The inhibition of monoacylglycerol lipase by URB602 showed an anti-inflammatory and anti-nociceptive effect in a murine model of acute inflammation
The inhibition of monoacylglycerol lipase by URB602 showed an anti-inflammatory and anti-nociceptive effect in a murine model of acute inflammation
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DOI：
10.1038/sj.bjp.0707425
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发表时间：
2007-11-01
影响因子：
7.3
通讯作者：
Costa, B.
中科院分区：
文献类型：
--
作者：
Comelli, F.;Giagnoni, G.;Costa, B.
背景与目的：2-花生四烯基甘油(2-AG)是一种内源性大麻素，其水解酶主要由单酰基甘油脂肪酶(MAGL)催化。MAGL抑制剂的发展为研究2-AG的抗炎和抗伤害性作用提供了机会，而2-AG的作用尚未阐明。在此基础上，将MAGL抑制剂URB602应用于小鼠炎症/炎性疼痛模型。实验方法：足底注射角叉菜胶致小鼠急性炎症。已经选择了在小鼠身上进行四元体仿大麻活性测试的最高剂量。URB602的抗炎和抗伤害性效果(分别用体积测量仪和足底试验评估)在预防方案(卡拉胶前30min给药)和治疗方案(卡拉胶后30min给药)中进行。为了阐明大麻素受体的参与，在URB602前15min分别给予利莫那班和SR144528、CB1和CB2选择性拮抗剂。关键结果：全身给药URB602产生剂量依赖的抗肥胖和抗伤害性效应，CB2受体拮抗剂完全逆转该效应。当以治疗方案给药时，URB602的疗效也持续存在，这表明URB602有能力改善已建立的疾病。结论和启示：本报告强调了选择性MAGL抑制剂URB602预防和治疗急性炎症性疾病的能力，而不会产生不良的精神反应。本文提供的数据也有助于阐明2-AG在炎症反应中的生理作用，表明它在身体中的保护作用。
Background and purpose: 2-arachidonoylglycerol (2-AG) is an endocannabinoid whose hydrolysis is predominantly catalysed by the enzyme monoacylglycerol lipase (MAGL). The development of MAGL inhibitors could offer an opportunity to investigate the anti-inflammatory and anti-nociceptive role of 2-AG, which have not yet been elucidated. On these bases, URB602, a MAGL inhibitor, was tested in a murine model of inflammation/inflammatory pain.Experimental approach: Acute inflammation was induced by intraplantar injection of lambda-carrageenan into mice. The highest dose to be employed has been selected performing the tetrad assays for cannabimimetic activity in mice. URB602 antiinflammatory and anti-nociceptive efficacy (assessed by plethysmometer and plantar test, respectively) was evaluated both in a preventive regimen (drug administered 30 min before carrageenan) and in a therapeutic regimen (URB602 administered 30 min after carrageenan). To elucidate the cannabinoid receptor involvement, rimonabant and SR144528, CB1 and CB2 selective antagonists, respectively, were given 15 min before URB602.Key results: Systemic administration of URB602 elicited a dose-dependent anti-oedemigen and anti-nociceptive effect that was reversed exclusively by the CB2 receptor antagonist. The efficacy of URB602 persisted also when the compound was administered in a therapeutic regimen, suggesting the ability of URB602 to improve established disease.Conclusions and implications: The present report highlighted the ability of the selective MAGL inhibitor, URB602, to prevent and treat an acute inflammatory disease without producing adverse psychoactive effects. The data presented herein also contributed to clarify the physiological role of 2-AG in respect to inflammatory reactions, suggesting its protective role in the body.