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Endocannabinoid Hydrolysis Generates Brain Prostaglandins That Promote Neuroinflammation

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Science  20 Oct 2011:
1209200
DOI: 10.1126/science.1209200

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.