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.

中文翻译：

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乙基甲基羟基吡啶琥珀酸盐限制老年大鼠大脑皮层应激诱发的神经炎症

摘要-

在衰老和年龄相关疾病的发生发展中，触发机制是下丘脑-垂体-肾上腺神经内分泌轴过度激活，糖皮质激素分泌过多，在过度和长期的刺激下，产生炎症和退行性作用。慢性压力会加剧衰老大脑中糖皮质激素依赖性萎缩性变化，增加神经炎症和神经功能障碍，是阿尔茨海默病的关键危险因素。在纠正老年和老年患者的无菌性神经炎症时，使用具有抗糖皮质激素（促合成代谢）和抗谷氨酸（抗兴奋性毒性）作用的抗炎药物在病理学上是合理的。琥珀酸/SUCNR1 信号传导参与免疫调节、营养和抗缺氧作用的发展；然而，它在应激反应机制中的作用仍有待探索。本研究的目的是测定琥珀酸/SUCNR1 信号对老年大鼠大脑皮层应激诱导的神经炎症发展的影响。这项工作是在 18 个月大的远交白化雄性大鼠身上进行的。通过将动物固定在单独的塑料箱中 6 小时，持续 5 天来模拟慢性束缚应激。Mexidol（2-乙基-6-甲基-3-羟基吡啶（EMHP）琥珀酸酯）被用作穿过血脑屏障的琥珀酸酯的一种形式。在应激发生前15分钟，对老年大鼠腹腔注射Mexidol，剂量为每天100 mg/kg，持续5天。促炎细胞因子（IL-1β、TNF-α）、抗炎细胞因子（TGF-β1、IL-10）、糖皮质激素受体（GRα）、转录共激活因子PGC-1α、琥珀酸受体SUCNR1/GPR91和血管内皮细胞的水平通过免疫印迹法测定大脑皮层 (CC) 样本中的生长因子 (VEGF)。结果表明，慢性固定应激导致应激过程中IL-1β和TNF-α水平升高，同时伴随抗炎细胞因子SUCNR1、GRα、PGC-1α含量下降。EMHP 琥珀酸盐的疗程限制了老年大鼠 CC 中应激诱导的神经炎症的发展，并防止了 SUCNR1、IL-10、TGF-β1、PGC-1α 和 GRα 水平的下降。该研究首次揭示了老年大鼠大脑中琥珀酸/SUCNR1信号传导的应激保护潜力，其与慢性应激条件下PGC-1α依赖性抗炎机制的激活相关。