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Science 334 (6057): 809-813

Copyright © 2011 by the American Association for the Advancement of Science

Endocannabinoid Hydrolysis Generates Brain Prostaglandins That Promote Neuroinflammation

Daniel K. Nomura,1,2,*,{dagger} Bradley E. Morrison,3,* Jacqueline L. Blankman,1 Jonathan Z. Long,1 Steven G. Kinsey,4 Maria Cecilia G. Marcondes,3 Anna M. Ward,1 Yun Kyung Hahn,5 Aron H. Lichtman,5 Bruno Conti,3 Benjamin F. Cravatt1,*,{dagger}

Abstract: Phospholipase A2(PLA2) enzymes are considered the primary source of arachidonic acid for cyclooxygenase (COX)–mediated biosynthesis of prostaglandins. Here, we show that a distinct pathway exists in brain, where monoacylglycerol lipase (MAGL) hydrolyzes the endocannabinoid 2-arachidonoylglycerol to generate a major arachidonate precursor pool for neuroinflammatory prostaglandins. MAGL-disrupted animals show neuroprotection in a parkinsonian mouse model. These animals are spared the hemorrhaging caused by COX inhibitors in the gut, where prostaglandins are instead regulated by cytosolic PLA2. These findings identify MAGL as a distinct metabolic node that couples endocannabinoid to prostaglandin signaling networks in the nervous system and suggest that inhibition of this enzyme may be a new and potentially safer way to suppress the proinflammatory cascades that underlie neurodegenerative disorders.

1 The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
2 Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, University of California, Berkeley, 127 Morgan Hall, Berkeley, CA 94720, USA.
3 Molecular and Integrative Neurosciences Department, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
4 Department of Psychology, West Virginia University, Post Office Box 6040, Morgantown, WV 26506, USA.
5 Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: dnomura{at} (D.K.N.) cravatt{at} (B.F.C.)

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