The Endocannabinoid System and Oligodendrocytes in Health and Disease

Abstract

Cannabinoid-based interventions are being explored for central nervous system (CNS) pathologies such as neurodegeneration, demyelination, epilepsy, stroke, and trauma. As these disease states involve dysregulation of myelin integrity and/or remyelination, it is important to consider effects of the endocannabinoid system on oligodendrocytes and their precursors. In this review, we examine research reports on the effects of the endocannabinoid system (ECS) components on oligodendrocytes and their precursors, with a focus on therapeutic implications. Cannabinoid ligands and modulators of the endocannabinoid system promote cell signaling in oligodendrocyte precursor survival, proliferation, migration and differentiation, and mature oligodendrocyte survival and myelination. Agonist stimulation of oligodendrocyte precursor cells (OPCs) at both CB1 and CB2 receptors counter apoptotic processes via Akt/PI3K, and promote proliferation via Akt/mTOR and ERK pathways. CB1 receptors in radial glia promote proliferation and conversion to progenitors fated to become oligodendroglia, whereas CB2 receptors promote OPC migration in neonatal development. OPCs produce 2-arachidonoylglycerol (2-AG), stimulating cannabinoid receptor-mediated ERK pathways responsible for differentiation to arborized, myelin basic protein (MBP)-producing oligodendrocytes. In cell culture models of excitotoxicity, increased reactive oxygen species, and depolarization-dependent calcium influx, CB1 agonists improved viability of oligodendrocytes. In transient and permanent middle cerebral artery occlusion models of anoxic stroke, WIN55212-2 increased OPC proliferation and maturation to oligodendroglia, thereby reducing cerebral tissue damage. In several models of rodent encephalomyelitis, chronic treatment with cannabinoid agonists ameliorated the damage by promoting OPC survival and oligodendrocyte function. Pharmacotherapeutic strategies based upon ECS and oligodendrocyte production and survival should be considered.

Cannabinoid Receptors: An Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases

“…The CB1R also regulates neural progenitor cell fate decisions, as evidenced by its involvement in the differentiation of neural progenitor cells toward an astroglial lineage [ 240 ]. Interestingly, both CB1Rs and CB2Rs have been shown to regulate oligodendrocyte progenitor cells function, via a PI3K/AKT pathway, whereby their activation exerts a protective role [ 81 , 241 ]. Although the role of CB2R in CNS development is not as well studied, there is evidence of its involvement in neural progenitor cell proliferation, and possibly in neurogenesis [ 242 ].…”

Targeting Endocannabinoid Metabolism: an Arrow with Multiple Tips Against Multiple Sclerosis

“…However, it clearly demonstrated that the exogenous administration of 2‐AG ameliorated both acute and chronic disease models, with a significant impact on acute relapse severity and chronic progressive disability, and a reduced mortality rate in severe MOG‐EAE. Not only the administration of exogenous 2‐AG but also increased levels of this neurotransmitter due to the blockade of its main catabolic enzyme, namely MAGL, exerted positive effects on oligodendrocyte excitotoxicity and helped preventing demyelination in vivo [111,139] . MAGL plays a pivotal role in the regulation of 2‐AG levels and its pharmacological inhibition could contribute to protect neurons from pro‐inflammatory and excitotoxic stimuli, through the activation of CBRs [140,141] .…”

Cannabinoid Actions on Neural Stem Cells: Implications for Pathophysiology

“…Concomitantly, in MS there is myelin damage and oligodendrocyte loss, and thus, finding new mechanisms to promote both re-myelination and OPC differentiation, either from precursors present in the brain parenchyma or derived from SVZ NSCs is crucial, since OPCs are able to migrate and partially remyelinate lesioned areas [249,419,420,421]. Cells from the oligodendroglial lineage are directly modulated by cannabinoids in distinct maturation stages, ranging from the regulation of OPC survival, proliferation, migration and differentiation to the modulation of mature oligodendrocyte survival and myelinating capacity [422,423]. For instance, it has been observed that OPCs express CB1Rs and CB2Rs and that cannabinoids promote OPC survival and oligodendrocyte differentiation through the PI3K/Akt/mTORC1 signaling pathway, which is known to participate in the myelination process [229,231,422,424,425,426,427,428,429].…”