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

Huizhi Du, Xiaolei Chen, Jian Zhang, Chu Chen

Research output: Contribution to journalArticlepeer-review

97 Scopus citations

Abstract

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 CB 1 receptor-dependent MAPK/NF-κB signalling pathway. The purpose of the present study was to determine whether PPARγ, an important nuclear receptor, mediates 2-AG-induced inhibition of NF-κB 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 PPARγ, and phosphorylation of NF-kB in mouse hippocampal neurons in culture. KEY RESULTS Exogenous and endogenous 2-AG-produced suppressions of NF-κB-p65 phosphorylation, COX-2 expression and excitatory synaptic transmission in response to pro-inflammatory interleukin-1β (IL-1β) and LPS were inhibited by GW9662, a selective PPARγ antagonist, in hippocampal neurons in culture. PPARγ agonists 15-deoxy-Δ 12,14-prostaglandin J 2 (15d-PGJ 2) and rosiglitazone mimicked the effects of 2-AG on NF-κB-p65 phosphorylation, COX-2 expression and mEPSCs, and these effects were eliminated by antagonism of PPARγ. 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-1β- and LPS-induced reduction of PPARγ expression. The 2-AG restoration of the reduced PPARγ expression was blocked or attenuated by pharmacological or genetic inhibition of the CB 1 receptor. CONCLUSIONS AND IMPLICATIONS Our results suggest that CB 1 receptor-dependent PPARγ expression is an important and novel signalling pathway in endocannabinoid 2-AG-produced resolution of neuroinflammation in response to pro-inflammatory insults.

Original languageEnglish (US)
Pages (from-to)1533-1549
Number of pages17
JournalBritish Journal of Pharmacology
Volume163
Issue number7
DOIs
StatePublished - Aug 2011
Externally publishedYes

Keywords

  • cyclooxygenase-2
  • endocannabinoids
  • monoacylglycerol lipase
  • neuroinflammation
  • nuclear factor κ-B
  • peroxisome proliferator-activated receptor-γ

ASJC Scopus subject areas

  • Pharmacology

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