Pacher P, Haskó G
Section on Oxidative Stress Tissue Injury, Laboratory of Physiological Studies, NIAAA, National Institutes of Health, Bethesda, MD 20892-9413, USA.
Br J Pharmacol. 2008 Jan;153(2):252-62. doi: 10.1038/sj.bjp.0707582. Epub 2007 Nov 19.
Ischaemia-reperfusion (I/R) is a pivotal mechanism of organ injury during stroke, myocardial infarction, organ transplantation and vascular surgeries. Ischaemic preconditioning (IPC) is a potent endogenous form of tissue protection against I/R injury. On the one hand, endocannabinoids have been implicated in the protective effects of IPC through cannabinoid CB1/CB2 receptor-dependent and -independent mechanisms. However, there is evidence suggesting that endocannabinoids are overproduced during various forms of I/R, such as myocardial infarction or whole body I/R associated with circulatory shock, and may contribute to the cardiovascular depressive state associated with these pathologies. Previous studies using synthetic CB1 receptor agonists or knockout mice demonstrated CB1 receptor-dependent protection against cerebral I/R injury in various animal models. In contrast, several follow-up reports have shown protection afforded by CB1 receptor antagonists, but not agonists. Excitedly, emerging studies using potent CB2 receptor agonists and/or knockout mice have provided compelling evidence that CB2 receptor activation is protective against myocardial, cerebral and hepatic I/R injuries by decreasing the endothelial cell activation/inflammatory response (for example, expression of adhesion molecules, secretion of chemokines, and so on), and by attenuating the leukocyte chemotaxis, rolling, adhesion to endothelium, activation and transendothelial migration, and interrelated oxidative/nitrosative damage. This review is aimed to discuss the role of endocannabinoids and CB receptors in various forms of I/R injury (myocardial, cerebral, hepatic and circulatory shock) and preconditioning, and to delineate the evidence supporting the therapeutic utility of selective CB2 receptor agonists, which are devoid of psychoactive effects, as a promising new approach to limit I/R-induced tissue damage.
缺血再灌注（I/R）是中风、心肌梗死、器官移植和血管手术期间器官损伤的关键机制。缺血预处理（IPC）是一种有效的内源性组织保护形式，可抵御I/R损伤。一方面，内源性大麻素已通过大麻素CB1/CB2受体依赖性和非依赖性机制参与IPC的保护作用。然而，有证据表明，在各种形式的I/R期间，如心肌梗死或与循环性休克相关的全身I/R，内源性大麻素会过度产生，并可能导致与这些病理状态相关的心血管抑制状态。先前使用合成CB1受体激动剂或基因敲除小鼠的研究表明，在各种动物模型中，CB1受体依赖性保护可抵御脑I/R损伤。相比之下，一些后续报告显示CB1受体拮抗剂具有保护作用，而激动剂则没有。令人兴奋的是，使用强效CB2受体激动剂和/或基因敲除小鼠的新兴研究提供了令人信服的证据，表明激活CB2受体可通过降低内皮细胞活化/炎症反应（例如，黏附分子的表达、趋化因子的分泌等），并通过减弱白细胞趋化性、滚动、黏附于内皮、活化和跨内皮迁移以及相关的氧化/亚硝化损伤，对心肌、脑和肝I/R损伤起到保护作用。本综述旨在讨论内源性大麻素和CB受体在各种形式的I/R损伤（心肌、脑、肝和循环性休克）及预处理中的作用，并阐述支持选择性CB2受体激动剂治疗效用的证据，这些激动剂无精神活性作用，是限制I/R诱导的组织损伤的一种有前景的新方法。
