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

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• 作者：Oscar Gomez ; Maria A. Sanchez-Rodriguez…
• 关键词：Oligodendrocyte progenitor ; Diacylglycerol lipase ; 2 ; AG ; p27 ; cyclin E ; cdk2
• 刊名：Journal of Neuroimmune Pharmacology
• 出版年：2015
• 出版时间：June 2015
• 年：2015
• 卷：10
• 期：2
• 页码：309-317
• 全文大小：1,585 KB
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• 作者单位：Oscar Gomez (1)
  Maria A. Sanchez-Rodriguez (1)
  Silvia Ortega-Gutierrez (2)
  Henar Vazquez-Villa (2)
  Carmen Guaza (3)
  Francisco Molina-Holgado (4)
  Eduardo Molina-Holgado (1)
  
  1. Laboratory of Neuroinflammation, Hospital Nacional de Parapléjicos-SESCAM, 45071, Toledo, Spain
  2. Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense, 28040, Madrid, Spain
  3. Neuroimmunology Group, Functional and System Neurobiology Department, Instituto Cajal (CSIC), 28002, Madrid, Spain
  4. Department of Life Sciences, Roehampton University, London, SW154JD, UK
  
• 刊物主题：Neurosciences; Immunology; Pharmacology/Toxicology; Virology; Cell Biology;
• 出版者：Springer US
• ISSN：1557-1904

文摘

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 p27kip1 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.