Нейропротективные свойства производного фурана - соединения ГИЖ-276 на модели геморрагического инсульта

The study of the neuroprotective properties new original compound GIZH-276 and evaluate changes activities of prolyl endopeptidase (PEP) and lactate dehydrogenase (LDH) in blood plasma of rats with post-traumatic hematoma (model of hemorrhagic stroke) is the aim of this investigation. Methodology of the study: Modeling of hemorrhagic stroke (HS) was carried out using the creation of intracerebral post-traumatic hematoma with the introduction of autologous blood into the site of injury. Assay of enzymes activities in plasma was carried out with fluorescent (PEP) and ultraviolet (LDH) methods. The results of the study: GIZH-276 at dose of 10 mg/kg (7 days, intraperitoneally) has a pronounced neuroprotective effect, attenuating neurological deficits in rats with hemorrhagic stroke 24 hours, 7 and 14 days after surgery and statistically significantly increasing the number of surviving rats by 14 days of observation. The weakening of neurological deficit and death of animals is accompanied by decreased activity of enzymes LDH and PEP, which indicates the improvement of security of brain tissue oxygen and reducing neuroinflammation. Conclusion: Safety and neuroprotective effect of GIZH-276 on the model of hemorrhagic stroke may be partially due to positive effect on inflammatory and hypoxia during the development of secondary brain damage in stroke.Целью настоящего исследования было изучение нейропротективных свойств нового оригинального соединения ГИЖ-276 с биохимической оценкой его влияния на активность ферментов пролилэндепептидазы (ПЭП и лактатдегидрогеназы (ЛДГ) в плазме крови крыс с посттравматической гематомой, моделью геморрагического инсульта. Методика исследования: моделирование геморрагического инсульта проведено с использованием методики создания интрацеребральной посттравматической гематомы с введением аутокрови в место повреждения. Флуориметрически, ультрофиолетовым методом проведено биохимическое исследование влияния ГИЖ-276 на активность ферментов ПЭП и ЛДГ в плазме крови крыс с ГИ. Результаты исследования: выявлено, что ГИЖ-276 в дозе 10 мг/кг (7 дней, внутрибрюшинно) оказывает выраженный нейропротективный эффект, ослабляя неврологический дефицит у крыс с геморрагическим инсультом через 24 ч, 7 и 14 сут. после операции и статистически достоверно увеличивая число выживших крыс к 14-м суткам наблюдения. Ослабление неврологического дефицита и гибели животных сопровождается снижением активности ферментов ЛДГ и ПЭП, что свидетельствует об улучшении обеспечения тканей мозга кислородом и уменьшении нейровоспаления. Заключение: защитный, нейропротективный эффект ГИЖ-276 на модели геморрагического инсульта может быть частично обусловлен его положительным влиянием на воспалительное и гипоксическое звено развития вторичных повреждений мозга при инсульте

Новое производное оксимов 4-бензоилпиридинов ГИЖ-298, обладающее противосудорожной активностью

Novel derivative of benzoylpyridine oximes - GIZH-298 (4-benzoylpyridine 0-(2-morpholinoethyl) oxime oxalate) was designed and synthesized in this work. This compound has a broad spectrum of anticonvulsant effects, eliminating primary generalized seizures in maximal electroshock (MES) and corazol antagonism tests in rodents in the doses of 0,5-100 mg/kg. LD50 for compound GIZH-298 is 316 mg/kg intraperitoneally (mouse). GIZH-298 has a large therapeutic breadth.В настоящей работе осуществлён дизайн и синтез нового производного оксима 4-бензоилпиридина - ГИЖ-298 (оксалат 0-(2-морфолиноэтил)оксима 4-бензоилпиридина). Это соединение обладает противосудорожной активностью, устраняя первично-генерализованные судороги в тестах антагонизма с максимальным электрошоком (МЭШ) и коразолом в дозах 0,5-100 мг/кг у грызунов внутрибрюшинно. ЛД50 при внутрибрюшинном введении для соединения ГИЖ-298 составляет 316 мг/кг (мыши). Таким образом, ГИЖ-298 имеет большую терапевтическую широту

4-BENZOYLPYRIDINE OXIME DERIVATIVE (GIZH-298) VERSUS VALPROIC ACID: THE ANTICONVULSANT POTENTIAL EFFECT IN A MODEL OF EPILEPSY IN RATS WITH COBALT-INDUCED LESIONS

Objective of the research is to evaluate the anticonvulsant effect of the new original compound GIZH-298 (4-benzoylpyridine oxime derivative) versus valproic acid (VPA) in a model of epilepsy in rats with cobalt-induced lesions.Materials and methods. Modeling of epileptic status was performed using the technique of creating a chronic epileptogenic focus caused by the application of cobalt to the sensorimotor zone of the rat cortex, followed by intraperitoneal administration of homolecysteine thiolactone. Compounds GIZH-298 and VPA were introduced against the background of development of electrographic status with behavioral convulsive seizure manifestations.Results. The study revealed that GIZH-298 at a dose of 60 mg/kg (i. p.) in 50 minutes after injection reduces the number of high-amplitude generalized discharges caused by homocysteine thiolactone in the ipsilateral and contralateral cortex (46-fold decrease), in the hippocampus and hypothalamus (28-fold decrease); eliminates (in 100% of the animals) the generalized tonic-clonic seizures that arise in the advanced stage of status epilepticus. VPA at a dose of 100 mg/kg (i. p.) in 3 hours after injection significantly suppresses the EpA in all evaluated structures with the maximum value in the hypothalamus (28-fold decrease), and after 5 hours in the ipsilateral and contralateral (33-fold decrease). At the same time, VPA eliminates generalized motility of status epilepticus only in 71% of the animals and protects from death 86% of the rats.Conclusion. The compound GIZH-298 significantly earlier (for 2 hours) than the VPA (100 mg/kg) and at a lower dose (60 mg/kg) fully eliminates electrographic (in all evaluated brain structures with the greatest efficiency in the contralateral cortex and the hypothalamus) and behavioral manifestations of unfolded status epilepticus and prevents deaths in 100%

ELECTROPHYSIOLOGICAL AND NEUROCHEMICAL STUDIES OF THE MECHANISMS OF THE ANTICONVULSANT EFFECT OF THE NEW ORIGINAL COMPOUND GIZH-298

The aim of this study was to investigate the electrophysiological and neurochemical mechanisms of the anticonvulsant effect of a new original compound  GIZH-298 and to define the leading structure as the target for influence compound. Materials and  Methods. The partial (focal) and secondary generalized seizures were modeled by methods of creation a chronic epileptic focus  that was caused  by cobalt applique on the brain of rats. The liquid chromatography  (HPLC) analysis used for neurochemical study of the effect GIZH-298. There was studied the effect on metabolism  and quantity of biogenic amines in the brain structures of rats. Results. It was found that GIZH-298 at a dose of 60 mg / kg (i.p.) has a pronounced effect on the primary and especially secondary generalized epileptic foci in various brain structures with a primary influence on the cortex. GIZH-298 at a dose  of 60 mg / kg caused  a statistically significant increase in the content of serotonin and dopamine in the frontal cortex after 30 minutes after the administration and reduced the rate of metabolism  of dopamine  in the  dorsal striatum.  Conclusion.  The anticonvulsant  effect  GIZH-298  is enhanced  with increased of epileptic system, may be due to increased synthesis of serotonin and dopamine in the cortex, and decreased metabolism  of the latter in the striatum