Нейропротективные эффекты при модуляции глутатионовой системы головного мозга: влияние на летальность, неврологический дефицит, оксидативный стресс в условиях экспериментальной ОНМК

Abstract

На моделі незворотньої односторонньої оклюзії загальної сонної артерії у монгольських піщанок вивчено вплив модуляторів системи глутатіону — глутоксіма, селенази і глутаредоксіна на летальність і неврологічний статус тварин. Відзначено вплив цих препаратів на динаміку показників тіол-дисульфідної системи і нітротирозину. Селеназа в дозі 50 мкг/кг, глутоксім в дозі 50 мг/кг і глутаредоксін в дозі 200 мкл/кг приводили до приросту відновленого глутатіону і вільних -SН груп, зниження нітротирозину. На тлі модуляції глутатіонової системи використовуваними препаратами зареєстровано зниження летальності і постінсультних неврологічних проявів у експериментальних тварин. The growth and spread of ischemic brain lesions among people around the world continues to grow steadily, in spite of the progress made in modern neuropharmacology. Under these circumstances an important aspect in the treatment of cerebral stroke becomes the pharmacological regulation of the molecular and biochemical mechanisms of endogenous neuroprotection. Stabilization of the functions of the antioxidant glutathione system will help protect brain tissue from oxidative and nitrosative manifestations of stress, prevent mitochondrial dysfunction, energy imbalance and other post-ischemic disorders. The aim of our study was to investigate the effect of modulators of the glutathione system — selenase, glutoxim and glutaredoxin — on mortality, neurological deficit and indicators of thiol-disulfide system in the brains of animals with stroke. Object and methods. The experimental part was conducted on 137 male Mongolian gerbils (Meriones unguiculatus) weighing between 60 and 80 g. In accordance to the research program, an irreversible one-way ligation of the common carotid artery was utilized, which presently is generally accepted as an experimental model of acute cerebral circulatory disorders. To study the effect of experimental drugs they were administered intraperitoneally one time daily for 4 days, starting from the first ones, after recovery from anesthesia. Comparison drug and physiological solution (control group) were administered in the same way. Efficiency of glutathione system modulators (selenase – 50 μg/kg, glutoxim – 50 mg/kg, glutaredoxin – 200 μl/kg) and comparison drug (pyracetam – 500 mg/ kg) evaluated by their influences on mortality, neurological deficit, the level of reduced glutathione, free thiols and nitrotyrosine in brain tissue. Results. The results of these studies show that compared with the sharm operated animals, the group of gerbils with stroke showed significantly higher mortality rates and severe neurological symptoms. A course of treatment with selenase, glutoxim and gutaredoxin reduced animal mortality from stroke and improved their neurological status on the McGrow scale. These indicators have a negative correlation with the level of reduced glutathione and free thiols and positively correlated with the level of nitrotyrosine. The results confirm the presence of antioxidant and neuroprotective properties in selenase, glutoxim and glutaredoxin This is determined by their ability to restore the thiol-disulfide equilibrium, decrease the high levels of nitrotyrosine in the ischemic brain of experimental animals. These properties were identified by their ability to restore the thiol-disulfide balance and reduce the high levels of nitrotyrosine in ischemic brain injury, resulting in the reduction of neuronal loss following a stroke. Conclusion. Increase in the levels of restored forms of glutathione and reduction of nitrotyrosine as a result of the conducted pharmacological correction of the glutathione system modulators in animals with cerebral ischemia contributes to positive neurological dynamics and a reduction in mortality.