title: Cannabinoid receptor agonists modulate oligodendrocyte differentiation by activating PI3K/Akt and the mammalian target of rapamycin (mTOR) pathways.
abstract: OBJECTIVE
  The endogenous cannabinoid system participates in oligodendrocyte progenitor differentiation in vitro. To determine the effect of synthetic cannabinoids on oligodendrocyte differentiation, we exposed differentiating cultures of oligodendrocytes with cannabinoid CB(1), CB(2) and CB(1)/CB(2) receptor agonists and antagonists. The response of the PI3K/Akt and the mammalian target of rapamycin (mTOR) signalling pathways were studied as effectors of cannabinoid activity.
  
  
  METHODS
  Purified oligodendrocyte progenitor cells (OPC) obtained from primary mixed glial cell cultures were treated for 48 h with CB(1), CB(2) and CB(1) /CB(2) receptor agonists (ACEA, JWH133 and HU210, respectively) in the presence or absence of the antagonists AM281 (CB(1) receptor) and AM630 (CB(2) receptor). Moreover, inhibitors of the phosphatidylinositol 3-kinase (PI3K)/Akt and mTOR pathways (LY294002 and rapamycin, respectively) were used to study the involvement of these pathways on cannabinoid-induced OPC maturation.
  
  
  RESULTS
  ACEA, JWH133 and HU-210 enhanced OPC differentiation as assessed by the expression of stage specific antigens and myelin basic protein (MBP). Moreover, this effect was blocked by the CB receptor antagonists. ACEA, JWH133 and HU210 induced a time-dependent phosphorylation of Akt and mTOR, whereas the inhibitors of PI3K/Akt (LY294002) or of mTOR (rapamycin) reversed the effects of HU-210 on oligodendrocyte differentiation and kinase activation.
  
  
  CONCLUSIONS
  Activation of cannabinoid CB(1) or CB(2) receptors with selective agonists accelerated oligodendrocyte differentiation through the mTOR and Akt signalling pathways.
authors.affiliation: Laboratory of Neuroinflammation, Unidad de Neurologia Experimental, Hospital Nacional de Parapléjicos (SESCAM), Toledo, Spain.
authors.forename: O
authors.initials: O
authors.lastname: Gomez
authors.forename: A
authors.initials: A
authors.lastname: Sanchez-Rodriguez
authors.forename: Mqu
authors.initials: M
authors.lastname: Le
authors.forename: C
authors.initials: C
authors.lastname: Sanchez-Caro
authors.forename: F
authors.initials: F
authors.lastname: Molina-Holgado
authors.forename: E
authors.initials: E
authors.lastname: Molina-Holgado
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D013759:Dronabinol / Q000031:analogs & derivatives / Q000494:pharmacology; D020536:Enzyme Activators / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009185:Myelin Proteins / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D001095:Arachidonic Acids; D002186:Cannabinoids; D002867:Chromones; D013759:Dronabinol; D020536:Enzyme Activators; D007211:Indoles; D009025:Morpholines; D009185:Myelin Proteins; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C119325:arachidonyl-2-chloroethylamide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C546845:mTOR protein, rat; C062018:HU 211; C109925:AM 281; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC; C094023:iodopravadoline