Beta-caryophyllene is a dietary cannabinoid |
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| Authors: | Gertsch Jürg Leonti Marco Raduner Stefan Racz Ildiko Chen Jian-Zhong Xie Xiang-Qun Altmann Karl-Heinz Karsak Meliha Zimmer Andreas |
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| Affiliation: | *Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Eidgenössische Technische Hochschule (ETH) Zurich, 8092 Zürich, Switzerland; ;‡Dipartimento Farmaco Chimico Tecnologico, University of Cagliari, 01924 Cagliari, Italy; ;¶Department of Molecular Psychiatry, University of Bonn, 53115 Bonn Germany; and ;‖Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15260 |
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| Abstract: | The psychoactive cannabinoids from Cannabis sativa L. and the arachidonic acid-derived endocannabinoids are nonselective natural ligands for cannabinoid receptor type 1 (CB(1)) and CB(2) receptors. Although the CB(1) receptor is responsible for the psychomodulatory effects, activation of the CB(2) 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 CB(2) receptor (K(i) = 155 +/- 4 nM) and that it is a functional CB(2) 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 CB(2) receptor, showing ligand pi-pi stacking interactions with residues F117 and W258. Upon binding to the CB(2) 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 CB(2) receptors, providing evidence that this natural product exerts cannabimimetic effects in vivo. These results identify (E)-BCP as a functional nonpsychoactive CB(2) receptor ligand in foodstuff and as a macrocyclic antiinflammatory cannabinoid in Cannabis. |
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| Keywords: | Cannabis CB2 cannabinoid receptor foodstuff inflammation natural product |
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