Highly Selective CB Receptor Agonist A836339 Has Gastroprotective Effect on Experimentally Induced Gastric Ulcers in Mice

Cannabinoid type 2 (CB) receptors are distributed in central and peripheral tissues, including immunocytes and the gastrointestinal (GI) tract, suggesting that CB receptor agonists represent potential therapeutics in GI inflammatory states. In this study, we investigated the effect of highly selective CB 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 CB receptors, a selective CB 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 HO and glutathione (GSH) levels were measured. Moreover, expression of CB 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 CB 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 HO levels and increased CAT and SOD activities. IHC studies revealed a co-localization of CB receptors and COX-2 in the gastric tissue. Activation of CB receptors exhibited gastroprotective effect through enhancement of anti-oxidative pathways in the stomach. Activation of CB receptors may thus become a novel therapeutic approach in the treatment of GU.