Beta-caryophyllene is a dietary cannabinoid

• DOI: 10.1073/pnas.0803601105
• Publication Date: 2008-06-24T01:42:04Z
• Authors: Jürg Gertsch; Marco Leonti; Stefan Raduner; Ildiko Racz; Jian-Zhong Chen; Xiang-Qun Xie; Karl-Heinz Altmann; Meliha Karsak; Andreas Zimmer
• Keywords: Lipopolysaccharides; 0301 basic medicine; Binding Sites; Cannabinoids; Interleukin-1beta; JNK Mitogen-Activated Protein Kinases; Administration, Oral; Computational Biology; GTP-Binding Protein alpha Subunits, Gi-Go; Carrageenan; Ligands; Binding, Competitive; Diet; 3. Good health; Enzyme Activation; Mice; 03 medical and health sciences; Animals; Edema; Humans; Cannabis; CB2 cannabinoid receptor; Foodstuff; Inflammation; Natural product; Administration, Oral; Animals; Binding Sites; Binding, Competitive; Cannabinoids; Cannabis; Carrageenan; Cells, Cultured; Computational Biology; Edema; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; GTP-Binding Protein alpha Subunits, Gi-Go; Humans; Interleukin-1beta; JNK Mitogen-Activated Protein Kinases; Ligands; Lipopolysaccharides; Mice; Monocytes; Oils, Volatile; Receptor, Cannabinoid, CB2; Sesquiterpenes; Signal Transduction; Tumor Necrosis Factor-alpha; Diet; Multidisciplinary; Genetics; Extracellular Signal-Regulated MAP Kinases; Cells, Cultured; Cannabis

The psychoactive cannabinoids fromCannabis sativaL. and the arachidonic acid-derived endocannabinoids are nonselective natural ligands for cannabinoid receptor type 1 (CB1) and CB2receptors. Although the CB1receptor is responsible for the psychomodulatory effects, activation of the CB2receptor 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 CB2receptor (Ki= 155 ± 4 nM) and that it is a functional CB2agonist. Intriguingly, (E)-BCP is a common constituent of the essential oils of numerous spice and food plants and a major component inCannabis. Molecular docking simulations have identified a putative binding site of (E)-BCP in the CB2receptor, showing ligand π–π stacking interactions with residues F117 and W258. Upon binding to the CB2receptor, (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 CB2receptors, providing evidence that this natural product exerts cannabimimetic effectsin vivo. These results identify (E)-BCP as a functional nonpsychoactive CB2receptor ligand in foodstuff and as a macrocyclic antiinflammatory cannabinoid inCannabis.