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.
J Neuroimmune Pharmacol
; 10(2): 309-17, 2015 Jun.
Article
en En
| MEDLINE
| ID: mdl-25900077
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 ß (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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Células Madre
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Oligodendroglía
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Ácidos Araquidónicos
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Fosfatidilinositol 3-Quinasas
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Endocannabinoides
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Proteínas Proto-Oncogénicas c-akt
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Serina-Treonina Quinasas TOR
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Glicéridos
Límite:
Animals
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Humans
Idioma:
En
Revista:
J Neuroimmune Pharmacol
Asunto de la revista:
ALERGIA E IMUNOLOGIA
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FARMACOLOGIA
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NEUROLOGIA
Año:
2015
Tipo del documento:
Article