Beta-caryophyllene is a dietary cannabinoid
Jürg Gertsch, Marco Leonti, Stephan Raduner, Ildiko Racz, Jian-Zhong Chen, Xiang-Qun Xie, Karl-Heinz Altmann, Meliha Karsak and Andreas Zimmer
PNAS (Proceedings of the National Academy of Sciences of the USA), 2008, 105, (26), 9099-9104.
Doi : 10.1073/pnas.0803601105
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 CB1 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)-β-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 π–π 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 anti-inflammatory cannabinoid in Cannabis.
Keywords : Cannabis, CB2 cannabinoid receptor, foodstuff, inflammation, natural product
Plant essential oils are typically composed of volatile aromatic terpenes and phenylpropanoids. These lipophilic volatiles freely cross cellular membranes and serve various ecological roles, like plant-insect interactions (1, 2). The sesquiterpene (E)-- caryophyllene [(E)-BCP] (Fig. 1) is a major plant volatile found in large amounts in the essential oils of many different spice and food plants, such as oregano (Origanum vulgare L.), cinnamon (Cinnamomum spp.) and black pepper (Piper nigrum L.) (3–5). In nature, (E)-BCP is usually found together with small quantities of its isomers (Z)--caryophyllene [(Z) BCP or isocaryophyllene] and -humulene (formerly -caryophyllene) or in a mixture with its oxidation product, BCP oxide (Fig. 1). Because of its weak aromatic taste, (E)-BCP is commercially used as a food additive and in cosmetics (6). (E)-BCP is also a major component (up to 35%) in the essential oil of Cannabis sativa L (7). Although Cannabis contains 400 different secondary metabolites, including 65
cannabinoid-like natural products, only 9-tetrahydrocannabinol (THC), 8-tetrahydrocannabinol, and cannabinol have been reported to activate cannabinoid receptor types 1 (CB1) and 2 (CB2) (8). Here, we show that the essential oil component (E)-BCP selectively binds to the CP55,940 binding site (i.e., THC binding site) in the CB2 receptor, leading to cellular activation and anti-inflammatory
CB1 and CB2 cannabinoid receptors are GTP-binding protein (G protein) coupled receptors that were first cloned in the early 1990s (9, 10). Although the CB1 receptor is expressed in the central nervous system and in the periphery, the CB2 receptor is primarily found in peripheral tissues (11). In vivo, CB receptors are activated by arachidonic acid-derived endocannabinoids, such as 2-arachidonoyl ethanolamine (anandamide or AEA) and 2-arachidonoylglycerol (2-AG) (12, 13). In addition to a wide range of primarily CB1 receptor-mediated physiological effects on the central nervous system, different cannabinoid ligands have been reported to modulate immune responses (14). In particular, CB2 receptor ligands have been shown to inhibit inflammation and edema formation (15), exhibit analgesic effects (16), and play a protective role in hepatic ischemia-reperfusion injury (17). In the gastrointestinal
tract, CB2 receptor agonists have been shown to prevent experimental colitis by reducing inflammation (18). Moreover, the CB2 receptor has been described as a potential target for the treatment
of atherosclerosis (19) and osteoporosis (20). Consequently, CB2 receptor-selective agonists that are devoid of the psychoactive side effects typically associated with CB1 receptor activation are potential
drug candidates for the treatment of a range of different diseases.