Δ8-四氢大麻素通过大麻素 CB2 受体减少氧化应激和炎症反应来预防肝缺血/再灌注损伤。
Δ8-Tetrahydrocannabivarin prevents hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB2 receptors.
机构信息
Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
出版信息
Br J Pharmacol. 2012 Apr;165(8):2450-61. doi: 10.1111/j.1476-5381.2011.01410.x.
BACKGROUND AND PURPOSE
Activation of cannabinoid CB(2) receptors protects against various forms of ischaemia-reperfusion (I/R) injury. Δ(8) -Tetrahydrocannabivarin (Δ(8) -THCV) is a synthetic analogue of the plant cannabinoid Δ(9) -tetrahydrocannabivarin, which exhibits anti-inflammatory effects in rodents involving activation of CB(2) receptors. Here, we assessed effects of Δ(8) -THCV and its metabolite 11-OH-Δ(8) -THCV on CB(2) receptors and against hepatic I/R injury.
EXPERIMENTAL APPROACH
Effects in vitro were measured with human CB(2) receptors expressed in CHO cells. Hepatic I/R injury was assessed in mice with 1h ischaemia and 2, 6 or 24h reperfusion in vivo.
KEY RESULTS
Displacement of [(3) H]CP55940 by Δ(8) -THCV or 11-OH-Δ(8) -THCV from specific binding sites in CHO cell membranes transfected with human CB(2) receptors (hCB(2) ) yielded K(i) values of 68.4 and 59.95 nM respectively. Δ(8) -THCV or 11-OH-Δ(8) -THCV inhibited forskolin-stimulated cAMP production by hCB(2) CHO cells (EC(50) = 12.95 and 14.3 nM respectively). Δ(8) -THCV, given before induction of I/R, attenuated hepatic injury (measured by serum alanine aminotransferase and aspartate aminotransferase levels), decreased tissue protein carbonyl adducts, 4-hydroxy-2-nonenal, the chemokines CCL3 and CXCL2,TNF-α, intercellular adhesion molecule 1 (CD54) mRNA levels, tissue neutrophil infiltration, caspase 3/7 activity and DNA fragmentation. Protective effects of Δ(8) -THCV against liver damage were still present when the compound was given at the beginning of reperfusion. Pretreatment with a CB(2) receptor antagonist attenuated the protective effects of Δ(8) -THCV, while a CB(1) antagonist tended to enhance it.
CONCLUSIONS AND IMPLICATIONS
Δ(8) -THCV activated CB(2) receptors in vitro, and decreased tissue injury and inflammation in vivo, associated with I/R partly via CB(2) receptor activation.
LINKED ARTICLES
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.
背景与目的
大麻素 CB(2) 受体的激活可预防各种形式的缺血再灌注（I/R）损伤。Δ(8)-四氢大麻色烯（Δ(8)-THCV）是植物大麻素 Δ(9)-四氢大麻色烯的合成类似物，在涉及 CB(2) 受体激活的啮齿动物中具有抗炎作用。在这里，我们评估了 Δ(8)-THCV 及其代谢物 11-OH-Δ(8)-THCV 对 CB(2) 受体和肝 I/R 损伤的影响。
实验方法
在 CHO 细胞中表达的人 CB(2) 受体上测量体外作用。体内采用 1h 缺血和 2、6 或 24h 再灌注评估肝 I/R 损伤。
主要结果
Δ(8)-THCV 或 11-OH-Δ(8)-THCV 从转染人 CB(2) 受体（hCB(2)）的 CHO 细胞膜上的[3H]CP55940 特异性结合位点置换产生的 K(i) 值分别为 68.4 和 59.95 nM。Δ(8)-THCV 或 11-OH-Δ(8)-THCV 抑制 hCB(2)CHO 细胞中 forskolin 刺激的 cAMP 产生（EC50 分别为 12.95 和 14.3 nM）。Δ(8)-THCV 在诱导 I/R 之前给予，可减轻肝损伤（通过血清丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平测量），降低组织蛋白羰基加合物、4-羟基-2-壬烯醛、趋化因子 CCL3 和 CXCL2、TNF-α、细胞间黏附分子 1（CD54）mRNA 水平、组织中性粒细胞浸润、caspase 3/7 活性和 DNA 片段化。当在再灌注开始时给予 Δ(8)-THCV 时，Δ(8)-THCV 对肝损伤的保护作用仍然存在。CB(2)受体拮抗剂预处理减弱了 Δ(8)-THCV 的保护作用，而 CB(1)受体拮抗剂则倾向于增强其作用。
结论和意义
Δ(8)-THCV 在体外激活 CB(2) 受体，在体内降低组织损伤和炎症，与 I/R 有关，部分与 CB(2) 受体激活有关。
相关文章
本文是生物与医学中的大麻素专题的一部分。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。要查看生物与医学中的大麻素第一部分，请访问 http://dx.doi.org/10.1111/bph.2011.163.issue-7。
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