Beta-caryophyllene is a dietary cannabinoid
Beta-caryophyllene is a dietary cannabinoid
复制标题
DOI：
10.1073/pnas.0803601105
复制
发表时间：
2008-07-01
影响因子：
11.1
通讯作者：
Zimmer, Andreas
中科院分区：
文献类型：
--
作者：
Gertsch, Juerg;Leonti, Marco;Zimmer, Andreas
大麻中的精神活性大麻素。并且花生四烯酸衍生的内源性大麻素是大麻素受体1型（CB 1）和CB 2受体的非选择性天然配体。虽然CB 1受体负责心理调节作用，但CB 2受体的激活是治疗炎症、疼痛、动脉粥样硬化和骨质疏松症的潜在治疗策略。在这里，我们报告说，广泛的植物挥发性（E）-β-carbellene [（E）-BCP]选择性地结合到CB 2。受体（Ki = 155 +/-4nM），并且它是功能性CB 2激动剂。有趣的是，（E）-BCP是许多香料和食品植物精油的常见成分，也是大麻的主要成分。分子对接模拟已经鉴定了CB 2受体中的（E）-BCP的推定结合位点，显示配体pi-pi与残基F117和W258的堆积相互作用。在与CB 2受体结合后，（E）-BCP抑制腺苷酸环化酶，导致细胞内钙瞬变，并弱激活原代人单核细胞中的促分裂原活化激酶Erk 1/2和p38。（E）-BCP（500 nM）抑制外周血中脂多糖（LPS）诱导的促炎细胞因子表达，并减弱单核细胞中LPS刺激的Erk 1/2和JNK 1/2磷酸化。此外，5 mg/kg的口服（E）-BCP强烈降低了野生型小鼠中角叉菜胶诱导的炎症反应，但在缺乏CB 2受体的小鼠中没有，这提供了这种天然产物在体内发挥大麻模拟作用的证据。这些结果鉴定了（E）-BCP作为食品中的功能性非精神活性CB 2受体配体和作为大麻中的大环大麻素。
The psychoactive cannabinoids from Cannabis sativa L. and the arachidonic acid-derived endocannabinoids are nonselective natural ligands for cannabinoid receptor type 1 (CB1) and CB2 receptors. Although the CB, receptor is responsible for the psychomodulatory effects, activation of the CB2 receptor is a potential therapeutic strategy for the treatment of inflammation, pain, atherosclerosis, and osteoporosis. Here, we report that the widespread plant volatile (E)-beta-caryophyllene [(E)-BCP] selectively binds to the CB2. receptor (K-i = 155 +/- 4 nM) and that it is a functional CB2 agonist. Intriguingly, (E)-BCP is a common constituent of the essential oils of numerous spice and food plants and a major component in Cannabis. Molecular docking simulations have identified a putative binding site of (E)-BCP in the CB2 receptor, showing ligand pi-pi stacking interactions with residues F117 and W258. Upon binding to the CB2 receptor, (E)-BCP inhibits adenylate cylcase, leads to intracellular calcium transients and weakly activates the mitogen-activated kinases Erk1/2 and p38 in primary human monocytes. (E)-BCP (500 nM) inhibits lipopolysaccharide (LPS)-induced proinflammatory cytokine expression in peripheral blood and attenuates LPS-stimulated Erk1/2 and JNK1/2 phosphorylation in monocytes. Furthermore, peroral (E)-BCP at 5 mg/kg strongly reduces the carrageenan-induced inflammatory response in wild-type mice but not in mice lacking CB2 receptors, providing evidence that this natural product exerts cannabimimetic effects in vivo. These results identify (E)-BCP as a functional nonpsychoactive CB2 receptor ligand in foodstuff and as a macrocyclic antiinflammatory cannabinoid in Cannabis.