Microglial-mediated neuroinflammation plays an important role in vascular dementia, and modulating neuroinflammation has emerged as a promising treatment target. Nicotinamide adenine dinucleotide (NAD+) shows anti-inflammatory and anti-oxidant effects in many neurodegenerative disease models, but its role in the chronic cerebral hypoperfusion (CCH) is still unclear. The bilateral common carotid artery occlusion (BCCAO) was performed to establish CCH models in Sprague-Dawley rats. The rats were given daily intraperitoneal injection of NAD+ for 8 weeks. The behavioral test and markers for neuronal death and neuroinflammation were analyzed. Mitochondrial damage and ROS production in microglia were also assessed. RNA-seq was performed to investigate the mechanistic pathway changes. For in vitro studies, Sirt1 was overexpressed in BV2 microglial cells to compare with NAD+ treatment effects on mitochondrial injury and neuroinflammation. NAD+ administration rescued cognitive deficits and inhibited neuroinflammation by protecting mitochondria and decreasing ROS production in CCH rats. Results of mechanistic pathway analysis indicated that the detrimental effects of CCH might be associated with decreased gene expression of PPAR-γ co-activator1α (PGC-1α) and its upstream transcription factor Sirt1, while NAD+ treatment markedly reversed their decrease. In vitro study confirmed that NAD+ administration had protective effects on hypoxia-induced neuroinflammation and mitochondrial damage, as well as ROS production in BV2 microglia via Sirt1/PGC-1α pathway. Sirt1 overexpression mimicked the protective effects of NAD+ treatment in BV2 microglia. NAD+ ameliorated cognitive impairment and dampened neuroinflammation in CCH models in vivo and in vitro, and these beneficial effects were associated with mitochondrial protection and ROS inhibition via activating Sirt1/PGC-1α pathway.

中文翻译：

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NAD+ 通过 Sirt1/PGC-1α 通路改善慢性脑灌注不足模型中的线粒体损伤和减少 ROS 产生，从而改善认知功能并减少神经炎症


小胶质细胞介导的神经炎症在血管性痴呆中发挥重要作用，调节神经炎症已成为一个有前途的治疗目标。烟酰胺腺嘌呤二核苷酸（NAD+）在许多神经退行性疾病模型中显示出抗炎和抗氧化作用，但其在慢性脑灌注不足（CCH）中的作用仍不清楚。采用双侧颈总动脉闭塞（BCCAO）方法建立Sprague-Dawley大鼠CCH模型。连续8周每天给大鼠腹腔注射NAD+。分析了神经元死亡和神经炎症的行为测试和标志物。还评估了小胶质细胞中的线粒体损伤和 ROS 产生。进行RNA-seq来研究机制途径的变化。在体外研究中，Sirt1 在 BV2 小胶质细胞中过表达，以与 NAD+ 治疗对线粒体损伤和神经炎症的效果进行比较。 NAD+ 给药通过保护线粒体和减少 CCH 大鼠中 ROS 的产生来挽救认知缺陷并抑制神经炎症。机制通路分析结果表明，CCH 的有害影响可能与 PPAR-γ 共激活因子 1α (PGC-1α) 及其上游转录因子 Sirt1 基因表达降低有关，而 NAD+ 治疗显着逆转了它们的降低。体外研究证实，NAD+ 给药对缺氧诱导的神经炎症和线粒体损伤以及通过 Sirt1/PGC-1α 通路在 BV2 小胶质细胞中产生 ROS 具有保护作用。 Sirt1 过表达模仿了 BV2 小胶质细胞中 NAD+ 治疗的保护作用。 NAD+ 可在体内和体外改善 CCH 模型中的认知障碍并抑制神经炎症，这些有益作用与通过激活 Sirt1/PGC-1α 途径保护线粒体和抑制 ROS 相关。