Journal of Neuroimmune Pharmacology

, Volume 10, Issue 2, pp 309–317 | Cite as

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

  • Oscar GomezEmail author
  • Maria A. Sanchez-Rodriguez
  • Silvia Ortega-Gutierrez
  • Henar Vazquez-Villa
  • Carmen Guaza
  • Francisco Molina-Holgado
  • Eduardo Molina-HolgadoEmail author


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.


Oligodendrocyte progenitor Diacylglycerol lipase 2-AG p27 cyclin E cdk2 



This research was funded by the Ministry of Economy and Competitiveness of Spain to EM-H (MINECO, Instituto de Salud Carlos III; PI11/1729). SO-G was funded by MINECO (SAF2013-48271) and Comunidad de Madrid (S2010/BMD-2353). CG was supported by Red Española de Esclerosis Múltiple (REEM) RD12/0032/0008 sponsored by the Instituto de Salud Carlos III. We thank Drs A. Arevalo-Martin and D. Garcia-Ovejero and G. Almazan for valuable discussion and critical reading of the manuscript. We are grateful to Drs J.A. Rodríguez-Alfaro and J. Mazario (Servicio de Microscopia, Hospital Nacional de Paraplejicos) for their excellent technical assistance. The contribution of Ms. C. Sanchez-Caro in this work is sincerely acknowledged.

Conflict of Interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Oscar Gomez
    • 1
    Email author
  • Maria A. Sanchez-Rodriguez
    • 1
  • Silvia Ortega-Gutierrez
    • 2
  • Henar Vazquez-Villa
    • 2
  • Carmen Guaza
    • 3
  • Francisco Molina-Holgado
    • 4
  • Eduardo Molina-Holgado
    • 1
    Email author
  1. 1.Laboratory of NeuroinflammationHospital Nacional de Parapléjicos-SESCAMToledoSpain
  2. 2.Departamento de Química Orgánica I, Facultad de Ciencias QuímicasUniversidad ComplutenseMadridSpain
  3. 3.Neuroimmunology Group, Functional and System Neurobiology DepartmentInstituto Cajal (CSIC)MadridSpain
  4. 4.Department of Life SciencesRoehampton UniversityLondonUK

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