PMID- 25900077
OWN - NLM
STAT- MEDLINE
DCOM- 20160401
LR  - 20220309
IS  - 1557-1904 (Electronic)
IS  - 1557-1890 (Linking)
VI  - 10
IP  - 2
DP  - 2015 Jun
TI  - 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.
PG  - 309-17
LID - 10.1007/s11481-015-9609-x [doi]
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.
FAU - Gomez, Oscar
AU  - Gomez O
AD  - Laboratory of Neuroinflammation, Hospital Nacional de Paraplejicos-SESCAM, 45071, 
      Toledo, Spain, oskargomeztorres@gmail.com.
FAU - Sanchez-Rodriguez, Maria A
AU  - Sanchez-Rodriguez MA
FAU - Ortega-Gutierrez, Silvia
AU  - Ortega-Gutierrez S
FAU - Vazquez-Villa, Henar
AU  - Vazquez-Villa H
FAU - Guaza, Carmen
AU  - Guaza C
FAU - Molina-Holgado, Francisco
AU  - Molina-Holgado F
FAU - Molina-Holgado, Eduardo
AU  - Molina-Holgado E
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150422
PL  - United States
TA  - J Neuroimmune Pharmacol
JT  - Journal of neuroimmune pharmacology : the official journal of the Society on 
      NeuroImmune Pharmacology
JID - 101256586
RN  - 0 (Arachidonic Acids)
RN  - 0 (Cannabinoid Receptor Agonists)
RN  - 0 (Endocannabinoids)
RN  - 0 (Glycerides)
RN  - 8D239QDW64 (glyceryl 2-arachidonate)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Arachidonic Acids/*pharmacology
MH  - Cannabinoid Receptor Agonists/pharmacology
MH  - Cell Proliferation/drug effects/physiology
MH  - Cells, Cultured
MH  - Endocannabinoids/*pharmacology
MH  - Glycerides/*pharmacology
MH  - Humans
MH  - Mice
MH  - Oligodendroglia/drug effects/*metabolism
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Signal Transduction/drug effects/physiology
MH  - Stem Cells/drug effects/*metabolism
MH  - TOR Serine-Threonine Kinases/*metabolism
EDAT- 2015/04/23 06:00
MHDA- 2016/04/02 06:00
CRDT- 2015/04/23 06:00
PHST- 2015/01/08 00:00 [received]
PHST- 2015/03/30 00:00 [accepted]
PHST- 2015/04/23 06:00 [entrez]
PHST- 2015/04/23 06:00 [pubmed]
PHST- 2016/04/02 06:00 [medline]
AID - 10.1007/s11481-015-9609-x [doi]
PST - ppublish
SO  - J Neuroimmune Pharmacol. 2015 Jun;10(2):309-17. doi: 10.1007/s11481-015-9609-x. 
      Epub 2015 Apr 22.