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Brain Advance Access published online on July 11, 2007
Brain, doi:10.1093/brain/awm160
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© The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The endocannabinoid system is dysregulated in multiple sclerosis and in experimental autoimmune encephalomyelitis

Diego Centonze1,2, Monica Bari3, Silvia Rossi1,2, Chiara Prosperetti1,2, Roberto Furlan4, Filomena Fezza2,3, Valentina De Chiara1,2, Luca Battistini2, Giorgio Bernardi1,2, Sergio Bernardini2,5, Gianvito Martino4 and Mauro Maccarrone2,6

1Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, Rome, Italy, 2Centro Europeo per la Ricerca sul Cervello (CERC)/Fondazione Santa Lucia, Rome, Italy, 3Dipartimento di Medicina Sperimentale e Scienze Biochimiche, Università Tor Vergata, Rome, Italy, 4Neuroimmunology Unit, DIBIT, San Raffaele Scientific Institute, Milan, Italy, 5Dipartimento di Medicina Interna, Medicina di Laboratorio, Università Tor Vergata, Rome, Italy and 6Dipartimento di Scienze Biomediche, Università degli Studi di Teramo, Teramo, Italy

Correspondence to: Diego Centonze, Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, Via Montpellier 1, 00133 Rome, Italy E-mail: centonze{at}uniroma2.it

Correspondence to: Mauro Maccarrone, Dipartimento di Scienze Biomediche, Università degli Studi di Teramo, Piazza A. Moro 45, 64100 Teramo, Italy E-mail: mmaccarrone{at}unite.it

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.

Key Words: animal models; arachidonic acid; autoimmune encephalitis; excitotoxicity; neuroprotective agents

Abbreviations: AEA, anandamide; 2-AG, 2-arachidonoylglycerol; CB, cannabinoid; CSF, cerebrospinal fluid; EAE, experimental autoimmune encephalomyelitis; ECS, endocannabinoid system; EPSC, excitatory postsynaptic current; FAAH, fatty acid amide hydrolase; HP, holding potential; IPSC, inhibitory postsynaptic current; MS, multiple sclerosis; NAPE-PLD, N-acyl-phosphatidylethanolamines (NAPE)-hydrolysing phospholipase D; PPR, paired pulse ratio

Received December 22, 2006. Revised May 10, 2007. Accepted June 14, 2007.


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