Beta-caryophyllene is a dietary cannabinoid

Edited by L. L. Iversen, University of Oxford, Oxford, United Kingdom, and approved May 6, 2008
July 1, 2008
105 (26) 9099-9104

Abstract

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 (Ki = 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 antiinflammatory cannabinoid in Cannabis.

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Acknowledgments.

We thank Dr. Irmgard Werner and Alex Hermann for their help and technical assistance for the GC measurements, Andreas Nievergelt-Meier for his help with the CBA analyses, and Dr. Michael Detheux (Euroscreen S.A., Brussels, Belgium) for the CB2-transfected CHO-K1 cell line. This work was supported by the Deutsche Forschungsgemeinschaft Grants FOR926 and GRK804.

Supporting Information

Supporting Information (PDF)
Supporting Information (PDF)

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 105 | No. 26
July 1, 2008
PubMed: 18574142

Classifications

Submission history

Received: April 14, 2008
Published online: July 1, 2008
Published in issue: July 1, 2008

Keywords

  1. Cannabis
  2. CB2 cannabinoid receptor
  3. foodstuff
  4. inflammation
  5. natural product

Acknowledgments

We thank Dr. Irmgard Werner and Alex Hermann for their help and technical assistance for the GC measurements, Andreas Nievergelt-Meier for his help with the CBA analyses, and Dr. Michael Detheux (Euroscreen S.A., Brussels, Belgium) for the CB2-transfected CHO-K1 cell line. This work was supported by the Deutsche Forschungsgemeinschaft Grants FOR926 and GRK804.

Notes

This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0803601105/DCSupplemental.

Authors

Affiliations

Jürg Gertsch [email protected]
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Eidgenössische Technische Hochschule (ETH) Zurich, 8092 Zürich, Switzerland;
Marco Leonti§
Dipartimento Farmaco Chimico Tecnologico, University of Cagliari, 01924 Cagliari, Italy;
Stefan Raduner§
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Eidgenössische Technische Hochschule (ETH) Zurich, 8092 Zürich, Switzerland;
Ildiko Racz
Department of Molecular Psychiatry, University of Bonn, 53115 Bonn Germany; and
Jian-Zhong Chen
Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15260
Xiang-Qun Xie
Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15260
Karl-Heinz Altmann
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Eidgenössische Technische Hochschule (ETH) Zurich, 8092 Zürich, Switzerland;
Meliha Karsak
Department of Molecular Psychiatry, University of Bonn, 53115 Bonn Germany; and
Andreas Zimmer
Department of Molecular Psychiatry, University of Bonn, 53115 Bonn Germany; and

Notes

To whom correspondence should be addressed. E-mail: [email protected]
Author contributions: J.G. and M.K. designed research; J.G., M.L., S.R., I.R., and J.-Z.C. performed research; A.Z. contributed new reagents/analytic tools; J.G., X.-Q.X., K.-H.A., M.K., and A.Z. analyzed data; and J.G. wrote the paper.
§
M.L. and S.R. contributed equally to this work.

Competing Interests

The authors declare no conflict of interest.

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    Beta-caryophyllene is a dietary cannabinoid
    Proceedings of the National Academy of Sciences
    • Vol. 105
    • No. 26
    • pp. 8803-9130

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