Miconazole Mitigates Acetic Acid-Induced Experimental Colitis in Rats: Insight into Inflammation, Oxidative Stress and Keap1/Nrf-2 Signaling Crosstalk

SIMPLE SUMMARY: The protective effect of miconazole, sulfasalazine (as a reference drug) and their combination on acetic acid (AA)-induced ulcerative colitis (UC) in a rat model was investigated. Pretreatment with miconazole significantly reduced wet colon weight and macroscopic scores, accompanied by a significant amelioration of the colonic architecture disorder. Miconazole and/or sulfasalazine revealed protective effects on AA-induced ulcerative colitis via activation of the Nrf2 pathway that improved the antioxidant defense system against oxidative stress and inflammation in UC, as demonstrated by the alleviation of colonic immunopathology, suppression of malondialdehyde (MDA) and elevation in GSH, SOD and HO-1, as well as downregulation of the levels of TNF-α, IL-6 and CRP and upregulation of the IL-10 level. Therefore, miconazole alone—particularly the high dose—or in combination treatment with sulfasalazine was the most efficient candidate compared with sulfasalazine alone and may be an alternative strategy for the treatment of UC. ABSTRACT: Ulcerative colitis (UC) is the most common type of inflammatory bowel disease, characterized by oxidative stress and elevated pro-inflammatory cytokines. Miconazole is an azole antifungal that stimulates the expression of antioxidant enzymes via Nrf2 activation, which consequently inhibits ROS formation and NF-κB activation. Hence, the present study aimed to investigate the protective effect of miconazole, sulfasalazine (as a reference drug) and their combination on acetic acid (AA)-induced UC in a rat model which was induced by intra-rectal administration of 4% AA. Rats were pretreated with miconazole (20 and 40 mg/kg, orally) or sulfasalazine (100 mg/kg, orally), or their combination (20 mg/kg miconazole and 50 mg/Kg of sulfasalazine, orally). Pretreatment with miconazole significantly reduced wet colon weight and macroscopic scores, accompanied by a significant amelioration of the colonic architecture disorder. Moreover, the treatment also significantly decreased the malondialdehyde (MDA) level and prevented the depletion of superoxide dismutase (SOD) activity and GSH content in inflamed colons. Additionally, the treatment showed suppressive activities on pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and C-reactive protein (CRP), and upregulated the anti-inflammatory cytokine interleukin-10 (IL-10). Moreover, the treatment upregulated the protein levels of Nrf-2 and heme oxygenase-1 (HO-1) in the colon tissue. Taken together, miconazole is effective in alleviating AA-induced colitis in rats, and the mechanism of its action is associated with the activation of Nrf2-regulated cytoprotective protein expression.