Ethylmethylhydroxypyridine Succinate Limits Stress-Induced Neuroinflammation in the Cerebral Cortex of Old Rats

Abstract

In the aging and the development of age-associated diseases, the trigger mechanism is the hyperactivation of the hypothalamic-pituitary-adrenal neuroendocrine axis, hypersecretion of glucocorticoids, which, under excessive and long-term stimulation, have inflammatory and degenerative effects. Chronic stress exacerbates glucocorticoid-dependent atrophic changes in the aging brain, increases neuroinflammation and neurological dysfunction, and is a key risk factor for Alzheimer’s disease. In the correction of aseptic neuroinflammation in elderly and senile patients, the use of anti-inflammatory agents that exhibit anti-glucocorticoid (pro-anabolic) and anti-glutamate (anti-excitotoxic) effects is pathogenetically justified. Succinate/SUCNR1 signalling is involved in the development of immunomodulatory, trophic, and anti-hypoxic effects; however, its role in the mechanisms of stress response remains unexplored. The aim of this study was to assay the impact of succinate/SUCNR1 signalling on the development of stress-induced neuroinflammation in the cerebral cortex of old rats. The work was performed on outbred albino male rats aged 18 months. Chronic restraint stress was modelled by immobilizing animals in individual plastic cases for 6 h daily for 5 days. Mexidol (2-ethyl-6-methyl-3-hydroxypyridine (EMHP) succinate) was used as a form of succinate that crosses the blood-brain barrier. Mexidol was administered intraperitoneally to old rats at a dose of 100 mg/kg daily for 5 days 15 min before the onset of stress. The levels of proinflammatory cytokines (IL-1β, TNF-α), anti-inflammatory cytokines (TGF-β1, IL-10), glucocorticoid receptors (GRα), transcriptional coactivator PGC-1α, succinate receptor SUCNR1/GPR91, and vascular endothelial growth factor (VEGF) were determined by immunoblotting in cerebral cortex (CC) samples. It was shown that chronic immobilization stress caused an increase in the level of IL-1β and TNF-α during stress, which was accompanied by a decrease in the content of anti-inflammatory cytokines, SUCNR1, GRα, PGC-1α. The course administration of EMHP succinate limited the development of stress-induced neuroinflammation in the CC of old rats and prevented a decrease in the levels of SUCNR1, IL-10, TGF-β1, PGC-1α, and GRα. The study reveals for the first time the stress-protective potential of succinate/SUCNR1 signalling in the brain of old rats associated with the activation of PGC-1α-dependent anti-inflammatory mechanisms under conditions of chronic stress.