A new cannabinoid CB2 receptor agonist HU-910 attenuates oxidative stress, inflammation and cell death associated with hepatic ischaemia/reperfusion injury
A new cannabinoid CB2 receptor agonist HU-910 attenuates oxidative stress, inflammation and cell death associated with hepatic ischaemia/reperfusion injury
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DOI：
10.1111/j.1476-5381.2011.01381.x
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发表时间：
2012-04-01
影响因子：
7.3
通讯作者：
Pacher, Pal
中科院分区：
文献类型：
--
作者：
Horvath, Bela;Magid, Lital;Pacher, Pal
背景和方法已报道类大麻素CB 2受体激活可减轻心肌、脑和肝缺血再灌注（I/R）损伤。（2，6-二甲氧基-4-（2-甲基辛-2-基）苯基）-7，7-二甲基二环[2.2.1]庚-2-烯-1-基）甲醇（HU-910）对由缺血1小时随后2，6或24小时再灌注，使用一个完善的小鼠节段性肝I/R模型。关键词HU-910从转染人CB 2或CB 1受体（hCB（1/2））的CHO细胞膜的特异性结合位点置换[H-3] CP 55940，得到的Ki值分别为6 nM和1.4 mM。HU-910抑制毛喉素刺激的hCB（2）CHO细胞环AMP生成（EC 50 = 162 nM），在使用hCB（2）表达CHO膜的[S-35]GTP γ S结合试验中产生的EC 50为26.4 nM。在缺血前给予HU-910显著减弱I/R诱导的肝促炎趋化因子（CCL 3和CXCL 2）、TNF-α、细胞间粘附分子-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发作后1小时给予时也持续存在。此外，HU-910减弱了分离的枯否细胞中细菌内毒素触发的TNF-α产生和TNF-α刺激的原代人肝窦内皮细胞中粘附分子的表达。预处理与CB 2受体拮抗剂减弱HU-910的保护作用，而预处理与CB 1拮抗剂倾向于增强them.CONCLUSION和IMPLICATIONSHU-910是一种有效的CB 2受体激动剂，可能发挥保护作用，在各种疾病相关的炎症和组织损伤。
BACKGROUND AND PURPOSECannabinoid CB2 receptor activation has been reported to attenuate myocardial, cerebral and hepatic ischaemia-reperfusion (I/R) injury.EXPERIMENTAL APPROACHWe have investigated the effects of a novel CB2 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.KEY RESULTSDisplacement of [H-3]CP55940 by HU-910 from specific binding sites in CHO cell membranes transfected with human CB2 or CB1 receptors (hCB(1/2)) yielded K-i values of 6 nM and 1.4 mM respectively. HU-910 inhibited forskolin-stimulated cyclic AMP production by hCB(2) CHO cells (EC50 = 162 nM) and yielded EC50 of 26.4 nM in [S-35]GTP gamma S binding assays using hCB(2) expressing CHO membranes. HU-910 given before ischaemia significantly attenuated levels of I/R-induced hepatic proinflammatory chemokines (CCL3 and CXCL2), TNF-alpha, 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-alpha production in isolated Kupffer cells and expression of adhesion molecules in primary human liver sinusoidal endothelial cells stimulated with TNF-alpha. Pretreatment with a CB2 receptor antagonist attenuated the protective effects of HU-910, while pretreatment with a CB1 antagonist tended to enhance them.CONCLUSION AND IMPLICATIONSHU-910 is a potent CB2 receptor agonist which may exert protective effects in various diseases associated with inflammation and tissue injury.