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

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-alpha and IL-1 beta 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-alpha and IL-1 beta 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.