Endocannabinoid 2-Arachidonoylglycerol Protects Neurons by Limiting COX-2 Elevation*
- Jian Zhang and
- Chu Chen1
- Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112
- 1 To whom correspondence should be addressed: Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, 2020 Gravier St., New Orleans, LA 70112. Tel.: 504-568-8458; Fax: 504-599-0488; E-mail: cchen{at}lsuhsc.edu.
Abstract
Endocannabinoids are involved in synaptic signaling and neuronal protection; however, our understanding of the mechanisms by which endocannabinoids protect neurons from harmful insults remains elusive. 2-Arachidonoylglycerol (2-AG), the most abundant endogenous cannabinoid and a full agonist for cannabinoid receptors (CB1 and CB2), is a substrate for cyclooxygenase-2 (COX-2) and can be metabolized by COX-2. Here we show, however, that 2-AG is also capable of suppressing elevation of hippocampal COX-2 expression in response to proinflammatory and excitotoxic stimuli. 2-AG prevents neurodegeneration from toxic assaults that elevate COX-2 expression and inhibits the COX-2 elevation-enhanced excitatory glutamatergic synaptic transmission. The action of 2-AG on suppression of COX-2 appeared to be mediated via the pertussis toxin-sensitive G protein-coupled CB1 receptor and MAPK/NF-κB signaling pathways. Our results reveal that 2-AG functions as an endogenous COX-2 inhibitor protecting neurons from harmful insults by preventing excessive expression of COX-2, which provides a mechanistic basis for opening up new therapeutic approaches for protecting neurons from inflammation- and excitotoxicity-induced neurodegeneration.
Footnotes
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↵2 The abbreviations used are: eCBs, endocannabinoids; COX-2, cyclooxygenase-2; 2-AG, 2-arachidonoylglycerol; AEA, arachidonoylethanolamide; PGE2, prostaglandin E2; TUNEL, terminal transferase dUTP nick end labeling; mEPSC, miniature excitatory postsynaptic current; CB, cannabinoid; PTX, pertussis toxin; MAPK, mitogen-activated protein kinases; NF-κB, nuclear factor-κB; ERK, extracellular signal-regulated kinase; AA, arachidonic acid; MGL, monoacylglycerol lipase; FAAH, fatty acid amide hydrolase; LPS, lipopolysaccharide; KA, kainic acid; SR-1, SR141716; SR-2, SR144528; GFAP, glial fibrillary acidic protein; DIV, days in vitro; ATFMK, arachidonyl trifluoromethyl ketone; WIN, WIN55,212-2; CP, CP55,940; MEM, minimum essential medium; PBS, phosphate-buffered saline; BSA, bovine serum albumin; IL, interleukin; ANOVA, analysis of variance.
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↵* This work was supported, in whole or in part, by National Institutes of Health Grant R01 NS054886. It was also supported by Alzheimer's Association Grant IIRG-05-13580. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–9.
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- Received January 22, 2008.
- Revision received May 28, 2008.
- The American Society for Biochemistry and Molecular Biology, Inc.
