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Neuroscience. 2017 Mar 6;344:293-304. doi: 10.1016/j.neuroscience.2016.12.034. Epub 2016 Dec 30.

URB597 improves cognitive impairment induced by chronic cerebral hypoperfusion by inhibiting mTOR-dependent autophagy.

Author information

1
Department of Neurosurgery, Tong Ji Hospital, Tong Ji University School of Medicine, Shanghai 200065, China.
2
Department of Pharmacy, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
3
Department of Cell Biology, Key Laboratory of Education Ministry for Cell Differentiation and Apoptosis, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
4
Department of Neurosurgery, Tong Ji Hospital, Tong Ji University School of Medicine, Shanghai 200065, China. Electronic address: haijiandoct@163.com.

Abstract

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.

KEYWORDS:

autophagy; chronic cerebral hypoperfusion; cognitive impairment; endocannabinoid system; mTOR signaling

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