Modulation of HSP70-dependent mechanisms of endogenous neuroprotection with selenium derivatives under conditions of ischemic-type acute cerebrovascular accident modeling

Abstract

The influence of selenium derivatives selenoline, cysteine selenate, and methionine selenate on the main indicators of HSP70-dependent mechanisms of endogenous neuroprotection under conditions of acute cerebrovascular accident (CVA) modeling has been investigated, and pathogenetic substantiation of prospects for their further study as potential neuroprotectors has been given. The experiments have been performed on white Wistar rats by bilateral irreversible ligation of the common carotid artery. Cysteine selenite and methionine selenite at a dose of 30 μg/kg, and selenoline at a dose of 50 μg/kg were introduced intraperitoneally to the experimental animals once-daily for 4 days. Every day for 4 days, the severity of neurological reactions was assessed in points on a stroke-index scale, and the mortality rate in animals was recorded. In the process of biochemical studies of brain tissue, the state of mRNA expression, HSP70 level, hypoxia-induced factors (HIF) – HIF1α and HIF-3α were evaluated using the method of polymerase chain reaction (PCR) with real-time reverse transcription. While false-operated animals developed mild neurological disorders, the control group developed bilateral ptosis, circling movements, paresis and paralysis of the limbs. On the 4th day the mean score on Stroke-index P. McGraw neurological deficit assessment scale was 16.7 ± 0.52, and 40 % of animals survived. In the cytosol and mitochondria of brain tissues, a decrease in HSP70 was detected by 47% and 59%, respectively. The administration of selenite cysteine, selenite methionine and selenoline contributed to the normalization of this indicator, to a greater extent under the action of selenite cysteine. In the control group there was a decrease in HSP70 mRNA expression. After administration of all the studied compounds, a tendency to increase the expression of HSP70 mRNA was observed compared to the controls. Under conditions of cerebral circulation insufficiency ACCI, in brain tissue, a decrease in the synthesis of HIF-1α at the stage of translation with ATP deficiency was noted. The course administration of selenium-containing drugs to rats with ACCI induced an increase in HIF1α levels: cysteine selenite – by 11.2 times, selenite methionine – by 3.13 times, and selenoline – by 1.1 times (p ˃0.05). A significant difference in relation to the expression of HIF-3α was shown only after administration of cysteine selenite (by 4.3 times higher than the control). The study of antioxidant modulation of HSP70-dependent mechanisms of endogenous neuroprotection of the brain have demonstrated that administration of selenium-containing medications cysteine selenite, methionine selenite, and selenoline lead to a decrease in neurological signs and the mortality rate in animals with ACCI. The action of selenium-containing drugs is realized due to their positive influence on the glutathione system, the preservation of energy-producing function of organs and mitoprotective effect. The obtained results indicate the relevance of further study of selenium-containing drugs on other models of pathological processes accompanied by ischemia.