Multiple Sclerosis (MS) is a demyelinating disease which causes inflammation, demyelination, and axonal injury. Currently, there is no cure for the disease. The endocannabinoid system has recently emerged as a promising therapeutic target for MS. The protective mechanisms of cannabinoids are thought to be mediated by activation ofcannabinoid receptor 1 (CB1) and 2 (CB2) expressed primarily in neurons and immune cells, respectively. However, the molecular mechanisms and the contribution of each receptor in ameliorating disease progression are still debatable. Although CB1 and CB2 are expressed in oligodendrocytes, the myelin producing cells in the central nervous system, the role of cannabinoids in oligodendrocyte survival has not been well investigated. Using primary cultures of mature oligodendrocytes, we tested the effect of a novel synthetic cannabinoid CB-52 on oligodendrocyte toxicity induced by peroxynitrite, the primary toxic species released by microglia. Interestingly, we found that CB-52 is more potent than a number of broad and selective CB1 and CB2 agonists in protecting oligodendrocytes against peroxynitrite-induced toxicity. The protection provided by CB-52 is likely due to its reduction of ERK1/2 phosphorylation and ROS generation in these cells. Using experimental autoimmune encephalomyelitis (EAE), an animal model of MS, we found that CB-52 reduces microglia activation, nitrotyrosine formation, T cell infiltration, oligodendrocyte toxicity, myelin loss and axonal damage in the mouse spinal cord white matter and alleviates the clinical scores when given either before or after disease onset. These effects are reversed by the CB1 receptor antagonist, but not by the CB2 receptor antagonist, suggesting that activation of CB1 receptors contributes significantly to the anti-inflammatory and neuroprotective effects of cannabinoids on MS.
Copyright © 2013. Published by Elsevier Ltd.

PMID:

 

24036373

 

[PubMed – as supplied by publisher]