Therapeutic Mechanisms for Cannabinoid-Promoted Survival of Oligodendrocytes

Loss of axonal myelination due to oligodendrocyte cell death is one of the major pathological features in Multiple Sclerosis (MS), and there is currently no effective treatment. Inflammation, a hallmark in the pathology of MS involves activation of microglia and release of cytotoxic factors including peroxynitrite, the most reactive free radical causing toxicity to oligodendrocytes. The cannabinoid system has recently emerged as a promising therapeutic target in MS. We and others have shown that the cannabinoid type I and type 2 (CB I and CB2) receptors are expressed in microglia andoligodendrocytes. Although activation of these receptors is thought to regulate the inflammatory response and cell survival, the mechanisms involved are still not well elucidated. The objective of this dissertation was to study the potential role of cannabinoids in preventing oligodendroglial cell death from two different angles. First, by testing the ability of these compounds in blocking the production of peroxynitrite bymicroglia and secondly, by determining whether cannabinoids can act directly onoligodendrocytes to provide protection from peroxynitrite induced toxicity. Pharmacological, biochemical and molecular approaches were used to elucidate the mechanisms of peroxynitrite production in reactive microglia and to determine how cannabinoids interfere with the signaling pathways of peroxynitrite formation and its toxicity to oligodendrocytes in vitro. Studies in vivo were performed to characterized the effect of a novel synthetic cannabinoid compound in preventing inflammation, demyelination and oligodendrocyte injury in a mouse model of MS