NDLI: The inhibition of 2-arachidonoyl-glycerol (2-AG) biosynthesis, rather than enhancing striatal damage, protects striatal neurons from malonate-induced death: a potential role of cyclooxygenase-2-dependent metabolism of 2-AG

Content Provider	PubMed Central
Author	Valdeolivas, S. Pazos, M. R. Bisogno, T. Piscitelli, F. Iannotti, F. A. Allarà, M. Sagredo, O. Fernández-ruiz, J. Di Marzo, V.
Copyright Year	2013
Abstract	The cannabinoid CB2 receptor, which is activated by the endocannabinoid 2-arachidonoyl-glycerol (2-AG), protects striatal neurons from apoptotic death caused by the local administration of malonate, a rat model of Huntington's disease (HD). In the present study, we investigated whether endocannabinoids provide tonic neuroprotection in this HD model, by examining the effect of O-3841, an inhibitor of diacylglycerol lipases, the enzymes that catalyse 2-AG biosynthesis, and JZL184 or OMDM169, two inhibitors of 2-AG inactivation by monoacylglycerol lipase (MAGL). The inhibitors were injected in rats with the striatum lesioned with malonate, and several biochemical and morphological parameters were measured in this brain area. Similar experiments were also conducted in vitro in cultured M-213 cells, which have the phenotypic characteristics of striatal neurons. O-3841 produced a significant reduction in the striatal levels of 2-AG in animals lesioned with malonate. However, surprisingly, the inhibitor attenuated malonate-induced GABA and BDNF deficiencies and the reduction in Nissl staining, as well as the increase in GFAP immunostaining. In contrast, JZL184 exacerbated malonate-induced striatal damage. Cyclooxygenase-2 (COX-2) was induced in the striatum 24 h after the lesion simultaneously with other pro-inflammatory responses. The COX-2-derived 2-AG metabolite, prostaglandin E2 glyceryl ester (PGE2-G), exacerbated neurotoxicity, and this effect was antagonized by the blockade of PGE2-G action with AGN220675. In M-213 cells exposed to malonate, in which COX-2 was also upregulated, JZL184 worsened neurotoxicity, and this effect was attenuated by the COX-2 inhibitor celecoxib or AGN220675. OMDM169 also worsened neurotoxicity and produced measurable levels of PGE2-G. In conclusion, the inhibition of 2-AG biosynthesis is neuroprotective in rats lesioned with malonate, possibly through the counteraction of the formation of pro-neuroinflammatory PGE2-G, formed from COX-2-mediated oxygenation of 2-AG. Accordingly, MAGL inhibition or the administration of PGE2-G aggravates the malonate toxicity.
Related Links	http://dx.doi.org/10.1038/cddis.2013.387
Starting Page	862
File Format	PDF
ISSN	20414889
e-ISSN	20414889
Journal	Cell Death & Disease
Issue Number	10
Volume Number	4
Language	English
Publisher	Nature Publishing Group
Publisher Date	2013-10-01
Access Restriction	Open
Rights Holder	Nature Publishing Group
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Medicine Cancer Research Immunology Cellular and Molecular Neuroscience

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