1. ¹Section on Oxidative Stress Tissue Injury, Laboratory of Physiological Studies, NIAAA, National Institutes of Health, Bethesda, MD, USA
2. ²Department of Surgery, UMDNJ-New Jersey Medical School, Newark, NJ, USA

Correspondence: Dr P Pacher, Section on Oxidative Stress and Tissue Injury, Laboratory of Physiological Studies, NIAAA, National Institutes of Health, 5625 Fishers Lane, MSC-9413, Bethesda, MD 20892-9413, USA. E-mail: pacher@mail.nih.gov

Received 16 July 2007; Revised 28 August 2007; Accepted 30 August 2007; Published online 19 November 2007.

Abstract

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.