Involvement of ERK1/2, cPLA2 and NF-κB in microglia suppression by cannabinoid receptor agonists and antagonists

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 A2 (cPLA2) 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.

► CB1/CB2 receptor non-selective and selective agonists blocked iNOS induction and ROS generation in LPS-activated microglia.
► The inhibitory effects are mediated by reducing ERK1/2 and cPLA2 phosphorylation and NFκB activation.
► Microglia suppression by CB1/CB2 receptor agonists was not reversed by the respective antagonists.
► The CB1/CB2 antagonists also blocked NO and ROS production in activated microglia.
► CB1/CB2 agonists and antagonists are likely to suppress microglia activation by CB1/CB2 receptor independent mechanisms.