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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
BRIEF REPORT

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 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.

Keywords

Oligodendrocyte progenitor Diacylglycerol lipase 2-AG p27 cyclin E cdk2 

Notes

Acknowledgments

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.

References

  1. Aguado T, Monory K, Palazuelos J, Stella N, Cravatt B, Lutz B et al (2005) The endocannabinoid system drives neural progenitor proliferation. FASEB J 19:1704–1706PubMedGoogle Scholar
  2. Aguado T, Palazuelos J, Monory K, Stella N, Cravatt B, Lutz B, Marsicano G, Kokaia Z, Guzmán M, Galve-Roperh I (2006) The endocannabinoid system promotes astroglial differentiation by acting on neural progenitor cells. J Neurosci 26:1551–1561PubMedCrossRefGoogle Scholar
  3. Arevalo-Martín A, Garcia-Ovejero D, Rubio-Araiz A, Gomez O, Molina-Holgado F, Molina-Holgado E (2007) Cannabinoids modulate Olig2 and polysialylated neural cell adhesion molecule expression in the subventricular zone of post-natal rats through cannabinoid receptor 1 and cannabinoid receptor 2. Eur J Neurosci 26:1548–1559PubMedCrossRefGoogle Scholar
  4. Bernal-Chico A, Canedo M, Manterola A, Victoria Sánchez-Gómez M, Pérez-Samartín A, Rodríguez-Puertas R, Matute C, Mato S (2015) Blockade of monoacylglycerol lipase inhibits oligodendrocyte excitotoxicity and prevents demyelination in vivo. Glia 63:163–176PubMedCrossRefGoogle Scholar
  5. Casaccia-Bonnefil P, Hardy RJ, Teng KK, Levine JM, Koff A, Chao MV (1999) Loss of p27Kip1 function results in increased proliferative capacity of oligodendrocyte progenitors but unaltered timing of differentiation. Development 126:4027–4037PubMedGoogle Scholar
  6. Compagnucci C, Di Siena S, Bustamante MB, Di Giacomo D, Di Tommaso M, Maccarrone M et al (2013) Type-1 (CB1) cannabinoid receptor promotes neuronal differentiation and maturation of neural stem cells. PLoS One 8:e54271PubMedCentralPubMedCrossRefGoogle Scholar
  7. Frederick TJ, Wood TL (2004) IGF-I and FGF-2 coordinately enhance cyclin D1 and cyclin E–cdk2 association and activity to promote G1 progression in oligodendrocyte progenitor cells. Mol Cell Neurosci 25:480–492PubMedCrossRefGoogle Scholar
  8. Galve-Roperh I, Chiurchiù V, Díaz-Alonso J, Bari M, Guzmán M, Maccarrone M (2013) Cannabinoid receptor signaling in progenitor/stem cell proliferation and differentiation. Prog Lipid Res 52:633–650PubMedCrossRefGoogle Scholar
  9. Ghiani CA, Eisen AM, Yuan X, DePinho RA, McBain CJ, Gallo V (1999) Neurotransmitter receptor activation triggers p27Kip1 and p21CIP1 accumulation and G1 cell cycle arrest in oligodendrocyte progenitors. Development 126:1077–1090PubMedGoogle Scholar
  10. Ghiani C, Gallo V (2001) Inhibition of cyclin E-cyclin-dependent kinase 2 complex formation and activity is associated with cell cycle arrest and withdrawal in oligodendrocyte progenitor cells. J Neurosci 21:1274–1282PubMedGoogle Scholar
  11. Gomez O, Arevalo-Martin A, Garcia-Ovejero D, Ortega-Gutierrez S, Cisneros JA, Almazan G, Sanchez-Rodriguez MA, Molina-Holgado F, Molina-Holgado E (2010) The constitutive production of the endocannabinoid 2-arachidonoylglycerol participates in oligodendrocyte differentiation. Glia 58:1913–1927PubMedCrossRefGoogle Scholar
  12. Gomez O, Sanchez-Rodriguez A, Le M, Sanchez-Caro C, Molina-Holgado F, Molina-Holgado E (2011) Cannabinoid receptor agonists modulate oligodendrocyte differentiation by activating PI3K/Akt and the mammalian target of rapamycin (mTOR) pathways. B J Pharmacol 163:1520–1532CrossRefGoogle Scholar
  13. Harkany T, Guzman M, Galve-Roperh I, Berghuis P, Devi LA, Mackie K (2007) The emerging functions of endocannabinoid signaling during CNS development. Trends Pharmacol Sci 28:83–92PubMedCrossRefGoogle Scholar
  14. Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC (1991) Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci 11:563–583PubMedGoogle Scholar
  15. Katona I, Freund TF (2012) Multiple functions of endocannabinoid signaling in the brain. Annu Rev Neurosci 35:529–558PubMedCentralPubMedCrossRefGoogle Scholar
  16. Long JZ, Li W, Booker L, Burston JJ, Kinsey SG, Schlosburg JE, Pavon FJ, Serrano AM, Selley DE, Parsons LH, Lichtman AH, Cravatt BF (2009) Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nat Chem Biol 5:37–44PubMedCentralPubMedCrossRefGoogle Scholar
  17. Mato S, Alberdi E, Ledent C, Watanabe M, Matute C (2009) CB1 cannabinoid receptor-dependent and -independent inhibition of depolarization-induced calcium influx in oligodendrocytes. Glia 57:295–306PubMedCrossRefGoogle Scholar
  18. Molina-Holgado E, Vela JM, Arevalo-Martın A, Almazan G, Molina-Holgado F, Borrell J, Guaza C (2002) Cannabinoids promote oligodendrocyte progenitor survival: Involvement of cannabinoid receptors and phosphatidylinositol-3kinase/Akt signaling. J Neurosci 22:9742–9753PubMedGoogle Scholar
  19. Molina-Holgado F, Rubio-Araiz A, García-Ovejero D, Williams RJ, Moore JD, Arévalo-Martín A et al (2007) CB2 cannabinoid receptors promote mouse neural stem cell proliferation. Eur J Neurosci 25:629–634PubMedCrossRefGoogle Scholar
  20. Palazuelos J, Aguado T, Egia A, Mechoulam R, Guzman M, Galve-Roperh I (2006) Non-psychoactive CB2 cannabinoid agonists stimulate neural progenitor proliferation. FASEB J 20:2405–2407PubMedCrossRefGoogle Scholar
  21. Palazuelos J, Ortega Z, Díaz-Alonso J, Guzmán M, Galve-Roperh I (2012) CB2 cannabinoid receptors promote neural progenitor cell proliferation via mTORC1 signaling. J Biol Chem 287:1198–11209PubMedCentralPubMedCrossRefGoogle Scholar
  22. Pertwee RG (2005) Pharmacological actions of cannabinoids. Handb Exp Pharmacol 168:1–51PubMedGoogle Scholar
  23. Sim FJ, Lang JK, Waldau B, Roy NS, Schwartz TE, Pilcher WH, Chandross KJ, Natesan S, Merrill JE, Goldman SA (2006) Complementary patterns of gene expression by human oligodendrocyte progenitors and their environment predict determinants of progenitor maintenance and differentiation. Ann Neurol 59:763–779PubMedCrossRefGoogle Scholar
  24. Trazzi S, Steger M, Mitrugno VM, Bartesaghi R, Ciani E (2010) CB1 cannabinoid receptors increase neuronal precursor proliferation through AKT/glycogen synthase kinase-3beta/beta-catenin signaling. J Biol Chem 285:10098–10109PubMedCentralPubMedCrossRefGoogle Scholar
  25. Williams EJ, Walsh FS, Doherty P (2003) The FGF receptor uses the endocannabinoid signaling system to couple to an axonal growth response. J Cell Biol 160:481–486PubMedCentralPubMedCrossRefGoogle Scholar
  26. Zuchero JB, Barres BA (2013) Intrinsic and extrinsic control of oligodendrocyte development. Curr Opin Neurobiol 23:914–920PubMedCentralPubMedCrossRefGoogle Scholar

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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