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.
Highlights
Phytocannabinoid use in management of multiple sclerosis (MS) symptoms (Consroe et al, 1997) has led to clinical trial evidence for the efficacy of tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (Sativex) in controlling spasticity and pain (Wade et al, 2010; Giacoppo et al, 2017)
Co-treatment with could be abolished by either AM281 (CB1) antagonist SR141716 (1 μM) abolished the anti-apoptotic effect of ACEA, but not of WIN55212-2 or HU210. Both SR141716 plus CB2 antagonist SR144528 (1 μM) were required to nullify the pro-survival effect of HU210. These results show that the activation of either CB1 or CB2 receptors could be sufficient in promoting oligodendrocyte precursor cells (OPCs) survival under conditions of trophic factor deprivation
These results extend the impact of cannabinoid receptor activation from promoting OPC survival (Molina-Holgado et al, 2002) to increasing proliferation, while implicating cannabinoidmediated Akt/mammalian target of rapamycin (mTOR) and Extracellular signal regulated-kinase (ERK) pathways, known to play a role throughout OPC development to myelination (Gonsalvez et al, 2016; Figlia et al, 2018)
Summary
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. 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. In several models of rodent encephalomyelitis, chronic treatment with cannabinoid agonists ameliorated the damage by promoting OPC survival and oligodendrocyte function.
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