期刊
SCIENCE
卷 334, 期 6057, 页码 809-813出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1209200
关键词
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资金
- NIH [DA017259, K99DA030908, R00DA030908, 5P01DA009789, P01DA01725, AG028040, R03DA027936, DA026261, T32DA007027]
- Institute for Drug and Alcohol Studies at Virginia Commonwealth University
- Ellison Medical Foundation
- Skaggs Institute for Chemical Biology
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.
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