The endocannabinoid 2-AG enhances spontaneous remyelination by targeting microglia

Remyelination is an endogenous process by which functional recovery of damaged neurons is achieved by reinstating the myelin sheath around axons. Remyelination has been documented in multiple sclerosis (MS) lesions and experimental models, although it is often incomplete or fails to affect the integrity of the axon, thereby leading to progressive disability. Microglia play a crucial role in the clearance of the myelin debris produced by demyelination and in inflammation-dependent OPC activation, two processes necessary for remyelination to occur. We show here that following corpus callosum demyelination in the TMEV-IDD viral murine model of MS, there is spontaneous and partial remyelination that involves a temporal discordance between OPC mobilization and microglia activation. Pharmacological treatment with the endocannabinoid 2-AG enhances the clearance of myelin debris by microglia and OPC differentiation, resulting in complete remyelination and a thickening of the myelin sheath. These results highlight the importance of targeting microglia during the repair processes in order to enhance remyelination.This work was supported by grants from the Ministerio de Economía y Competitividad (MINECO SAF2013-42784-R, SAF2016 76449-R), and the Red Española de Esclerosis Múltiple (REEM: RD12/0032/0008, RD16/0015/0021) sponsored by the Fondo de Investigación Sanitaria (FIS).Peer reviewe