CN103239440A - Application of mitiglinide in preparation of medicine for treating cerebral arterial thrombosis - Google Patents
Application of mitiglinide in preparation of medicine for treating cerebral arterial thrombosis Download PDFInfo
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- CN103239440A CN103239440A CN2013101727038A CN201310172703A CN103239440A CN 103239440 A CN103239440 A CN 103239440A CN 2013101727038 A CN2013101727038 A CN 2013101727038A CN 201310172703 A CN201310172703 A CN 201310172703A CN 103239440 A CN103239440 A CN 103239440A
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Abstract
The invention provides an application of mitiglinide (MGN) in preparation of a medicine for treating the cerebral arterial thrombosis. An experiment shows that under the condition that the dosage of blood sugar is not reduced, the MGN can obviously improve the neurological disorder of a mice model or a rat model suffering from the cerebral arterial thrombosis and reduce the volume of the cerebral infarction; and the MGN inhibits the reduction of the survival rate of SH-SY5Y cells of a neuron cell strain caused by the oxygen-glucose deprivation (OGD), so that release of lactic dehydrogenase (LDH) is reduced, and the neuronal apoptosis caused by the OGD is improved. A result shows that the MGN has pharmacological effects of treating the cerebral arterial thrombosis and reducing the neuron damage caused by the OGD; and the treatment effect is bidirectional. The invention aims to prepare the medicine for treating the cerebral arterial thrombosis by taking the MGN as an active component.
Description
Technical field
The invention belongs to the application of Mitiglinide, the particularly application of Mitiglinide in preparation treatment ischemic cerebral apoplexy Chinese medicine.
Background technology
Apoplexy (stroke) is one group of unexpected onset, is the cerebral blood circulation obstacle disease of feature with focal neurological deficit.Its cause of disease mainly is that various factors causes in the brain stricture of artery, obturation or breaks, thereby cause the acute brain disturbance of blood circulation, show as the sings and symptoms of a property crossed or permanent delayed ischemic neurological deficits clinically, have characteristics such as high incidence, high fatality rate, high disability rate, high relapse rate, leave over dysfunctions such as hemiplegia, aphasia among the survival patient more.In American-European countries, apoplexy be after tumor, heart disease the third-largest cause of death, and occupy second of the cause of death in China.Bring great financial burden and harmful effect for patient, family and even society.80% belongs to cerebral infarction in the patients with cerebral apoplexy, at present clinical in early stage thrombolytic measure, acute ischemic cerebral apoplexy (acute ischemic stroke, AIS) clinical treatment still lacks effective means, and the time window of thromboembolism treatment is extremely short and can not interrupt the secondary lesion due to the AIS and the vicious cycle that causes thereof.The application experiment animal prepares the central nervous system injury Study of model and finds; a series of waterfall sample retardance biochemical reactions of being induced by ischemia are the key reasons that causes apoplexy tissue injury and long-term action obstacle; its pathomechanism comprises excitatory toxicity; ion imbalance; oxidative stress; inflammatory reaction and aregeneratory etc.; further investigation apoplexy nerve injury and Neuroprotective Mechanisms; the developing effectively medicine for the treatment of apoplexy has become the social problems that can not be ignored, so research and develop desirable cerebral infarction neuroprotective and therapeutic strategy seems very urgent and necessary.
Mitiglinide belongs to phenylalanine derivative, the non-sulfonylurea Drugs Promoting Insulin Secretion, and specific effect suppresses the K-ATP passage in the Kir6.2/SUR1 hypotype, by closing the K on the beta Cell of islet
+-ATP passage makes the depolarization of β cell membrane, and calcium channel is open, Ca
2+Interior stream, Ca in the cell
2+Concentration increases and impels the vesicle of insulin-containing to take off granule, thereby stimulates insulin secretion, in recent years as antidiabetic drug early stage and light, moderate type 2 diabetes mellitus patient first-line treatment.Compare with sulfonylurea drugs, that Mitiglinide has is quick-acting, potent, the characteristics of fugitive blood sugar lowering, and receptor-specific height, administration are flexible, safe, better tolerance, do not have advantage such as accumulate in vivo, are considered to following a kind of desirable blood sugar regulator used during user having meals.Recent study finds when Mitiglinide reduces post-prandial glycemia, also to have and reduce oxidative stress and role of cytokines after the meal.In addition; discover that Mitiglinide can keep and prolong the ischemia pretreatment to the protective effect of myocardial ischemia; but its protective effect to nerve injury diseases such as cerebral ischemia nerve injury, neurodegenerative diseases has not yet to see report, it is developed into the cerebral infarction medicine have high potential value and social meaning.
Summary of the invention
Goal of the invention
The objective of the invention is by the Mitiglinide Pharmacological action study, design it in the application of Mitiglinide in preparation treatment ischemic cerebral apoplexy Chinese medicine.
Technical scheme
The application of Mitiglinide in preparation treatment ischemic cerebral apoplexy Chinese medicine.
Described cerebral infarction is the cerebral infarction of acute stage or the phase of reparation.
The consumption of Mitiglinide can use once a day or repeatedly according to the variations to some extent such as the order of severity of route of administration, patient age, body weight, body surface area, the disease for the treatment of in not causing the scope that blood glucose reduces.
The single application amount of described Mitiglinide is mice 0.01mg/kg～1.0mg/kg for the single application amount, rat 0.0035mg/kg～0.35mg/kg, people 0.00056mg/kg～0.056mg/kg; Standard body weight people (70kg) single use amount 0.04mg～4mg.
Beneficial effect:
1, up to now, seek and find that new apoplexy neuroprotective all is a challenge for clinician and researcher.The present invention uses temporary cerebral infarction mouse model, permanent cerebral infarction rat with Mitiglinide, and stripped oxygen sugar is deprived the scale-model investigation of (OGD) cell injury and found: (1) Mitiglinide significantly improves transience middle cerebral artery thromboembolism model (tMCAo) mice delayed ischemic neurological deficits under the dosage of blood sugar lowering not, reduce brain infarction area; Increase with Mitiglinide dosage, blood sugar reducing function strengthens, and the cerebral ischemia protective effect but weakens or do not have; (2) Mitiglinide reduces permanent middle cerebral artery thromboembolism model (pMCAo) rat cerebral infarction volume; (3) Mitiglinide significantly improves the active reduction with cell viability of SH-SY5Y neuronal cell strain due to the OGD, suppresses the release of LDH, reduces apoptosis.These results of study show that Mitiglinide has the treatment cerebral infarction, reduces the effect of neuronal damage due to the OGD, can be used for preparing the medicine of cerebral infarction.
2, the single dose of Mitiglinide is significant to therapeutic effect among the present invention, is specially to be below or above dosage and all not have effect or poor effect.
3, the present invention confirms that first Mitiglinide has therapeutical effect to cerebral infarction when blood sugar lowering dosage not, and medication will have huge market value and social benefit as preparation treatment cerebral infarction with it.
Description of drawings:
Accompanying drawing 1:MCAO Preparation of model and monitoring, A: middle cerebral artery occlusion model diagram; B: the local cerebral blood flow of laser Doppler flowmetry monitoring;
Accompanying drawing 2: Mitiglinide is to influence (* P＜0.05, * * P＜0.01, the vs.tMCAO0 of tMCAo mouse blood sugar; #P＜0.05, ##P＜0.01, ###P＜0.001vs.BeforeI/R; Mean ± S.E.M, n=6);
Accompanying drawing 3: Mitiglinide is to influence (* P＜0.05, * * P＜0.01, the vs.Sham of tMCAo mice delayed ischemic neurological deficits; #P＜0.05, ##P＜0.01VS.tMCAO0; Mean ± S.E.M, n=6);
Accompanying drawing 4: Mitiglinide is to influence (* P＜0.05, * * * P＜0.001, the tMCAO0 of tMCAo mouse brain Infarction volume; Mean ± S.E.M, n=6);
Accompanying drawing 5: Mitiglinide is to influence (the A:pMCAo rat brain slice TTC dyeing of pMCAo rat cerebral infarction volume; B:pMCAo mouse brain Infarction volume statistics, * P＜0.05, vs.pMCAo; Mean ± S.E.M, n=6);
Accompanying drawing 6. Mitiglinides to SH-SY5Y cell OGD after influence (* P＜0.05, * * P＜0.01, the * * * P＜0.001vs.Control of cell viability; #P＜0.05, ##P＜0.01, ###P＜0.001vs.OGD; Mean ± S.E.M, n=4.);
Accompanying drawing 7: Mitiglinide to SH-SY5Y cell OGD after the LDH influence (* P＜0.05, * * P＜0.01, the * * * P＜0.001vs.Control that discharge; #P＜0.05, ##P＜0.01, ###P＜0.001vs.OGD; Mean ± S.E.M, n=4.);
Accompanying drawing 8. Mitiglinides are to the influence of apoptosis due to the SH-SY5Y cell OGD
The specific embodiment:
1.1 experiment material
1.1.12-3 the monthly age, male C 57 BL/6 J mouse, 24-28g.Available from Nanjing Medical University's Experimental Animal Center, animal production licence number: SCXK(Soviet Union) 2008-0004.Feeding conditions comprises standard feed, tap water, room temperature remains on (24 ± 2) ℃, humidity 50-60%, illumination every day and interlunation each 12h.Before the experiment, place experimental situation to adapt to 3 days animal.
1.1.2 Mitiglinide Calcium (Lianyungang Ruizhong Pharmaceutical Co., Ltd., lot number 1612001) is with normal saline preparation, mother liquid concentration 1.2mg/ml ,-20 ℃ of storages.2,3,5-triphenyltetrazolium chloride (2,3,5-triphenyltetrazoliumchloride, TTC is available from sigma company), the surplus commercial goods that is.
1.2 method
1.2.1tMCAo mouse model: fasting 8-10h before the mice art, freely drink water.Lumbar injection chloral hydrate (350mg/kg) anesthetized mice, with reference to the Longa method, with right side middle cerebral artery occlusion (middle cerebral artery occlusion, MCAO) model in nylon monofilament line (Doccol Corp) the preparation monofilament tube chamber of 6-0 silica gel bag quilt.After 60 minutes, beat easily out nylon wire at ischemia, and recover the confession of common carotid artery blood.All (UK) monitoring confirms (Fig. 1) for Moor Instruments, Devon, and body temperature maintains 36 ℃-37 ℃ by laser Doppler flowmetry (LDF) for ischemia and refilling process.Pseudo-operation treated animal is accepted identical anesthesia and operation process, except not carrying out tMCAO.
1.2.2 administration detects with sampling: the C57BL/6J mice is divided into temporary middle cerebral artery thromboembolism re-perfusion model group (tMCAo) at random, Mitiglinide various dose group.Mice is poured into back 60min again at the middle cerebral artery thromboembolism and irritates the Mitiglinide that stomach gives various dose, and 0.2ml/10g body weight, model group give the normal saline of equivalent with method.Before the mice ischemia, behind the ischemia 2,24h tail vein measuring blood sugar of blood extracting value, postoperative 24h carries out pharmacodynamics evaluations such as delayed ischemic neurological deficits scoring, cerebral infarction volume.
1.2.3 delayed ischemic neurological deficits scoring: according to the five-grade marking system standards of grading, each group mice is carried out the neuromotor dysfunction scoring: 0 minute, normal, impassivity was learned sign; 1 minute, can not the full extension left fore; 2 minutes, during walking turn-taked in the left side; 3 minutes, toppled in the left side during walking; 4 minutes, nothing was independently walked and is reduced with level of consciousness; 5 minutes, death.
1.2.4 cerebral infarction stereometry: the mice sacrificed by decapitation, take out cerebral tissue rapidly, remove olfactory bulb, cerebellum and low brain stem ,-20 ℃ of freezing 10min.Cut the crown section of 1mm thickness brain continuously from the preceding utmost point (anterior pole), put 2% 2,3,5-triphenyltetrazolium chloride (2,3,5-triphenyltetrazoliumchloride, TTC, available from sigma company) 37 ℃ of lucifuges are hatched 10min in the normal saline solution, and 10% formaldehyde neutral buffered liquid (pH7.4) fixedly spends the night.The microspur camera is taken, and Image pro plus5.1 image analysis software is calculated and the statistical brain Infarction volume.
1.3 result
1.3.1 blood sugar monitoring: tMOAC mice single is irritated before stomach 0.05,0.1,0.33mg/kg Mitiglinide blood glucose fluctuation and the administration relatively there was no significant difference (P ﹥ 0.05), and the filling stomach gives 1,3,6mg/kg Mitiglinide mouse blood sugar significantly is lower than (P ﹤ 0.05 or P ﹤ 0.01 or P ﹤ 0.001) before the administration; During administration 2h, 3,6mg/kg Mitiglinide group mouse blood sugar contrast significantly reduce (with tMCAO0 relatively P ﹤ 0.05 or P ﹤ 0.01), as shown in Figure 2.Prompting, the above dosage of 1mg/kg Mitiglinide have the effect that reduces the tMCAO mouse blood sugar.
1.3.2 function of nervous system estimates: the not tensible of left fore of damage offside appears in tMCAo model group mice operation back, during walking turn-take or topple in the left side, in addition can't independently walk, level of consciousness reduces or significant cerebral infarction delayed ischemic neurological deficits symptom such as death.Single gavages Mitiglinide function of nervous system's moving obstacle due to the mice tMCAo is two-way reaction; when dosage increase effect strengthens; protective effect the strongest (comparing P ﹤ 0.05 or P ﹤ 0.001 with tMCAO) during to 0.33mg/kg weakens or a few nothing (Fig. 3) greater than the increase protective effect with dosage behind this dosage.The contrast blood sugar detection found that: the increase mouse blood sugar with dosage reduces, and function of nervous system's moving obstacle increases.The prompting Mitiglinide has the effect that alleviates delayed ischemic neurological deficits due to the mice tMCAo, and the protective effect of cerebral infarction nerve injury is dosage correlation.
1.3.3 cerebral infarction volume: Fig. 4 result shows similar to Fig. 3; single gavages Mitiglinide the increase of cerebral infarction volume due to the mice tMCAo is two-way reaction; increasing the cerebral infarction volume with dosage reduces; protective effect the strongest (comparing P ﹤ 0.05 or P ﹤ 0.001 with tMCAO) during to 0.33mg/kg; after this increase protective effect with dosage weakens or a few nothing, and this effect and Mitiglinide blood sugar lowering degree are inverse ratio.The prompting Mitiglinide has the effect that reduces tMCAo mouse brain Infarction volume.
Present embodiment prompting Mitiglinide has the amphicheirality to the therapeutical effect of cerebral infarction, can alleviate the cerebral infarction delayed ischemic neurological deficits under the dosage of blood sugar lowering not, reduces the cerebral infarction volume; Increase with Mitiglinide dosage, blood sugar reducing function strengthens, and the cerebral ischemia protective effect weakens or do not have.Show that Mitiglinide has the possibility for the treatment of cerebral infarction.
2.1 experiment material
2.1.1 animal: 2-3 monthly age, male SD rat, 230-270g.Available from Nanjing Medical University's Experimental Animal Center, animal production licence number: SCXK(Soviet Union) 2008-0004.Feeding conditions comprises standard feed, tap water, room temperature remains on (24 ± 2) ℃, humidity 50-60%, illumination every day and interlunation each 12h.Before the experiment, place experimental situation to adapt to 3 days animal.
2.1.2 same 1.1.2.
2.2 method
The pMCAo rat model: fasting 12h before the rat art, lumbar injection chloral hydrate (350mg/kg) anesthetized rat makes rat stop autonomic activities, and is of flaccid muscles.With reference to the tMCAo mouse model, right side middle cerebral artery occlusion (middle cerebral artery occlusion, MCAo) model in the preparation monofilament tube chamber.Lead and fixing vascular peg stay line are wiped out in ligation ICA hemostasis, layer-by-layer suture muscle, body of gland and skin, and the local antibiotic that uses is protected from infection behind the wound disinfection, lies on the back to place incubator to treat that anesthesia regains consciousness.Operation process confirms that by the laser Doppler flowmetry monitoring body temperature maintains 36 ℃-37 ℃.Pseudo-operation treated animal is accepted identical anesthesia and operation process, except not inserting bolt line and ligation ICA in blood vessel.
Grouping and administration: the SD rat is divided into permanent middle cerebral artery thromboembolism model group (pMCAo) at random, 0.16mg/kg Mitiglinide treatment group.Rat is irritated stomach at middle cerebral artery thromboembolism 3h and gives Mitiglinide, the 0.2ml/100g body weight, and matched group gives the normal saline of equivalent with method, and every day 1 time, successive administration carries out the evaluation of cerebral infarction volume after 3 days.
Evaluation index: the evaluation methodology of cerebral infarction volume is with 1.2. among the embodiment 1
2.3. result
The continuous 3d of pMCAo rat irritates stomach and gives 0.16mg/kg Mitiglinide, compares the cerebral infarction volume with model and significantly reduces (Fig. 5, p＜0.05), and the prompting Mitiglinide has the effect of the permanent cerebral infarction for the treatment of.
3.1 experiment material
The SH-SY5Y cell strain: the neuronal cell strain, purchase the consonance cell institute in the Chinese Academy of Medical Sciences.First formylmerphalan azoles indigo plant (MTT) is available from Guangzhou Chemical Reagent Factory; Microplate reader is available from Thermo company.
LDH measures test kit: bio-engineering research institute product is built up in Nanjing.
3.2 method
3.2.1SH-SY5Y cell oxygen sugar deprivation model: the SH-SY5Y cell strain be incubated in the DMEM culture medium that contains 10%FBS (37 ℃, 5%CO
2), be inoculated in before the experiment on 96 orifice plates and cultivated 24 hours.Experiment day, administration is in advance changed pastille sugar-free DMEM culture medium after hatching 30min, and to three gas incubators (37 ℃, 1%O
2, 94%N
2, 5%CO
2) oxygen sugar recovers the normal 24h of cultivation of oxygen sugar after depriving and cultivating 60min, sampling detects.Mitiglinide drug incubation concentration is respectively 10
-10, 10
-9, 10
-8, 10
-7, 10
-6With 10
-5Mol.3.2.2LDH with cell viability: give SH-SY5Y cell that different pharmaceutical handles through oxygen sugar deprive recover the normal 24h of cultivation of oxygen sugar after, collect supernatant and be used for measuring LDH; The MTT solution 20 μ l that add 5mg/ml again continue to hatch and stop behind the 4h cultivating.The careful suction abandoned supernatant, and every hole adds 150 μ lDMSO mixings, selects the 570nm wavelength to measure each hole absorbance value, the record result.Cell viability (%)=experimental group absorbance value/matched group absorbance value * 100%.
3.2.3. apoptosis: give the SH-SY5Y cell of different pharmaceutical processing after oxygen sugar is deprived, D-Hanks solution rinsing twice, digestion centrifuge cell.Resuspended cleaning twice adds the resuspended mixing of 500 μ lPI/AnnexinV mixed liquors.The effect of room temperature lucifuge used flow cytometer to detect the apoptosis of respectively organizing cell after 10 minutes.
3.3 result
Vitro study finds that oxygen sugar is deprived 1h and caused the SH-SY5Y cell survival rate to reduce, and promotes LDH to discharge, and increases apoptosis, than the control group significant difference is arranged all.10
-10Mol/L～10
-7The mol/L Mitiglinide significantly improves cell survival rate due to the OGD and reduces, reduces LDH and discharge, suppress the apoptosis that OGD induces (Fig. 6～Fig. 8) is with 10
-8The effect of mol/L Mitiglinide is stronger.
Present embodiment shows, Mitiglinide significantly improves neuronal activity due to the OGD and the reduction of multiplication capacity, suppresses the release of LDH, reduces apoptosis, has the effect of neuronal damage due to the protection OGD.
Claims (4)
1. the application of Mitiglinide in preparation treatment ischemic cerebral apoplexy Chinese medicine.
2. according to the application of claims 1 described Mitiglinide in preparation treatment ischemic cerebral apoplexy Chinese medicine, it is characterized in that described Ischemic Stroke is the cerebral infarction of acute stage or the phase of reparation.
3. according to the application of claims 2 described Mitiglinides in preparation treatment ischemic cerebral apoplexy Chinese medicine, the single application amount that it is characterized in that described Mitiglinide only limits to the dosage that do not cause that blood glucose reduces.
4. according to the application of claims 2 described Mitiglinides in preparation treatment ischemic cerebral apoplexy Chinese medicine, the single application amount that it is characterized in that described Mitiglinide is mice 0.01mg/kg～1.0mg/kg, rat 0.0035 mg/kg～0.35mg/kg, people 0.00056mg/kg～0.056mg/kg; Standard body weight people 70kg single use amount 0.04mg～4mg.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008089103A2 (en) * | 2007-01-12 | 2008-07-24 | University Of Maryland, Baltimore | Targeting ncca-atp channel for organ protection following ischemic episode |
| CN102743755A (en) * | 2006-02-07 | 2012-10-24 | 持田制药株式会社 | Composition and method for preventing recurrence of stroke |
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2013
- 2013-05-10 CN CN2013101727038A patent/CN103239440A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102743755A (en) * | 2006-02-07 | 2012-10-24 | 持田制药株式会社 | Composition and method for preventing recurrence of stroke |
| WO2008089103A2 (en) * | 2007-01-12 | 2008-07-24 | University Of Maryland, Baltimore | Targeting ncca-atp channel for organ protection following ischemic episode |
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Application publication date: 20130814 |