The emerging coloprotective effect of sildenafil against ulcerative colitis in rats via exerting counterbalance between NF-κB signaling and Nrf-2/HO-1 pathway

The current work explored the influences of time dependent Sildenafil (SILD) administration, and the possible outcomes from its concomitant administration with dexamethasone against acetic acid-induced ulcerative colitis in rats. Rats were assigned into six random groups: diseased group (AA), injected once with 2 ml acetic acid (3%) intrarectally, 2 days before sacrification. SILD + AA, received sildenafil (25 mg/kg, orally) for 6 days starting 3 days pre-injection of AA; SILD-t + AA, received sildenafil (25 mg/kg, orally), starting at time of AA injection and continued for 3 days; DEXA + AA, received dexamethasone (2 mg/kg, i.p.) for 3 days, starting at time of AA injection; SILD-t +DEXA +AA, received sildenafil (25 mg/kg, orally) and dexamethasone (2 mg/kg, i.p.), as mentioned. Sildenafil markedly ameliorated disease activity index (DAI), ulcer scores, colon length shortening and colonic histopathological changes. Mechanistically, Sildenafil markedly attenuated immunoexpression of NF-kappa B p65/ TNE-alpha and COX-2, diminished oxidative stress (down arrow MDA/NO levels and up arrow GSH level and SOD activity), increased levels of Nrf-2/HO-1, compared to untreated group. Taken together, Sildenafil treatment suppressed acetic acid-induced ulcerative colitis, probably via inhibiting NF-kappa B/TNE-alpha signaling dependent of Nrf-2/HO-1 pathway, reducing oxidative stress and attenuating inflammation. Surprisingly, effects of sildenafil were unpromoted in a time dependant manner. Short term treatment with sildenafil was sufficient to exert its coloprotective effect, while longer term pretreatment was only superior among other treatments in the macroscopical changes. Moreover, concurrent administration of sildenafil and dexamethasone had the preference in boosting the antioxidant defense and anti-inflammatory mechanisms, visualized by histopathological/immunohistochemical changes.

Automated summary

This study investigated the effects of time dependent administration of Sildenafil and its combination with dexamethasone on acetic acid-induced ulcerative colitis in rats. The results showed that Sildenafil improved disease activity index, ulcer scores, colon length and colonic histopathological changes. Mechanistically, Sildenafil reduced inflammation and oxidative stress, most likely through inhibiting the NF-kappa B/TNE-alpha signaling pathway and activating the Nrf-2/HO-1 pathway. Surprisingly, the effects of Sildenafil were influenced by the duration of treatment. Short term treatment was sufficient to exert its coloprotective effect, while longer term pretreatment had superior macroscopical changes. Moreover, the concurrent administration of Sildenafil and dexamethasone enhanced antioxidant defense and anti-inflammatory mechanisms.