Nosach S. Purposeful search for neuroprotective compounds with an antioxidant mechanism of action among xanthine derivatives

The dissertation is devoted to the actual task of pharmacology - the search for new effective medicamentous remedies for violations of cerebral circulation on the basis of derivatives of 3-alkyl (aryl, aralkyl) xanthine. In vitro studies (inhibition of NO, protein oxide modification and Fe2+ dependent free radical oxidation (FRO), and also the evaluation of the efficacy of the compound under the conditions of simulation of acute cerebrovascular accident were performed in 52 samples of xanthine derivatives of 8-benzylamino-thiophenyl-7-acetic acid hydrazide (C-3) and experimentally substantiated application as a neuroprotector with an antioxidant mechanism of action. It was established that the compound C-3 belongs to the IV class of toxicity: LD50 in the intragastric administration of rats is 2100 ± 142.8 mg/kg. In order to determine further studies of the most promising compound of S-3-hydrazide 8-benzylaminoteo-filillin-7-acetate, and taking into account the parameters of its acute toxicity, an effective dose of the compound has been experimentally determined. Morphometric studies have shown that ischemia modeling and the injection of autologous blood into the inner brain capsule resulted in a significant decrease in neuron density of the sensorimotor zone of the cerebral cortex compared with intact animals, both on the 4th and on the 18th day of the experiment. At the same time there was a significant decrease in the area of neuronal bodies, a decrease in the content of RNA in the neurons of 26% relative to the pseudo-operated group of animals at the same time of observation. The course assignment of the C-3 compound leads to improvement of morpho-functional parameters of the neurons of the sensorimotor zone of the cortex on the 4th day of the experiment after the occlusion of the carotid arteries and intrahepatic hemorrhage, increasing the density of neurons of the brain by 20% and 10%, increasing the RNA of the brain neurons by 37% and 34% respectively, a decrease in apoptotic and necrotic changes in cells on the 4th day by 49% and 14% compared with the control group. There was an increase in c-Fos-positive cells on the 18th day in 1.5 – 0.9 (p <0.05) times. The practical value of the results is obtained. The results obtained from the experimental study of the neuroprotective compound of hydrazide 8-benzylaminotheophyllinyl-7-acetate acid are the justification for further in-depth study of the compound as a potential drug for the complex therapy of stroke. The prospect of finding new antioxidants and neuroprotectors in the series of derivatives of xanthinyl-7-acetate and xanthinyl-8-thioacetate acids and 3-R-hydroxymethylxanthines is performed.