urb-597 and Cognitive-Dysfunction

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.

Topics: Amidohydrolases; Animals; Apoptosis; Autophagy; Benzamides; CA1 Region, Hippocampal; Carbamates; Carotid Artery, Common; Cerebrovascular Disorders; Cognition; Cognitive Dysfunction; Disease Models, Animal; Long-Term Potentiation; Male; Maze Learning; Neurons; Neuroprotective Agents; Nootropic Agents; Phosphorylation; Rats, Sprague-Dawley; TOR Serine-Threonine Kinases

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.

Topics: Animals; Benzamides; Benzoxazines; Cannabinoid Receptor Agonists; Carbamates; Cognitive Dysfunction; Fatty Acids; Glycogen Synthase Kinase 3; Long-Term Potentiation; Male; Maze Learning; Mixed Function Oxygenases; Morpholines; Naphthalenes; Neuroprotective Agents; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Receptors, Cannabinoid; Signal Transduction