according to claim 5 is characterized in that, described huperzine A is to have the chemical compound that improves retina cell apoptosis, retina cell inflammatory phenomena.
7. a pharmaceutical composition for the treatment of the optic nerve injury that glaucoma and/or ischemia bring out is characterized in that it comprises the huperzine A and the acceptable accessories for the treatment of effective dose.
8. the pharmaceutical composition of the optic nerve injury that treatment glaucoma according to claim 7 and/or ischemia bring out is characterized in that, described pharmaceutical composition is used by eye drip, oral, parenteral, suction-type spraying or by the mode of implanted reservoir.
9. pharmaceutical preparation for the treatment of the optic nerve injury that glaucoma and/or ischemia bring out, it comprises the huperzine A for the treatment of effective dose, it is characterized in that the dosage form of described preparation is water solublity eye drop, gel-type eye drop, eye ointment, tablet, capsule, pill or injection.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103833998A (en) * | 2012-11-26 | 2014-06-04 | 杨子剑 | Novel compound with ethacrynic acid structure as well as preparation method and application of novel compound |
| CN113041217A (en) * | 2021-03-22 | 2021-06-29 | 沈阳何氏眼产业集团有限公司 | Huperzine A water-soluble eye drops containing cyclodextrin or cyclodextrin derivative and preparation method and application thereof |
| CN115336553A (en) * | 2022-06-28 | 2022-11-15 | 温州医科大学附属眼视光医院 | Construction method and application of open-angle glaucoma disease animal model |
| CN116115614A (en) * | 2023-03-15 | 2023-05-16 | 浙江大学 | Application of huperzine A in preparing medicament for preventing and treating diabetic retinopathy |
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| CN1110140A (en) * | 1994-04-07 | 1995-10-18 | 中国人民解放军军事医学科学院毒物药物研究所 | Drug composition for curing dysmnesia and dementia and its preparing method |
| US20080090808A1 (en) * | 2006-10-17 | 2008-04-17 | Franklin Volvovitz | Pharmaceutical compositions and methods for preventing, treating, or reversing neuronal dysfunction |
| CN101797223A (en) * | 2009-02-06 | 2010-08-11 | 上海交通大学医学院 | Huperzine A preparations for eyes and application thereof |
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2010
- 2010-05-28 CN CN201010185040XA patent/CN102258518A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1110140A (en) * | 1994-04-07 | 1995-10-18 | 中国人民解放军军事医学科学院毒物药物研究所 | Drug composition for curing dysmnesia and dementia and its preparing method |
| US20080090808A1 (en) * | 2006-10-17 | 2008-04-17 | Franklin Volvovitz | Pharmaceutical compositions and methods for preventing, treating, or reversing neuronal dysfunction |
| CN101797223A (en) * | 2009-02-06 | 2010-08-11 | 上海交通大学医学院 | Huperzine A preparations for eyes and application thereof |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103833998A (en) * | 2012-11-26 | 2014-06-04 | 杨子剑 | Novel compound with ethacrynic acid structure as well as preparation method and application of novel compound |
| CN103833998B (en) * | 2012-11-26 | 2017-10-27 | 杨子剑 | Noval chemical compound and preparation method and purposes containing ethacrynic acid structure |
| CN113041217A (en) * | 2021-03-22 | 2021-06-29 | 沈阳何氏眼产业集团有限公司 | Huperzine A water-soluble eye drops containing cyclodextrin or cyclodextrin derivative and preparation method and application thereof |
| CN115336553A (en) * | 2022-06-28 | 2022-11-15 | 温州医科大学附属眼视光医院 | Construction method and application of open-angle glaucoma disease animal model |
| CN116115614A (en) * | 2023-03-15 | 2023-05-16 | 浙江大学 | Application of huperzine A in preparing medicament for preventing and treating diabetic retinopathy |
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Application publication date: 20111130 |