Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arachidonic Acid / metabolism
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Arachidonic Acids / metabolism*
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Benzodioxoles / pharmacology
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Brain / drug effects
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Brain / metabolism*
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Brain / pathology
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Cannabinoid Receptor Modulators / metabolism*
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Cyclooxygenase 1 / metabolism
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Cytokines / metabolism
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Eicosanoids / metabolism
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Endocannabinoids*
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Enzyme Inhibitors / pharmacology
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Glycerides / metabolism*
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Hydrolysis
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Inflammation / metabolism*
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Inflammation / pathology
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Inflammation Mediators / pharmacology
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Lipopolysaccharides / pharmacology
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Liver / metabolism
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Lung / metabolism
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Metabolomics
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Mice
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Mice, Inbred C57BL
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Monoacylglycerol Lipases / antagonists & inhibitors
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Monoacylglycerol Lipases / genetics
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Monoacylglycerol Lipases / metabolism*
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Neuroprotective Agents / pharmacology
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Parkinsonian Disorders / metabolism
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Parkinsonian Disorders / pathology
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Phospholipases A2 / genetics
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Phospholipases A2 / metabolism
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Piperidines / pharmacology
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Prostaglandins / biosynthesis
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Prostaglandins / metabolism*
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Signal Transduction
Substances
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Arachidonic Acids
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Benzodioxoles
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Cannabinoid Receptor Modulators
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Cytokines
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Eicosanoids
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Endocannabinoids
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Enzyme Inhibitors
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Glycerides
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Inflammation Mediators
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JZL 184
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Lipopolysaccharides
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Neuroprotective Agents
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Piperidines
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Prostaglandins
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Arachidonic Acid
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glyceryl 2-arachidonate
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Cyclooxygenase 1
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Monoacylglycerol Lipases
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Phospholipases A2