title: Involvement of ERK1/2, cPLA2 and NF-κB in microglia suppression by cannabinoid receptor agonists and antagonists.
abstract: Cannabinoids have been consistently shown to suppress microglia activation and the release of cytotoxic factors including nitric oxide, superoxide and proinflammatory cytokines. However, the underlying molecular mechanisms and whether the action of cannabinoids is coupled to the activation of cannabinoid type 1 (CB1) and type 2 (CB2) receptors are still poorly defined. In this study we observed that the CB1 and CB2 receptor non-selective or selective agonists dramatically attenuate iNOS induction and ROS generation in LPS-activated microglia. These effects are due to their reduction of phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2), cytosolic phospholipase A (cPLA) and activation of NF-κB. Surprisingly, instead of reversing the effect of the respective CB1 and CB2 receptor agonists, the antagonists also suppress iNOS induction and ROS generation in activated microglia by similar mechanisms. Taken together, these results indicate that both cannabinoid receptor agonists and antagonists might suppress microglia activation by CB1 and CB2 receptor independent mechanisms, and provide a new insight into the mechanisms of microglia inhibition by cannabinoids.
authors.affiliation: Program in Neuroscience, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. Rachel.ribeiro@usuhs.edu
authors.forename: Rachel
authors.initials: R
authors.lastname: Ribeiro
authors.forename: Jie
authors.initials: J
authors.lastname: Wen
authors.forename: Shihe
authors.initials: S
authors.lastname: Li
authors.forename: Yumin
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D015153:Blotting, Western; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D054513:Group IV Phospholipases A2 / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism
chemical_list: C439263:AM 1241; D001095:Arachidonic Acids; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D002186:Cannabinoids; D007211:Indoles; D008070:Lipopolysaccharides; D009025:Morpholines; D016328:NF-kappa B; D011720:Pyrazoles; D017382:Reactive Oxygen Species; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C088155:methanandamide; D052247:Nitric Oxide Synthase Type II; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054513:Group IV Phospholipases A2; C109925:AM 281; C094023:iodopravadoline; C402944:JHW 015