The Mechanisms of Pharmacological Preconditioning of the Brain and the Comparative Efficacy of the Drugs — Direct- and Indirect-Acting Glycogen Synthase Kinase-3β Inhibitors: Experimental Study

Objective: to investigate the activity of sevoflurane, dalargin, and lithium chloride in protecting the rat brain from total ischemia/reperfusion and to define whether the GSK=3^ deposphorylation contributes to the mechanism of pharmacological preconditioning. Materials and methods. Experiments were carried out on 80 male albino rats in which temporary circulatory arrest (CA) was simulated by ligating the cardiovascular fascicle for 10 and 20 minutes. The animals were revived by mechanical ventilation external cardiac massage, and the intratracheal injection of adrenaline (epinephrine, Moscow Endocrinology Plant) at a dose of 0.1 mg/kg. Animals were divided into 9 groups and sevorane (sevoflurane, Abbott Laboratories), dalargin (Microgen Research-and-Production Association), or lithium chloride (Sigma Chemical Co.) were separately given with and without CA. Brain tissue homogenate specimens were obtained from euthanized animals. The concentration of total glycogen synthase kinase-3^ (GSK-3^) was colorimetrically determined using a Hitachi-557 spectrophotometer (Hitachi Ltd., Japan). The content of phosphorylated GSK-3/3 (pGSK-3^) in brain homogenate was estimated by Western blotting. Results. The total level of GSK-3^ in each group was similar (80—90 relative units) and remained unchanged throughout each experiment. Twenty-minute ischemia maximally activated GSK-30 through dephosphorylation. Ten-minute ischemia elevated pGSK-3^ levels by more than 5 times as compared to the baseline value revealing the «training» effect. The quantity of pGSK-3^ was unchanged in the ischemia/perfusion group during sevoflurane insufflation and was decreased by 27% during dalargin administration. Conclusion. The experimental model of total ischemia provided evidence that the test drugs had a pharmacological preconditioning effect on brain neurons. According to their increasing effect, the drugs were arranged in the following order: dalargin < sevoflurane < lithium chloride. The data warranties further studies to reveal the clinical significance of dalargin, sevofluran and lithium for preconditioning to protect the brain. Key words: lithium, dalargin, sevofluran, preconditioning, brain.

литий, даларгин, севофлуран, прекондиционирование, головной мозг.

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