URB597 improves cognitive impairment induced by chronic cerebral hypoperfusion by inhibiting mTOR-dependent autophagy
URB597 improves cognitive impairment induced by chronic cerebral hypoperfusion by inhibiting mTOR-dependent autophagy
复制标题
URB597 通过抑制 mTOR 依赖性自噬改善慢性脑灌注不足引起的认知障碍
DOI：
10.1016/j.neuroscience.2016.12.034
复制
发表时间：
2017-03
期刊：
影响因子：
3.3
通讯作者：
Hai Jian
中科院分区：
文献类型：
--
作者：
Wang Dapeng;Lin Qi;Su Shaohua;Liu Kejia;Wu Yifang;Hai Jian
慢性脑低灌注（CCH）与以认知功能障碍为特征的各种缺血性脑血管病有关。自噬在CCH条件下认知功能障碍中的作用知之甚少。为了解决这个问题，本研究调查了脂肪酸酰胺水解酶（FAAH）抑制剂URB597对CCH模型中自噬和认知的影响以及潜在的机制。用Morris水迷宫和长时程增强（LTP）评估认知功能。自噬相关蛋白和哺乳动物雷帕霉素靶蛋白（mTOR）信号通路组分的表达通过免疫荧光和蛋白质印迹分析进行评估，并通过透射电子显微镜（EM）检查超微结构变化。URB597通过抑制CCH诱导的自噬来改善认知障碍，自噬与mTOR信号传导相关。此外，由CCH引起的超微结构恶化通过用URB597长期治疗得到改善。这些发现表明URB597以mTOR依赖性方式调节自噬，并减轻由CCH引起的神经元损伤和认知恶化。
Chronic cerebral hypoperfusion (CCH) is associated with various ischemic cerebrovascular diseases that are characterized by cognitive impairment. The role of autophagy in cognitive dysfunction under conditions of CCH is poorly understood. To address this issue, the present study investigated the effect of the fatty acid amide hydrolase (FAAH) inhibitor URB597 on autophagy and cognition in a CCH model as well as the underlying mechanisms. Cognitive function was evaluated with the Morris water maze and by assessing long-term potentiation (LTP). The expression of autophagy-related proteins and mammalian target of rapamycin (mTOR) signaling pathway components was evaluated by immunofluorescence and western blot analyses, and ultrastructural changes were examined by transmission electron microscopy (EM). URB597 improved cognitive impairment by inhibiting CCH-induced autophagy, which was associated with mTOR signaling. Moreover, the ultrastructural deterioration resulting from CCH was improved by chronic treatment with URB597. These findings indicate that URB597 modulates autophagy in an mTOR-dependent manner, and mitigates neuronal damage and cognitive deterioration caused by CCH.
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影响因子：
4.6
作者：
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作者：
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