Blockade of the 2-ag hydrolase abhd6 ameriorates disease progression in the experimental autoimmune encephalomyelitis model of multiple sclerosis

Manterola, A. 1 , Bernal-Chico, A. . 1, 2 , Sánchez-Gómez, M. V. . 1, 2 , Canedo, M. 1, 2 , Hsu, K. 3 , Cravatt, B. . 3 , Matute, C. . 1, 2 & Mato, S. . 1, 2

1 Department of Neurosciences, University of the Basque Country-UPV/EHU, Leioa, Vizcaya, Spain
2 Achucarro Basque Center for Neuroscience, Zamudio, Vizcaya, Spain.
3 Department of Chemical Physiology, the Scripps Research Institute, La Jolla, USA

Preclinical and clinical research has demonstrated the utility of activating cannabinoid receptors in inflammatory diseases of the central nervous system such as multiple sclerosis (MS). Nevertheless, the therapeutic use of exogenous agonists is limited by the possible adverse responses related to memory and learning impairment. An alternative therapeutic strategy consists of enhancing the concentration of the endocannabinoids anandamide and/or 2-arachidonoylglycerol (2-AG) by decreasing their enzymatic metabolism. In this context, we have investigated the potential of targeting the recently characterized 2-AG hydrolitic enzyme ABHD6 (?/? hydrolase domain lipase 6) as novel therapeutic strategy in MS. With this aim, we have studied the effects of centrally acting and peripherally restricted ABHD6 selective inhibitors in the experimental autoimmune encephalomyelitis (EAE) model of MS. Chronic EAE was induced in C57BL/6 mice by immunization with MOG in Freund?s adjuvant supplemented with Mycobacterium tuberculosis. Mice were treated daily with KT182 or KT203 (2 mg/kg) starting at the day of immunization. Comparison of the motor score curves indicated that although both ABHD6 inhibitors ameliorated the deficits observed in vehicle-treated mice during the disease course, the brain permeable compound was more effective than the peripherally acting one. The ability of both to attenuate the gene expression of proinflammatory cytokines in the brain of EAE mice is currently under investigation.

Funded by the Basque Country Government, MINECO, ARSEP Foundation and CIBERNED.