Oxiracetam ameliorates cognitive deficits in vascular dementia rats by regulating the expression of neuronal apoptosis/autophagy-related genes associated with the activation of the Akt/mTOR signaling pathway

Oxiracetam (ORC) is a commonly used nootropic drug for improving cognition and memory impairments. The therapeutic effect and underlying mechanism of ORC in vascular dementia (VaD) treatment remain unknown. In this study, 3-month-old male Sprague-Dawley rats with permanent bilateral common carotid artery occlusion-induced VaD were treated orally with low (100 mg/kg) or high (200 mg/kg) dose ORC once a day for 4 weeks. The results of the Morris water maze test and Nissl staining showed that ORC treatment significantly alleviated learning and memory deficits and neuronal damage in rats with VaD. Mechanistically, the protein levels of a panel of genes associated with neuronal apoptosis (Bcl-2, Bax) and autophagy (microtubule-associated protein 1 chain 3, Beclin1, p62) were significantly altered by ORC treatment compared with VaD, suggesting a protective role of ORC against VaD-induced neuronal apoptosis and autophagy. Moreover, the Akt/mTOR pathway, which is known to be the upstream signaling governing apoptosis and autophagy, was found to be activated in ORC-treated rats, suggesting an involvement of Akt/mTOR activation in ORC-rendered protection in VaD rats. Taken together, this study demonstrated that ORC may alleviate learning and memory impairments and neuronal damage in VaD rats by altering the expression of apoptosis/autophagy-related genes and activation of the Akt/mTOR signaling pathway in neurons.

奥拉西坦(Oxiracetam, ORC)是一种常用于改善认知与记忆损伤的益智药物。奥拉西坦用于治疗血管性痴呆(vascular dementia, VaD)的疗效及潜在机制仍不明晰。本研究选取3月龄雄性斯普拉格-道利大鼠(Sprague-Dawley rats)，通过永久性双侧颈总动脉闭塞构建血管性痴呆模型，随后以低剂量(100 mg/kg)或高剂量(200 mg/kg)的奥拉西坦经口灌胃给药，每日1次，连续给药4周。莫里斯水迷宫实验(Morris water maze test)与尼氏染色(Nissl staining)结果显示，奥拉西坦干预可显著缓解血管性痴呆模型大鼠的学习记忆障碍与神经元损伤。机制分析表明，与血管性痴呆模型组大鼠相比，奥拉西坦给药显著改变了一系列与神经元凋亡（Bcl-2、Bax）及自噬（微管相关蛋白1轻链3、Beclin1、p62）相关基因的蛋白表达水平，提示奥拉西坦可通过调控上述通路发挥对抗血管性痴呆诱导的神经元凋亡与自噬的神经保护作用。此外，已知调控细胞凋亡与自噬的上游信号通路Akt/mTOR，在奥拉西坦给药大鼠体内被激活，表明Akt/mTOR通路的激活参与了奥拉西坦对血管性痴呆模型大鼠的保护效应。综上，本研究证实，奥拉西坦可通过调控神经元中凋亡/自噬相关基因的表达以及激活Akt/mTOR信号通路，缓解血管性痴呆模型大鼠的学习记忆损伤与神经元损伤。