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J. Biol. Chem., Vol. 283, Issue 33, 22601-22611, August 15, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/33/22601    most recent M800524200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Zhang, J. Articles by Chen, C. PubMed PubMed Citation Articles by Zhang, J. Articles by Chen, C. Social Bookmarking                      What's this?

Endocannabinoid 2-Arachidonoylglycerol Protects Neurons by Limiting COX-2 Elevation^*

From the Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112

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-B 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.

Received for publication, January 22, 2008 , and in revised form, May 28, 2008.

^* 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–9.

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.

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