Laboratory of Physiologic Studies Liver Disease, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892-9413, USA.
Br J Pharmacol. 2012 Apr;165(8):2462-78. doi: 10.1111/j.1476-5381.2011.01381.x.
Cannabinoid CB(2) receptor activation has been reported to attenuate myocardial, cerebral and hepatic ischaemia-reperfusion (I/R) injury.
We have investigated the effects of a novel CB(2) receptor agonist ((1S,4R)-2-(2,6-dimethoxy-4-(2-methyloctan-2-yl)phenyl)-7,7-dimethylbicyclo[2.2.1]hept-2-en-1-yl)methanol (HU-910) on liver injury induced by 1 h of ischaemia followed by 2, 6 or 24 h of reperfusion, using a well-established mouse model of segmental hepatic I/R.
Displacement of [(3) H]CP55940 by HU-910 from specific binding sites in CHO cell membranes transfected with human CB(2) or CB(1) receptors (hCB(1/2) ) yielded K(i) values of 6 nM and 1.4 µM respectively. HU-910 inhibited forskolin-stimulated cyclic AMP production by hCB(2) CHO cells (EC(50) = 162 nM) and yielded EC(50) of 26.4 nM in [(35) S]GTPγS binding assays using hCB(2) expressing CHO membranes. HU-910 given before ischaemia significantly attenuated levels of I/R-induced hepatic pro-inflammatory chemokines (CCL3 and CXCL2), TNF-α, inter-cellular adhesion molecule-1, neutrophil infiltration, oxidative stress and cell death. Some of the beneficial effect of HU-910 also persisted when given at the beginning of the reperfusion or 1 h after the ischaemic episode. Furthermore, HU-910 attenuated the bacterial endotoxin-triggered TNF-α production in isolated Kupffer cells and expression of adhesion molecules in primary human liver sinusoidal endothelial cells stimulated with TNF-α. Pretreatment with a CB(2) receptor antagonist attenuated the protective effects of HU-910, while pretreatment with a CB(1) antagonist tended to enhance them.
HU-910 is a potent CB(2) receptor agonist which may exert protective effects in various diseases associated with inflammation and tissue injury.
This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.
大麻素 CB(2)受体的激活被报道可以减轻心肌、脑和肝的缺血再灌注（I/R）损伤。
我们研究了一种新型 CB(2)受体激动剂((1S,4R)-2-(2,6-二甲氧基-4-(2-甲基辛烷-2-基)苯基)-7,7-二甲基双环[2.2.1]庚-2-烯-1-基)甲醇（HU-910）对 1 小时缺血后 2、6 或 24 小时再灌注引起的肝损伤的影响，使用了一种成熟的肝段 I/R 小鼠模型。
HU-910 从转染人 CB(2)或 CB(1)受体（hCB(1/2)）的 CHO 细胞膜上的[3H]CP55940 特异性结合位点的置换，得到的 K(i)值分别为 6 nM 和 1.4 µM。HU-910 抑制了 forskolin刺激的 hCB(2)CHO 细胞中环磷酸腺苷的产生（EC50=162 nM），并在使用表达 hCB(2)的 CHO 膜的[35S]GTPγS 结合测定中得到 26.4 nM 的 EC50。在缺血前给予 HU-910 可显著降低 I/R 诱导的肝前炎症趋化因子（CCL3 和 CXCL2）、TNF-α、细胞间黏附分子-1、中性粒细胞浸润、氧化应激和细胞死亡的水平。HU-910 的一些有益作用在再灌注开始时或缺血后 1 小时给予时也能持续存在。此外，HU-910 还能减弱内毒素触发的分离的枯否细胞中 TNF-α的产生和 TNF-α刺激的原代人肝窦内皮细胞中黏附分子的表达。CB(2)受体拮抗剂的预处理减弱了 HU-910 的保护作用，而 CB(1)受体拮抗剂的预处理则倾向于增强其作用。
HU-910 是一种有效的 CB(2)受体激动剂，可能在与炎症和组织损伤相关的各种疾病中发挥保护作用。
本文是关于大麻素在生物学和医学中的作用的专题文章的一部分。要查看该部分中的其他文章，请访问 http://dx.doi.org/10.1111/bph.2012.165.issue-8。要查看大麻素在生物学和医学中的作用的第一部分，请访问 http://dx.doi.org/10.1111/bph.2011.163.issue-7。
