title: Cannabinoid receptor agonist WIN55,212-2 and fatty acid amide hydrolase inhibitor URB597 suppress chronic cerebral hypoperfusion-induced neuronal apoptosis by inhibiting c-Jun N-terminal kinase signaling.
abstract: The endocannabinoid system (ECS) has therapeutic potential for treating chronic cerebral hypoperfusion (CCH)-induced cerebral diseases. This study investigated the protective effects of two ECS compounds, cannabinoid receptor agonist WIN55,212-2 (WIN) and fatty acid amide hydrolase inhibitor URB597 (URB) on CCH-induced neuronal apoptosis in vivo. CCH was induced in male Sprague-Dawley rats by bilateral common carotid artery occlusion (BCCAo); the rats were then treated with WIN or URB for 12weeks and their spatial learning and memory abilities were assessed using the Morris water maze. Changes in neuronal number were examined by labeling neurons with an antibody against the neuronal nuclei antigen, and apoptosis of cortical and hippocampal CA1 neurons was detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling. The expression of B cell lymphoma (Bcl)-2, Bcl-2-associated X protein (Bax), and activated caspase-3 as well as mitogen-activated protein kinases including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38, phosphorylated (p-)ERK, p-JNK, and p-P38 was examined by Western blotting. Rats treated with WIN or URB showed better learning and memory performance than controls. The neuroprotective effects of URB were greater than those of WIN, and co-administration of WIN and URB had a synergistic effect. In addition, WIN and URB blocked JNK phosphorylation as well as the decrease in Bcl-2/Bax ratio and caspase-3 activation induced by CCH, implying that these agents modulate neuronal survival. Moreover, the selective JNK inhibitor SP600125 improved mitochondrial membrane dysfunction and blocked neuronal apoptosis induced by JNK-dependent Bcl-2 signaling. WIN and URB enhanced the effects of SP600125, implying that they may exert anti-apoptotic effects in part by inhibiting a non-nuclear JNK pathway. These findings indicate that WIN and URB promote neuronal survival and may potentially be used to protect neurons against chronic ischemic insults.
authors: Department of Neurosurgery, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China; Department of Neurosurgery, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
authors: S-H
authors: SH
authors: Su
authors: Department of Neurosurgery, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.
authors: Y-F
authors: YF
authors: Wu
authors: Department of Pharmacy, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors: Q
authors: Q
authors: Lin
authors: Department of Neurosurgery, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.
authors: F
authors: F
authors: Yu
authors: Department of Neurosurgery, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China. Electronic address: haijiando@163.com.
authors: J
authors: J
authors: Hai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000627:therapeutic use*; D048588:Benzoxazines / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D002219:Carbamates / Q000627:therapeutic use*; D016893:Carotid Stenosis / Q000188:drug therapy / Q000473:pathology; D002540:Cerebral Cortex / Q000473:pathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009025:Morpholines / Q000627:therapeutic use*; D009281:Naphthalenes / Q000627:therapeutic use*; D009474:Neurons / Q000187:drug effects*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
chemical_list: D001549:Benzamides; D048588:Benzoxazines; D002121:Calcium Channel Blockers; D002219:Carbamates; D004791:Enzyme Inhibitors; D009025:Morpholines; D009281:Naphthalenes; 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; D048031:JNK Mitogen-Activated Protein Kinases; D010751:Phosphopyruvate Hydratase
keywords: JNK-dependent non-nuclear pathway; MAPK; apoptosis; chronic cerebral hypoperfusion; endocannabinoid system