title: URB597 improves cognitive impairment induced by chronic cerebral hypoperfusion by inhibiting mTOR-dependent autophagy.
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.
authors.affiliation: Department of Neurosurgery, Tong Ji Hospital, Tong Ji University School of Medicine, Shanghai 200065, China.
authors.forename: Dapeng
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Lin
authors.affiliation: Department of Neurosurgery, Tong Ji Hospital, Tong Ji University School of Medicine, Shanghai 200065, China.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Su
authors.affiliation: 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.
authors.forename: Kejia
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Tong Ji Hospital, Tong Ji University School of Medicine, Shanghai 200065, China.
authors.forename: Yifang
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Neurosurgery, Tong Ji Hospital, Tong Ji University School of Medicine, Shanghai 200065, China. Electronic address: haijiandoct@163.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Hai
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D001549:Benzamides / Q000494:pharmacology*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002219:Carbamates / Q000494:pharmacology*; D017536:Carotid Artery, Common; D002561:Cerebrovascular Disorders / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D060825:Cognitive Dysfunction / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D018697:Nootropic Agents / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001549:Benzamides; D002219:Carbamates; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D058570:TOR Serine-Threonine Kinases; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C546845:mTOR protein, rat
keywords: autophagy; chronic cerebral hypoperfusion; cognitive impairment; endocannabinoid system; mTOR signaling