Endocannabinoid Hydrolysis Generates Brain Prostaglandins That Promote Neuroinflammation

被引:561
作者
Nomura, Daniel K. [1 ,2 ,3 ]
Morrison, Bradley E. [4 ]
Blankman, Jacqueline L. [1 ,2 ]
Long, Jonathan Z. [1 ,2 ]
Kinsey, Steven G. [5 ]
Marcondes, Maria Cecilia G. [4 ]
Ward, Anna M. [1 ,2 ]
Hahn, Yun Kyung [6 ]
Lichtman, Aron H. [6 ]
Conti, Bruno [4 ]
Cravatt, Benjamin F. [1 ,2 ]
机构
[1] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA
[2] Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92037 USA
[3] Univ Calif Berkeley, Dept Nutr Sci & Toxicol, Program Metab Biol, Berkeley, CA 94720 USA
[4] Scripps Res Inst, Mol & Integrat Neurosci Dept, La Jolla, CA 92037 USA
[5] W Virginia Univ, Dept Psychol, Morgantown, WV 26506 USA
[6] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA
关键词
MOUSE MODEL; PARKINSONS-DISEASE; PHOSPHOLIPASE A(2); MICE; INHIBITION; CYCLOOXYGENASE-2; INFLAMMATION; SYSTEM; INJURY; LIPOPOLYSACCHARIDE;
D O I
10.1126/science.1209200
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:809 / 813
页数:5
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