A Basal Tone of 2-Arachidonoylglycerol Contributes to Early Oligodendrocyte Progenitor Proliferation by Activating Phosphatidylinositol 3-Kinase (PI3K)/AKT and the Mammalian Target of Rapamycin (MTOR) Pathways

Abstract

A basal tone of the endocannabinoid 2-arachidonoylglycerol (2-AG) enhances late oligodendrocyte progenitor cell (OPC) differentiation. Here, we investigated whether endogenous 2-AG may also promote OPC proliferation in earlier stages. We found that the blockade of 2-AG synthesizing enzymes, sn-1-diacylglycerol lipases α and β (DAGLs), with RHC-80267 or the antagonism of either CB1 or CB2 cannabinoid receptors with AM281 and AM630, respectively, impaired early OPC proliferation stimulated by platelet-derived growth factor (PDGF-AA) and basic fibroblast growth factor (bFGF). On the contrary, increasing the levels of endogenous 2-AG by blocking the degradative enzyme monoacylglycerol lipase (MAGL) with JZL-184, significantly increased OPC proliferation as did agonists of cannabinoid receptor CB1 (ACEA), CB2 (JWH133) or both (HU-210). To elucidate signaling pathways underlying OPC proliferation, we studied the involvement of phosphatidylinositol 3-kinase (PI3K)/Akt and its downstream target mammalian target of rapamycin (mTOR). We show that phosphorylation of Akt and mTOR is required for OPC proliferation stimulated by growth factors (PDGF-AA and bFGF) or by CB1/CB2 agonists (ACEA/JWH133), since it was strongly decreased after LY294002 or rapamycin treatment. In line with this, blockade of CB1 (AM281), CB2 (AM630) or DAGLs (RHC-80267), decreased phosphorylation of Akt, mTOR and 4E-BP1, diminished cyclin E-cdk2 complex association and increased p27(kip1) levels. Our data suggest that proliferation of early OPCs stimulated by PDGF-AA and bFGF depends on the tonic activation of cannabinoid receptors by endogenous 2-AG and provide further evidence on the role of endocannabinoids in oligodendrocyte development, being important for the maintenance and self-renewal of the OPCs. The results highlight the therapeutic potential of the endocannabinoid signaling in the emerging field of brain repair.

Dissecting the Signaling Pathways Involved in the Crosstalk between Metabotropic Glutamate 5 and Cannabinoid Type 1 Receptors

“…CB 1 receptor activation influences multiple effector systems; because of its wide distribution in the brain, the CB 1 receptor is believed to be responsible for mediating the majority of the cannabinoids' effects in the CNS (Cabral and Marciano-Cabral, 2005;Di Marzo, 2009). Evidence obtained by multiple groups supports the hypothesis that the CB 1 receptor plays a key role in various cellular events (Ferreira-Vieira et al, 2014;Gomez et al, 2015;Zhang et al, 2015). Moreover, it has been reported that the CB 1 receptor is involved in cognitive and affective processes, as well as in the control of motor activity, stress, addiction, and neuroprotection (Nagayama et al, 1999;Broadbent et al, 2004;Finn, 2010;Naydenov et al, 2014;McReynolds et al, 2016).…”

Interaction between Cannabinoid System and Toll-Like Receptors Controls Inflammation

“…Akt may activate mammalian target of rapamycin (mTOR) present in complex 1 (mTORC1), and, in turn, mTORC1 regulates protein synthesis, glucose metabolism, and autophagy. Rapamycin, a mTOR inhibitor, blocks cannabinoid-induced neural progenitor cell proliferation and cannabinoid-enhanced oligodendrocyte differentiation [53, 54]. On the other hand, WIN 55,212-2 decreases mTORC1 activation in prostate cancer cells [55].…”

2‐arachidonoylglycerol reduces chondroitin sulphate proteoglycan production by astrocytes and enhances oligodendrocyte differentiation under inhibitory conditions

“…The promotion of oligodendrocyte maturation by 2‐AG was reproduced by administering this endocannabinoid or by impeding its hydrolysis by inhibiting MAGL, inducing OPC proliferation and differentiation in vitro (Bernal‐Chico et al, ; Gómez et al, , , ), and regulating their migration in culture (Sánchez‐Rodríguez et al, ). These effects are mediated through CB1R and CB2R both present on OPCs and mature oligodendrocytes, being the Pi3k‐Akt signaling pathway involved in the promotion of oligodendrocytes differentiation by the endocannabinoid (Gómez et al, , ).…”

“…Indeed, cannabinoid signaling may enhance the activity of reparative mechanisms, as they can protect OPCs from inflammatory and excitotoxic damage (Bernal‐Chico et al, ; Gómez et al, ; Mecha et al, ; Molina‐Holgado et al, ). In particular, the endocannabinoid 2‐arachidonoylglycerol (2‐AG) promotes the proliferation and differentiation of OPCs (Gómez et al, , , ) and it regulates their migration in culture (Sánchez‐Rodríguez, Gómez, Esteban, García‐Ovejero, & Molina‐Holgado, ). Actually, in vivo studies also demonstrated that inhibiting 2‐AG catabolism through the inhibition of monoacylglycerol lipase (MAGL) or the direct administration of 2‐AG attenuates symptomatology and promotes remyelination in the autoimmune EAE model (Bernal‐Chico et al, ; Hernández‐Torres et al, ; Lourbopoulos et al, ), as well as in the Theiler virus model of MS (Feliu et al, ; Mecha et al, ).…”