title: Cannabinoid receptor agonist WIN55,212-2 and fatty acid amide hydrolase inhibitor URB597 may protect against cognitive impairment in rats of chronic cerebral hypoperfusion via PI3K/AKT signaling.
abstract: The present study further investigated the protective effects of cannabinoid receptor agonist WIN55,212-2 (WIN) and fatty acid amide hydrolase (FAAH) inhibitor URB597 (URB) on chronic cerebral hypoperfusion (CCH)-induced cognitive impairment in rats. Spatial learning and memory were assessed with the Morris water maze and by measuring Long-term potentiation. The expression of microtubule-associated protein-2 (MAP)-2, growth-associated protein-43 (GAP)-43, synaptophysin, cannabinoid receptor 1 (CB1), brain-derived neurotrophic factor (BDNF), FAAH, N-acylphosphatidylethanolamine phospholipase D(NAPE-PLD) and monoacyl glycerol lipase (MGL) as well as phosphoinositide 3-kinase (PI3K)/AKT signaling pathway molecules and downstream targets including AKT, phosphorylated (p-)AKT, cyclic AMP response element- binding protein (CREB), p-CREB, Bcl-2-associated death protein (BAD), p-BAD, glycogen synthase kinase (GSK)-3β, p-GSK-3β, forkhead box protein (FOXO) 3A and p-FOXO3A was determined by western blotting. WIN and URB treatment improved learning and memory performance, effects that were abolished by co-administration of the PI3K/AKT inhibitor LY294002. Moreover, WIN and URB reversed the decreases in MAP-2 and synaptophysin expression resulting from CCH, and stimulated BDNF and CB1 expression as well as CREB, FOXO3A, GSK-3β, and BAD phosphorylation, confirming that WIN and URB mediate neuroprotection by preventing neuronal apoptosis and improving cognition via PI3K/AKT signaling. These findings suggest that WIN and URB are promising agents for therapeutic management of CCH.
authors.affiliation: Department of Neurosurgery, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.
authors.forename: Shao-Hua
authors.initials: SH
authors.lastname: Su
authors.affiliation: BYBO Dental Group, Shanghai 201900, China.
authors.forename: Yue-Qing
authors.initials: YQ
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.
authors.forename: Yi-Fang
authors.initials: YF
authors.lastname: Wu
authors.affiliation: Department of Neurosurgery, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.
authors.forename: Da-Peng
authors.initials: DP
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, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China. Electronic address: haijiando@163.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Hai
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D048588:Benzoxazines / Q000494:pharmacology*; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D060825:Cognitive Dysfunction / Q000188:drug therapy; D005227:Fatty Acids / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D009025:Morpholines / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001549:Benzamides; D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D002219:Carbamates; D005227:Fatty Acids; D038362:Glycogen Synthase Kinase 3; D006899:Mixed Function Oxygenases; D009025:Morpholines; D009281:Naphthalenes; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D043882:Receptors, Cannabinoid; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
keywords: Chronic cerebral hypoperfusion; Cognitive impairment; Endocannabinoid system; PI3K/AKT signaling