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-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.