Cannabidiol induces intracellular calcium elevation and cytotoxicity in oligodendrocytes

Heavy marijuana use has been linked to white matter histological alterations. However, the impact of cannabis constituents on oligodendroglial pathophysiology remains poorly understood. Here, we investigated the in vitro effects of cannabidiol, the main nonpsychoactive marijuana component, on oligodendrocytes. Exposure to cannabidiol induced an intracellular Ca2+ rise in optic nerve oligodendrocytes that was not primarily mediated by entry from the extracellular space, nor by interactions with ryanodine or IP3 receptors. Application of the mitochondrial protonophore carbonylcyanide‐p‐trifluoromethoxyphenylhydrazone (FCCP; 1 μM) completely prevented subsequent cannabidiol‐induced Ca2+ responses. Conversely, the increase in cytosolic Ca2+ levels elicited by FCCP was reduced after previous exposure to cannabidiol, further suggesting that the mitochondria acts as the source of cannabidiol‐evoked Ca2+ rise in oligodendrocytes. n addition, brief exposure to cannabidiol (100 nM–10 μM) led to a concentration‐dependent decrease of oligodendroglial viability that was not prevented by antagonists of CB1, CB2, vanilloid, A2A or PPARγ receptors, but was instead reduced in the absence of extracellular Ca2+. The oligodendrotoxic effect of cannabidiol was partially blocked by inhibitors of caspase‐3, ‐8 and ‐9, PARP‐1 and calpains, suggesting the activation of caspase‐dependent and ‐independent death pathways. Cannabidiol also elicited a concentration‐dependent alteration of mitochondrial membrane potential, and an increase in reactive oxygen species (ROS) that was reduced in the absence of extracellular Ca2+. Finally, cannabidiol‐induced cytotoxicity was partially prevented by the ROS scavenger trolox. Together, these results suggest that cannabidiol causes intracellular Ca2+ dysregulation which can lead to oligodendrocytes demise. © 2010 Wiley‐Liss, Inc.