RT Journal Article
T1 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
A1 Gómez, Oscar
A1 Sánchez Rodríguez, María A.
A1 Ortega Gutiérrez, Silvia
A1 Vázquez Villa, María Del Henar
A1 Guaza, Carmen
A1 Molina Holgado, Francisco
A1 Molina Holgado, Eduardo
AB 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 alpha and beta (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.
PB Springer Nature
SN 1557-1890
YR 2015
FD 2015-04-22
LK https://hdl.handle.net/20.500.14352/113914
UL https://hdl.handle.net/20.500.14352/113914
LA eng
NO Gomez, O., Sanchez-Rodriguez, M.A., Ortega-Gutierrez, S., Vazquez-Villa, H., Guaza, C., Molina-Holgado, F., Molina-Holgado, E..f 2-Arachidonoylglycerol Contributes to Early Oligodendrocyte Progenitor Proliferation by Activating Phosphatidylinositol 3-Kinase (PI3K)/AKT and the Mammalian Target of Rapamycin (MTOR) Pathways. J Neuroimmune Pharmacol 2015, 10, 309–317.
NO Ministería de Economía y Competetividad
NO Instituto de Salud Carlos III
NO Comunidad de Madrid
NO Red Española de Esclerosis Múltiple
DS Docta Complutense
RD 17 abr 2025