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

By A. M. Abdelhamid, Simona Cavalu, Sameh Saber et al.

The current therapies for UC lack relative effectiveness and are associated with adverse effects. Therefore, novel therapeutic options should be developed. It has been well documented that modulating the Nrf2/NFκB is a promising therapeutic target in inflammation. Carbocisteine is a mucoregulatory medication and its efficacy in COPD was found to be more closely related to its antioxidant and anti-inflammatory properties.
Carbocisteine has not yet been examined for the management of UC. Hence, our approach was to investigate the potential coloprotective role of carbocisteine in acetic acid-induced colitis in rats. Copyright Sameh Saber, Simona Cavalu et al.

Effect of CRBST 250 and 500 mg/kg on colon weight/length ratio (A); DAI (B); MDI (C); and the colon pictures (D) in rats with AA-induced UC. Results
in figure (A) are shown as the mean ± SD and in figure (B,C) are shown as the median ± interquartile range (n = 6). Normal, normal
control rats administered the vehicle; CRBST 500, normal rats administered carbocisteine (500 mg/kg); UC, AA-induced UC rats administered the vehicle; UC/CRBST
250, AA-induced UC rats treated with carbocisteine (250 mg/kg); UC/CRBST 500, AA-induced UC rats treated with carbocisteine (500 mg/kg). Copyright Simona Cavalu, Sameh Saber et al.
Effect of CRBST 250 and 500 mg/kg on histopathological characteristics and histopathological score in rats with AA-induced UC. Representative histological appearance of colon tissue specimens stained with H&E from Normal (A) and CRBST 500 (B) control groups, Colonic sections from UC group (C) showing deepithelialization,erosions (green arrow), disrupted mucosa (M) and submucosa (SM), inflammatory cell infiltration (blue diamond), edema (orange double arrow), congestion (brown arrow) and complete necrosis of the crypts (blue arrow); Colonic sections from UC/CRBST 250 (D) and UC/CRBST 500 (E) showing a moderate restoration of architecture. Copyright Simona Cavalu, Sameh Saber et al.
The proposed mechanism of action of carbocisteine. Copyright Simona Cavalu, Sameh Saber et al.

Nrf2 and NF-κB are the two key transcription factors that regulate cellular responses to oxidative stress and inflammation respectively. Pharmacological and genetic studies indicate
functional cross-talk between these two critical pathways. Carbocisteine, at
doses that are quite higher than the human effective dose, inhibited oxidative stress, inflammatory response, and apoptosis in acetic acid-induced colitis in rats through activating Nrf2 and suppressing NFκB. The current study provides a potential basis for repurposing the safe and
commonly used mucoregulator, carbocisteine, for the treatment of UC. However, further research into other pathways that run parallel to those proposed in the current study is required to assess the reliability of carbocisteine as a treatment for UC. Copyright Simona Cavalu, Sameh Saber et al.

Full text available at https://doi.org/10.3389/fphar.2022.887233

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