Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation.
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.
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. dnomura@berkeley.edu
Daniel K
DK
Nomura
Bradley E
BE
Morrison
Jacqueline L
JL
Blankman
Jonathan Z
JZ
Long
Steven G
SG
Kinsey
Maria Cecilia G
MC
Marcondes
Anna M
AM
Ward
Yun Kyung
YK
Hahn
Aron H
AH
Lichtman
Bruno
B
Conti
Benjamin F
BF
Cravatt
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001095:Arachidonic Acids / Q000378:metabolism*; D052117:Benzodioxoles / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D015777:Eicosanoids / Q000378:metabolism; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005989:Glycerides / Q000378:metabolism*; D006868:Hydrolysis; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D018836:Inflammation Mediators / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000473:pathology; D054467:Phospholipases A2 / Q000235:genetics / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D011453:Prostaglandins / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction
D001095:Arachidonic Acids; D052117:Benzodioxoles; D063385:Cannabinoid Receptor Modulators; D016207:Cytokines; D015777:Eicosanoids; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; D018836:Inflammation Mediators; C534333:JZL 184; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D010880:Piperidines; D011453:Prostaglandins; D016718:Arachidonic Acid; C094503:glyceryl 2-arachidonate; D051545:Cyclooxygenase 1; D008994:Monoacylglycerol Lipases; D054467:Phospholipases A2