The endocannabinoid system is dysregulated in multiple sclerosis and in experimental autoimmune encephalomyelitis.
The ability of cannabinoids to modulate both inflammatory and degenerative neuronal damage prompted investigations on the potential benefits of such compounds in multiple sclerosis (MS) and in animal models of this disorder. Here we measured endocannabinoid levels, metabolism and binding, and physiological activities in 26 patients with MS (17 females, aged 19-43 years), 25 healthy controls and in mice with experimental autoimmune encephalomyelitis (EAE), a preclinical model of MS. Our results show that MS and EAE are associated with significant alterations of the endocannabinoid system. We found that anandamide (AEA), but not 2-arachidonoylglycerol (2-AG), was increased in the CSF of relapsing MS patients. AEA concentrations were also higher in peripheral lymphocytes of these patients, an effect associated with increased synthesis and reduced degradation of this endocannabinoid. Increased synthesis, reduced degradation, and increased levels of AEA were also detected in the brains of EAE mice in the acute phase of the disease, possibly accounting for its anti-excitotoxic action in this disorder. Accordingly, neurophysiological recordings from single neurons confirmed that excitatory transmission in EAE slices is inhibited by CB1 receptor activation, while inhibitory transmission is not. Our study suggests that targeting the endocannabinoid system might be useful for the treatment of MS.
Centonze
Diego
D
Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, Rome, Italy. centonze@uniroma2.it
Bari
Monica
M
Rossi
Silvia
S
Prosperetti
Chiara
C
Furlan
Roberto
R
Fezza
Filomena
F
De Chiara
Valentina
V
Battistini
Luca
L
Bernardi
Giorgio
G
Bernardini
Sergio
S
Martino
Gianvito
G
Maccarrone
Mauro
M
D000208:Acute Disease; D000328:Adult; D000818:Animals; D001095:Arachidonic Acids / Q000097:blood / Q000134:cerebrospinal fluid; D001921:Brain / Q000378:metabolism*; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D013759:Dronabinol / Q000031:analogs & derivatives / Q000494:pharmacology; D004594:Electrophysiology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D063388:Endocannabinoids; D005260:Female; D005989:Glycerides / Q000097:blood / Q000134:cerebrospinal fluid; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D053284:Polyunsaturated Alkamides / Q000097:blood / Q000134:cerebrospinal fluid; D009435:Synaptic Transmission / Q000187:drug effects; D046509:Tissue Culture Techniques
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; D018696:Neuroprotective Agents; D053284:Polyunsaturated Alkamides; D013759:Dronabinol; C094503:glyceryl 2-arachidonate; C062018:HU 211; C078814:anandamide