The cannabinoid receptor CB2 exerts antifibrotic effects in experimental dermal fibrosis

Arthritis Rheum. 2009 Mar 30;60(4):1129-1136.
The cannabinoid receptor CB2 exerts antifibrotic effects in experimental dermal fibrosis.
Akhmetshina A, Dees C, Busch N, Beer J, Sarter K, Zwerina J, Zimmer A, Distler O, Schett G, Distler JH.

University of Erlangen-Nuremberg, Erlangen, Germany.

OBJECTIVE: The cannabinoid receptor CB2 is predominantly expressed in non-neuronal tissue and exerts potent immunomodulatory effects. This study was undertaken to evaluate the role of CB2 in the pathogenesis of dermal fibrosis. METHODS: Mice deficient in CB2 (CB2(-/-) mice) and their wild-type littermates (CB2(+/+) mice) were injected with bleomycin to induce experimental fibrosis. Mice were treated with selective agonists and antagonists of CB2. Lesional skin was evaluated for dermal thickness and numbers of infiltrating leukocytes. Bone marrow transplantation experiments were performed. RESULTS: CB2(-/-) mice were more sensitive to bleomycin-induced dermal fibrosis than were CB2(+/+) mice, and showed increased dermal thickness. Leukocyte counts were significantly higher in the lesional skin of CB2(+/+) mice. Increased dermal fibrosis was also observed upon treatment with the CB2 antagonist AM-630. In contrast, the selective CB2 agonist JWH-133 reduced leukocyte infiltration and dermal thickening. The phenotype of CB2(-/-) mice was mimicked by transplantation of CB2(-/-) bone marrow into CB2(+/+) mice, whereas CB2(-/-) mice transplanted with bone marrow from CB2(+/+) mice did not display an increased sensitivity to bleomycin-induced fibrosis, indicating that leukocyte expression of CB2 critically influences experimental fibrosis. CONCLUSION: Our findings indicate that CB2 limits leukocyte infiltration and tissue fibrosis in experimental dermal fibrosis. Since selective CB2 agonists are available and well tolerated, CB2 might be an interesting molecular target for the treatment of early inflammatory stages of systemic sclerosis.

What is a natural CB2 agonist?

The answer is N-alkyl amides from two different Echinacea varieties, Echinacea purpurea and Echinacea angustifolia.

J Recept Signal Transduct Res. 2006;26(5-6):709-30.
New natural noncannabinoid ligands for cannabinoid type-2 (CB2) receptors.
Gertsch J, Raduner S, Altmann KH.

Institute of Pharmaceutical Sciences, ETH Zurich, Zürich, Switzerland. juerg.gertsch@pharma.ethz.ch

Since the discovery that Delta 9-tetrahydrocannabinol and related cannabinoids from Cannabis sativa L. act on specific physiological receptors in the human body and the subsequent elucidation of the mammalian endogenous cannabinoid system, no other natural product class has been reported to mimic the effects of cannabinoids. We recently found that N-alkyl amides from purple coneflower (Echinacea spp.) constitute a new class of cannabinomimetics, which specifically engage and activate the cannabinoid type-2 (CB2) receptors. Cannabinoid type-1 (CB1) and CB2 receptors belong to the family of G protein-coupled receptors and are the primary targets of the endogenous cannabinoids N-arachidonoyl ethanolamine and 2-arachidonoyl glyerol. CB2 receptors are believed to play an important role in distinct pathophysiological processes, including metabolic dysregulation, inflammation, pain, and bone loss. CB2 receptors have, therefore, become of interest as new targets in drug discovery. This review focuses on N-alkyl amide secondary metabolites from plants and underscores that this group of compounds may provide novel lead structures for the development of CB2-directed drugs.

It might be a good diea to keep a close tabs on the effects of CB-2 ligands. As more research comes out, they may prove to be of good use.