title: Blockade of monoacylglycerol lipase inhibits oligodendrocyte excitotoxicity and prevents demyelination in vivo.
abstract: The endocannabinoids 2-araquidonoylglycerol (2-AG) and anandamide (AEA) are bioactive lipids crucially involved in the regulation of brain function in basal and pathological conditions. Blockade of endocannabinoid metabolism has emerged as a promising therapeutic strategy for inflammatory diseases of the central nervous system, including myelin disorders such as multiple sclerosis. Nevertheless, the biological actions of endocannabinoid degradation inhibitors in oligodendrocytes and white matter tracts are still ill defined. Here we show that the selective monoacylglycerol lipase (MAGL) inhibitor JZL184 suppressed cell death by mild activation of AMPA receptors in oligodendrocytes in vitro, an effect that was mimicked by MAGL substrate 2-AG and by the second major endocannabinoid AEA, in a concentration-dependent manner, whereas inhibition of the AEA metabolizing enzyme fatty acid amide hydrolase with URB597 was devoid of effect. Pharmacological experiments suggested that oligodendrocyte protection from excitotoxicity resulting from MAGL blockade involved the activation of cannabinoid CB1 receptors and the reduction of AMPA-induced cytosolic calcium overload, mitochondrial membrane depolarization, and production of reactive oxygen species. Administration of JZL184 under a therapeutic regimen decreased clinical severity, prevented demyelination, and reduced inflammation in chronic experimental autoimmune encephalomyelitis. Furthermore, MAGL inactivation robustly preserved myelin integrity and suppressed microglial activation in the cuprizone-induced model of T-cell-independent demyelination. These findings suggest that MAGL blockade may be a useful strategy for the treatment of immune-dependent and -independent damage to the white matter.
authors.affiliation: Department of Neurosciences, School of Medicine, University of the Basque Country-UPV/EHU, Leioa, Spain; Achucarro Basque Center for Neuroscience, Zamudio, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Bernal-Chico
authors.forename: Manuel
authors.initials: M
authors.lastname: Canedo
authors.forename: Andrea
authors.initials: A
authors.lastname: Manterola
authors.forename: María
authors.initials: M
authors.lastname: Victoria Sánchez-Gómez
authors.forename: Alberto
authors.initials: A
authors.lastname: Pérez-Samartín
authors.forename: Rafael
authors.initials: R
authors.lastname: Rodríguez-Puertas
authors.forename: Carlos
authors.initials: C
authors.lastname: Matute
authors.forename: Susana
authors.initials: S
authors.lastname: Mato
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D001549:Benzamides; D052117:Benzodioxoles / Q000494:pharmacology*; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D002219:Carbamates; D003711:Demyelinating Diseases / Q000517:prevention & control*; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors*; D009103:Multiple Sclerosis / Q000276:immunology / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001549:Benzamides; D052117:Benzodioxoles; D063385:Cannabinoid Receptor Modulators; D002219:Carbamates; D008994:Monoacylglycerol Lipases; D010880:Piperidines; D043884:Receptor, Cannabinoid, CB1; D000099252:Fatty Acid Amide Hydrolases; C534333:JZL 184; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester
keywords: 2-AG; AMPA receptors; CB1 receptors; multiple sclerosis; myelin