Inhibition of COX-2 expression by endocannabinoid 2-arachidonoylglycerol is mediated via PPAR-γ

BACKGROUND AND PURPOSE Endocannabinoids have both anti-inflammatory and neuroprotective properties against harmful stimuli. We previously demonstrated that the endocannabinoid 2-arachidonoylglycerol (2-AG) protects hippocampal neurons by limiting the inflammatory response via a CB1 receptor-dependent MAPK/NF-kappa B signalling pathway. The purpose of the present study was to determine whether PPAR gamma, an important nuclear receptor, mediates 2-AG-induced inhibition of NF-kappa B phosphorylation and COX-2 expression, and COX-2-enhanced miniature spontaneous excitatory postsynaptic currents (mEPSCs). EXPERIMENTAL APPROACH By using a whole-cell patch clamp electrophysiological recording technique and immunoblot analysis, we determined mEPSCs, expression of COX-2 and PPAR gamma, and phosphorylation of NF-kappa B in mouse hippocampal neurons in culture. KEY RESULTS Exogenous and endogenous 2-AG-produced suppressions of NF-kappa B-p65 phosphorylation, COX-2 expression and excitatory synaptic transmission in response to pro-inflammatory interleukin-1 beta (IL-1 beta) and LPS were inhibited by GW9662, a selective PPAR gamma antagonist, in hippocampal neurons in culture. PPAR gamma agonists 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) and rosiglitazone mimicked the effects of 2-AG on NF-kappa B-p65 phosphorylation, COX-2 expression and mEPSCs, and these effects were eliminated by antagonism of PPAR gamma. Moreover, exogenous application of 2-AG or elevation of endogenous 2-AG by inhibiting its hydrolysis with URB602 or JZL184, selective inhibitors of monoacylglycerol lipase (MAGL), prevented the IL-1 beta-and LPS-induced reduction of PPAR gamma expression. The 2-AG restoration of the reduced PPAR gamma expression was blocked or attenuated by pharmacological or genetic inhibition of the CB1 receptor. CONCLUSIONS AND IMPLICATIONS Our results suggest that CB1 receptor-dependent PPAR gamma expression is an important and novel signalling pathway in endocannabinoid 2-AG-produced resolution of neuroinflammation in response to pro-inflammatory insults.