Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation

By Daniel K. Nomura, Brad E. Morrison, Jacqueline L. Blankman, Jonathan Z. Long, S. Kinsey, M. C. Marcondes, A. Ward, A. Lichtman, B. Conti, B. Cravatt. Science, 2011

686 citations recorded by the source corpus.

A new tissue-specific pathway for the synthesis of proinflammatory prostaglandins is described. 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.

Subfields: Endocrine and Autonomic Systems, Pathology and Forensic Medicine, Pharmacology

View Paper: https://www.semanticscholar.org/paper/fc6f82c0b827da97c2561386df25338717b2ddf8

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In Pharmacology

1. Hui-Chen Lu
2. K. Mackie

Citations in the corpus

• An introduction to the endogenous cannabinoid system (2015, background): “For example, 2-AG in the brain, liver, and lung, but not in the gut, heart, kidney, or spleen, is the major source of arachidonic acid used for prostaglandin synthesis (40).”