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Endocannabinoid Hydrolysis Generates Brain Prostaglandins That Promote Neuroinflammation

2011; American Association for the Advancement of Science; Volume: 334; Issue: 6057 Linguagem: Inglês

10.1126/science.1209200

1095-9203

Daniel K. Nomura, Brad E. Morrison, Jacqueline L. Blankman, Jonathan Z. Long, Steven G. Kinsey, Maria Cecília Garibaldi Marcondes, Anna M. Ward, Yun K. Hahn, Aron H. Lichtman, Bruno Conti, Benjamin F. Cravatt,

Neuroscience of respiration and sleep

Phospholipase A(2)(PLA(2)) 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 PLA(2). 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.