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

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.

Carbocisteine as a Modulator of Nrf2/HO-1 and NFκB Interplay in Rats: New Inspiration for the Revival of an Old Drug for Treating Ulcerative Colitis

“…Thus, we evaluated the effect of CRBST on Nrf2 expression in order to investigate its antioxidant and anti-inflammatory properties, and we discovered that AA administration in the UC group significantly reduced Nrf2 expression. Our findings are consistent with prior research that found that AA exposure reduced Nrf2 expression ( Yalniz et al, 2012 ; Alsharif et al, 2022 ). When compared to the UC group, there was a significant increase in Nrf2 after CRBST treatment.…”

Anti-ulcerative colitis effects of chemically characterized extracts from Calliandra haematocephala in acetic acid-induced ulcerative colitis

“…Oxidative stress acts as a major partner to the immune system in the pathogenesis of UC and occurs due to the imbalance between the oxidant and antioxidant systems in the colon. This imbalance leads to increased lipid peroxidation ( Alsharif et al, 2022 ) and decreased levels of antioxidant enzymes such as superoxide dismutase (SOD) in colon tissues. Decrease in SOD activity results in compromised detoxifying activity and ultimately free radicals create an oxidative and nitrosative storm ( Elmaksoud et al, 2021 ).…”

Hepatoprotective effect of L-carnitine is achieved via activating Nrf2 and targeting TLR4 signaling pathways in Thioacetamide –induced liver fibrosis in rats

“…Inhibiting oxidative stress and the in ammatory response is a defense mechanism that is mediated by Nfr2 and its downstream antioxidant genes [36]. Speci c genes for antioxidant defense, including SOD, CAT, HO-1, and GSH, are regulated by Nrf2-ARE pathway activation [37]. When Nrf2 is stimulated and translocates to the nucleus, it activates the transcription of anti-oxidant genes through phosphorylation of AKT by activated phosphatidylinositol kinase (PI3K) [38].…”