Correction of psychoneurological disorders arising against the background of chronic toxic brain damage with inhibitors of GPCR/cAMP and JAC/STAT signaling pathways

Introduction. Impaired central nervous system function resulting from chronic ethanol consumption is often associated with suppressed neurogenesis. The GPCR/cAMP-dependent pathway and JAK/STAT signaling are considered to be among the key signaling cascades involved in regulating the proliferation and differentiation of neural and neuronal stem cells. Clearly, the search for fundamentally new approaches to treating ethanol-induced neurodegeneration by targeting intracellular signaling molecules is highly relevant and in demand in practical medicine.

Aim. The aim of this study was to investigate the effect of JAC/STAT and GPCR/cAMP inhibitors on the psychoneurological status of mice, the state of neural stem cells, and the secretion of neurotrophins by glia under conditions of chronic toxic brain injury.

Material and methods. The studies were conducted on 90 C57BL/6 mice. Alcohol-induced neurodegeneration was modeled by per os administration of 30 % C₂H₅OH solution at a dose of 3 g/kg/day for 8 weeks. JAC/STAT and GPCR/cAMP inhibitors were administered subcutaneously once a day for 7 days at a dose of 15 and 10 μg/kg, respectively. The psychopharmacological effects of the blockers were assessed in the open field test and by the degree of preservation of the conditioned passive avoidance reflex. The content of neural stem cells and committed neuronal precursors in the subventricular zone of the brain, their proliferative activity and maturation intensity were studied using cultural methods; the production of neurotrophic factors by glial cells was investigated.

Results and discussion. The introduction of JAC/STAT and GPCR/cAMP inhibitors corrected the functional signs of alcoholic brain pathology (changes in exploratory behavior were abolished). At the same time, the course use of a GPCR/cAMP inhibitor leveled out, and the introduction of a JAC/STAT blocker aggravated the decrease in the level of reproduction of the conditioned passive avoidance reflex in alcoholized mice. In the groups of animals receiving JAC/STAT and GPCR/cAMP inhibitors, an increase in the number of neural stem cells and committed neuronal precursors was observed, accompanied by an increase in their mitotic activity and intensity of specialization. The introduction of a GPCR/cAMP inhibitor after modeling ethanol-induced brain damage was accompanied by an increase in the secretion of neurotrophins by astrocytes and microglia.

Conclusion. The obtained results indicate the prospects of developing a new approach to the treatment of chronic alcohol-induced brain damage by targeting individual links in the intracellular signal transduction system, in particular, the use of GPCR/cAMP inhibitors.

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