Monoacylglycerol Lipase Regulates Fever Response.
Monoacylglycerol Lipase Regulates Fever Response.
复制标题
DOI：
10.1371/journal.pone.0134437
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Conti B
中科院分区：
文献类型：
--
作者：
Sanchez-Alavez M;Nguyen W;Mori S;Moroncini G;Viader A;Nomura DK;Cravatt BF;Conti B
环氧合酶抑制剂如布洛芬已被用于数十年来通过降低热原脂质递质前列腺素E2（PGE 2）的水平来控制发热。历史上，磷脂酶被认为是用于产生PGE 2和其他类花生酸的花生四烯酸（AA）前体库的主要产生者。然而，最近的研究表明，单酰甘油脂肪酶（MAGL），通过内源性大麻素2-花生四烯酸甘油水解，提供了一个主要来源的AA的PGE 2在哺乳动物大脑基础和神经炎症状态下的合成。我们在这里表明，无论是遗传或药理学消融MAGL导致显着减少发热反应，在中枢或外周给药的脂多糖或白细胞介素-1 β诱导的小鼠发热模型。我们还表明，大麻素CB 1受体拮抗剂不会减弱MAGL抑制剂的这些抗热原作用。因此，就像传统的非甾体抗炎药一样，MAGL抑制剂可以控制发热，但似乎是通过限制神经系统中前列腺素的产生来实现的。
Cyclooxygenase inhibitors such as ibuprofen have been used for decades to control fever through reducing the levels of the pyrogenic lipid transmitter prostaglandin E2 (PGE2). Historically, phospholipases have been considered to be the primary generator of the arachidonic acid (AA) precursor pool for generating PGE2 and other eicosanoids. However, recent studies have demonstrated that monoacyglycerol lipase (MAGL), through hydrolysis of the endocannabinoid 2-arachidonoylglycerol, provides a major source of AA for PGE2 synthesis in the mammalian brain under basal and neuroinflammatory states. We show here that either genetic or pharmacological ablation of MAGL leads to significantly reduced fever responses in both centrally or peripherally-administered lipopolysaccharide or interleukin-1β-induced fever models in mice. We also show that a cannabinoid CB1 receptor antagonist does not attenuate these anti-pyrogenic effects of MAGL inhibitors. Thus, much like traditional nonsteroidal anti-inflammatory drugs, MAGL inhibitors can control fever, but appear to do so through restricted control over prostaglandin production in the nervous system.