title: Cannabinoid CB1 receptors regulate neuronal TNF-α effects in experimental autoimmune encephalomyelitis.
abstract: Cannabinoid CB1 receptors (CB1Rs) regulate the neurodegenerative damage of experimental autoimmune encephalomyelitis (EAE) and of multiple sclerosis (MS). The mechanism by which CB1R stimulation exerts protective effects is still unclear. Here we show that pharmacological activation of CB1Rs dampens the tumor necrosis factor α (TNFα)-mediated potentiation of striatal spontaneous glutamate-mediated excitatory postsynaptic currents (EPSCs), which is believed to cogently contribute to the inflammation-induced neurodegenerative damage observed in EAE mice. Furthermore, mice lacking CB1Rs showed a more severe clinical course and, in parallel, exacerbated alterations of sEPSC duration after induction of EAE, indicating that endogenous cannabinoids activate CB1Rs and mitigate the synaptotoxic action of TNFα in EAE. Consistently, we found that mice lacking the fatty acid amide hydrolase (FAAH), and thus expressing abnormally high brain levels of the endocannabinoid anandamide, developed a less severe EAE associated with preserved TNFα-induced sEPSC alterations. CB1Rs are important modulators of EAE pathophysiology, and might play a mechanistic role in the neurodegenerative damage of MS patients.
authors.affiliation: Neurologic Clinic, Department of Neuroscience, Tor Vergata University, 00133 Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rossi
authors.forename: Roberto
authors.initials: R
authors.lastname: Furlan
authors.forename: Valentina
authors.initials: V
authors.lastname: De Chiara
authors.forename: Luca
authors.initials: L
authors.lastname: Muzio
authors.forename: Alessandra
authors.initials: A
authors.lastname: Musella
authors.forename: Caterina
authors.initials: C
authors.lastname: Motta
authors.forename: Valeria
authors.initials: V
authors.lastname: Studer
authors.forename: Francesca
authors.initials: F
authors.lastname: Cavasinni
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
authors.forename: Gianvito
authors.initials: G
authors.lastname: Martino
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
authors.forename: Mauro
authors.initials: M
authors.lastname: Maccarrone
authors.forename: Diego
authors.initials: D
authors.lastname: Centonze
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000581:Amidohydrolases / Q000172:deficiency; D000818:Animals; D001095:Arachidonic Acids / Q000096:biosynthesis / Q000502:physiology; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D003342:Corpus Striatum / Q000503:physiopathology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D013759:Dronabinol / Q000031:analogs & derivatives / Q000494:pharmacology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000503:physiopathology*; D063388:Endocannabinoids; D000068800:Etanercept; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D005260:Female; D018698:Glutamic Acid / Q000502:physiology; D007074:Immunoglobulin G / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration; D009474:Neurons / Q000502:physiology; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency / Q000187:drug effects / Q000502:physiology*; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000581:Amidohydrolases; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D016291:Dizocilpine Maleate; D013759:Dronabinol; D063388:Endocannabinoids; D000068800:Etanercept; D018698:Glutamic Acid; D007074:Immunoglobulin G; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000099252:Fatty Acid Amide Hydrolases; C062018:HU 211; C078814:anandamide