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

• Published in: Behavioural brain research Vol. 313; pp. 334 - 344
• Main Authors: Su, Shao-Hua, Wang, Yue-Qing, Wu, Yi-Fang, Wang, Da-Peng, Lin, Qi, Hai, Jian
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.10.2016
• Subjects: Animals; Benzamides - pharmacology; Benzoxazines - pharmacology; Cannabinoid Receptor Agonists - pharmacology; Carbamates - pharmacology; Chronic cerebral hypoperfusion; Cognitive Dysfunction - drug therapy; Cognitive impairment; Endocannabinoid system; Fatty Acids - metabolism; Glycogen Synthase Kinase 3 - metabolism; Long-Term Potentiation - drug effects; Male; Maze Learning - physiology; Mixed Function Oxygenases - antagonists & inhibitors; Morpholines - pharmacology; Naphthalenes - pharmacology; Neuroprotective Agents - pharmacology; Phosphatidylinositol 3-Kinases - metabolism; PI3K/AKT signaling; Proto-Oncogene Proteins c-akt - metabolism; Rats, Sprague-Dawley; Receptors, Cannabinoid - drug effects; Signal Transduction - drug effects; Endocannabinoid system; Chronic cerebral hypoperfusion; PI3K/AKT signaling; Cognitive impairment
• ISSN: 0166-4328; 1872-7549; 1872-7549
• DOI: 10.1016/j.bbr.2016.07.009

•WIN55,212-2 and URB597 protect neurons against cognitive impairment.•WIN55,212-2 and URB597 inhibited cognitive impairment via the PI3K/AKT pathway.•WIN55,212-2 and URB597 may be the potential agents for cognitive impairment. 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.