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Highly selective CB2 receptor agonist A836339 has gastroprotective effect on experimentally induced gastric ulcers in mice

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Abstract

Cannabinoid type 2 (CB2) receptors are distributed in central and peripheral tissues, including immunocytes and the gastrointestinal (GI) tract, suggesting that CB2 receptor agonists represent potential therapeutics in GI inflammatory states. In this study, we investigated the effect of highly selective CB2 agonist, A836339, on the development of gastric lesions. We used two models of gastric ulcer (GU) induced by ethanol (EtOH) and diclofenac. To confirm the involvement of CB2 receptors, a selective CB2 antagonist, AM630 was used. Clinical parameters for gastroprotection were assessed based on inhibition of the gastric lesion area. To investigate the anti-inflammatory effect of A836339, the expression of TNF-α and IL-1β was assessed. To establish the mechanism of gastroprotective action, catalase (CAT), superoxide dismutase (SOD) activity and H2O2 and glutathione (GSH) levels were measured. Moreover, expression of CB2 and cyclooxygenase-2 (COX-2) was characterized using immunohistochemistry (IHC). A836339 reduced ulcer index in a dose-dependent manner in both EtOH- and diclofenac-induced GU models. This effect was reversed by the CB2 antagonist AM630. Administration of A836339 reduced TNF-α and IL-1β levels in gastric tissue. Furthermore, A836339 exhibited potent anti-oxidant activity, as demonstrated by reduced H2O2 levels and increased CAT and SOD activities. IHC studies revealed a co-localization of CB2 receptors and COX-2 in the gastric tissue. Activation of CB2 receptors exhibited gastroprotective effect through enhancement of anti-oxidative pathways in the stomach. Activation of CB2 receptors may thus become a novel therapeutic approach in the treatment of GU.

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Acknowledgments

This study was supported by the Iuventus Plus program of the Polish Ministry of Science and Higher Education (IP2015 068774 to MS), with grants from the Medical University of Lodz (502-03/1-156-04/502-14-298 to M Salaga, 502-03/1-156-02/502-14-141 to MZ and 503/1-156-04/503-11-001 to JF) and the National Science Centre (UMO-2013/11/N/NZ7/02354 to M Salaga, UMO-2013/11/N/NZ7/00724 to MZ, UMO-2013/11/B/NZ7/01301 to JF and UMO-2014/13/B/NZ4/01179 to JF). Hubert Zatorski is the recipient of Diamentowy Grant Program of the Polish Ministry of Science and Higher Education (No. 0202/DIA/2015/44).

Authors’ contributions

M Salaga, H Zatorski, M Zielinska, P Mosinska, J-P Timmermans and R Kordek performed the research. M Salaga, H Zatorski and J Fichna designed the research study. M Storr and J Fichna contributed essential tools and reagents. M Salaga, H Zatorski, M Zielińska, J-P Timmermans and R Kordek analysed the data. J-P Timmermans and M Storr critically reviewed the manuscript. M Salaga, H Zatorski and J Fichna wrote the paper.

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Author notes

  1. M. Salaga and H. Zatorski have equal contributions.

Authors and Affiliations

  1. Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland

    M. Salaga, H. Zatorski, M. Zielińska, P. Mosinska & J. Fichna

  2. Department of Pathology Faculty of Medicine, Medical University of Lodz, Lodz, Poland

    R. Kordek

  3. Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium

    J-P. Timmermans

  4. Department of Medicine, Division of Gastroenterology, Ludwig Maximilians University of Munich, Munich, Germany

    M. Storr

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  1. M. Salaga
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Correspondence to J. Fichna.

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The study was carried out in accordance with the recommendations described in the Guide for the Care and Use of Laboratory Animals of the Medical University of Lodz, Poland. All experiments on animals were approved by the Local Ethical Committee for Animal Experiments (Protocol #17/LB654/2013).

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The authors declare that they have no conflict of interest.

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Salaga, M., Zatorski, H., Zielińska, M. et al. Highly selective CB2 receptor agonist A836339 has gastroprotective effect on experimentally induced gastric ulcers in mice. Naunyn-Schmiedeberg's Arch Pharmacol 390, 1015–1027 (2017). https://doi.org/10.1007/s00210-017-1402-3

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