MOLECULAR AND BIOCHEMICAL ASPECTS OF ENERGOTROPIC MECHANISM OF THIOL-DISULFIDE SYSTEM UNDER CONDITIONS OF ACUTE CEREBRAL CIRCULATION IMPAIRMENT

Under conditions of cerebral circulation impairment an imbalance of energetic metabolism could have negative influence on neurons and could lead to their death. In the case of energetic deficiency it is observed a significant carbohydrate metabolism disorder when aerobic pathways of oxidation are inhibited, anaerobic glycolysis is enhanced and lactate is accumulated. These processes evoke an impairment of cellular redox homeostasis, shift of thiol-disulfide balance and deprivation of heat shock proteins (HSP) expression. A promising concept of pharmacological correction under conditions of ischemia is a maintenance of thiol redox status of a cell in order to prevent any metabolic impairments which are stipulated by mitochondrial dysfunction.

Modelling of experimental acute cerebral circulation impairment by means of bilateral occlusion of common carotid arteries caused typical disorders of energetic carbohydrate metabolism inside neurons. This was exhibited in a compensatory activation of anaerobic glycolysis and inhibition of reactions of tricarboxylic acids cycle. That is proved by the inhibition of malate dehydrogenase activity by 21.6%, decrease of malate and pyruvate level by 61.5% and 2.5 times correspondingly with regard to analogous indexes of falseoperated animals. The obtained data are the evidence of inhibition of tricarboxylic acids cycle reactions on a site “citrate — succinate”. The numerated pathobiochemical shifts of energetic metabolism appeared against a background of impairments of thiol-disulfide balance, in other words the decrease of reduced glutathione form, accumulation of oxidized glutathione form and inhibition of protein HSP70 expression.

During the performed investigations it was established that the introduction of thiol-disulfide system modulators caused activation of aerobic pathways of oxidation as well as anaerobic ones. It was proved by the fact of significant reduction of lactate level that was accompanied by the increase of contents of tricarboxylic acids cycle components such as malate and pyruvate.

Realization of metabolite-tropic action of preparations is connected with their positive influence on glutathione link of thiol-disulfide system. We assume that the revealed mechanism is not only connected with antioxidant properties of used preparations. Confinement of oxidative and nitrosative stress reactions prevents nitrosylation of thiol redox-dependent sites of genes and prevents deprivation of HSP70 expression that is proved by the obtained results of the given investigation. The increase of HSP70 level promoted a maintenance of malate dehydrogenase activity and percolation of malate aspartate pathway of reduced equivalents transport into mitochondria. Thus, modulators of thiol- disulfide system produce a pronounced metabolite-tropic effect which is specified by their action in mechanisms of endogenous neuroprotection, namely the direct increase of the reduced glutathione form and mediated activation of HSP70 protein expression.