The monoacylglycerol lipase inhibitor JZL184 attenuates LPS-induced increases in cytokine expression in the rat frontal cortex and plasma: differential mechanisms of action
The monoacylglycerol lipase inhibitor JZL184 attenuates LPS-induced increases in cytokine expression in the rat frontal cortex and plasma: differential mechanisms of action
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DOI：
10.1111/j.1476-5381.2012.02237.x
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发表时间：
2013-06-01
影响因子：
7.3
通讯作者：
Roche, M.
中科院分区：
文献类型：
--
作者：
Kerr, D. M.;Harhen, B.;Roche, M.
背景与目的JZL184是单酰基甘油脂肪酶（MAGL）的选择性抑制剂，该酶优先分解内源性大麻素2-花生四烯醇甘油（2-AG）。在这里，我们研究了JZL184对急性免疫攻击后脑和血浆中炎症细胞因子的影响，以及所涉及的潜在受体和分子机制。实验方法JZL184和/或CB1受体拮抗剂AM251或cb2受体拮抗剂AM630在脂多糖（LPS）治疗前30分钟给药。2h后测定大鼠额叶皮质、血浆和脾脏细胞因子表达水平、MAGL活性、2-AG、花生四烯酸和前列腺素水平。JZL184能减弱lps诱导的大鼠额叶皮层中IL-1、IL-6、TNF-和IL-10的表达，但不能抑制NFkB （IB）抑制剂的表达。AM251减弱了jzl184诱导的额叶皮质IL-1表达的下降。虽然jzl184处理的大鼠额叶皮层花生四烯酸水平降低，但MAGL活性、2-AG、PGE2和PGD2不变。相比之下，JZL184可抑制脾脏MAGL活性，提高脾脏2-AG水平。在血浆中，lps诱导的TNF-和IL-10水平升高被JZL184减弱，这一作用被AM251部分阻断。此外，在JZL184存在（而非不存在）的情况下，AM630阻断了lps诱导的血浆IL-1升高。结论和意义JZL184抑制大鼠外周MAGL抑制lps诱导的循环细胞因子，进而调节中枢细胞因子的表达。这些数据为内源性大麻素系统作为治疗中枢和外周炎症性疾病的治疗靶点提供了进一步的证据。这篇文章是大麻素主题部分的一部分。要查看本节中的其他文章，请访问http://dx.doi.org/10.1111/bph.2013.169.issue-4和http://dx.doi.org/10.1111/bph.2012.167.issue-8
Background and purpose JZL184 is a selective inhibitor of monoacylglycerol lipase (MAGL), the enzyme that preferentially catabolizes the endocannabinoid 2-arachidonoyl glycerol (2-AG). Here, we have studied the effects of JZL184 on inflammatory cytokines in the brain and plasma following an acute immune challenge and the underlying receptor and molecular mechanisms involved. Experimental approach JZL184 and/or the CB1 receptor antagonist, AM251 or the CB2receptor antagonist, AM630 were administered to rats 30min before lipopolysaccharide (LPS). 2h later cytokine expression and levels, MAGL activity, 2-AG, arachidonic acid and prostaglandin levels were measured in the frontal cortex, plasma and spleen. Key results JZL184 attenuated LPS-induced increases in IL-1, IL-6, TNF- and IL-10 but not the expression of the inhibitor of NFkB (IB) in rat frontal cortex. AM251 attenuated JZL184-induced decreases in frontal cortical IL-1 expression. Although arachidonic acid levels in the frontal cortex were reduced in JZL184-treated rats, MAGL activity, 2-AG, PGE2 and PGD2 were unchanged. In comparison, MAGL activity was inhibited and 2-AG levels enhanced in the spleen following JZL184. In plasma, LPS-induced increases in TNF- and IL-10 levels were attenuated by JZL184, an effect partially blocked by AM251. In addition, AM630 blocked LPS-induced increases in plasma IL-1 in the presence, but not absence, of JZL184. Conclusion and implications Inhibition of peripheral MAGL in rats by JZL184 suppressed LPS-induced circulating cytokines that in turn may modulate central cytokine expression. The data provide further evidence for the endocannabinoid system as a therapeutic target in treatment of central and peripheral inflammatory disorders. Linked Articles This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-4 & http://dx.doi.org/10.1111/bph.2012.167.issue-8