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Inhibition of COX-2 expression by endocannabinoid 2-arachidonoylglycerol is mediated via PPAR-γ.
Br J Pharmacol. 2011 Aug; 163(7):1533-49.BJ

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.

Authors+Show Affiliations

Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

21501147

Citation

Du, Huizhi, et al. "Inhibition of COX-2 Expression By Endocannabinoid 2-arachidonoylglycerol Is Mediated Via PPAR-γ." British Journal of Pharmacology, vol. 163, no. 7, 2011, pp. 1533-49.
Du H, Chen X, Zhang J, et al. Inhibition of COX-2 expression by endocannabinoid 2-arachidonoylglycerol is mediated via PPAR-γ. Br J Pharmacol. 2011;163(7):1533-49.
Du, H., Chen, X., Zhang, J., & Chen, C. (2011). Inhibition of COX-2 expression by endocannabinoid 2-arachidonoylglycerol is mediated via PPAR-γ. British Journal of Pharmacology, 163(7), 1533-49. https://doi.org/10.1111/j.1476-5381.2011.01444.x
Du H, et al. Inhibition of COX-2 Expression By Endocannabinoid 2-arachidonoylglycerol Is Mediated Via PPAR-γ. Br J Pharmacol. 2011;163(7):1533-49. PubMed PMID: 21501147.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of COX-2 expression by endocannabinoid 2-arachidonoylglycerol is mediated via PPAR-γ. AU - Du,Huizhi, AU - Chen,Xiaolei, AU - Zhang,Jian, AU - Chen,Chu, PY - 2011/4/20/entrez PY - 2011/4/20/pubmed PY - 2012/1/19/medline SP - 1533 EP - 49 JF - British journal of pharmacology JO - Br J Pharmacol VL - 163 IS - 7 N2 - 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. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/21501147/Inhibition_of_COX_2_expression_by_endocannabinoid_2_arachidonoylglycerol_is_mediated_via_PPAR_γ_ L2 - https://doi.org/10.1111/j.1476-5381.2011.01444.x DB - PRIME DP - Unbound Medicine ER -