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Selenocoxib-3, a novel anti-inflammatory therapeutic effectively resolves colitis

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Abstract

Ulcerative colitis (UC) is an idiopathic, chronic and relapsing colonic inflammatory disease. Despite the involvement of diverse intricate mechanisms, COX mediated inflammatory pathway is crucial in the pathophysiology of colitis. Thus, COX inhibition is imperative for managing colitis-associated inflammation. However, the use of COX inhibitory classical non-steroidal anti-inflammatory drugs (NSAIDs) for inflammation resolution has been linked to sudden increased flare-ups. Therefore, considering the anti-inflammatory and pro-resolution effects of antioxidant and essential trace element Selenium (Se), a Seleno-derivative of Celecoxib called Selenocoxib-3 was characterized and evaluated for its favourable pharmacokinetics, safety margins and anti-inflammatory therapeutic potential in DSS-induced experimental colitis. The serum pharmacokinetic profiling [elimination rate constant (K) and clearance (Cl) and toxicity profiling suggested enhanced efficacy, therapeutic potential and lesser toxicity of Selenocoxib-3 as compared to its parent NSAID Celecoxib. In vivo studies demonstrated that Selenocoxib-3 efficiently resolves the gross morphological signs of DSS-induced colitis such as diarrhoea, bloody stools, weight loss and colon shortening. Further, intestinal damage evaluated by H & E staining and MPO activity suggested of histopathological disruptions, such as neutrophil infiltration, mucodepletion and cryptitis, by Selenocoxib-3. The expression profiles of COX-1/2 demonstrated mitigation of pro-inflammatory mediators thereby promoting anti-inflammatory efficacy of Selenocoxib-3 when compared with Celecoxib. The current study suggests translational applicability of Se-containing novel class of COX inhibitors for efficiently managing inflammatory disorders such as UC.

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The authors declare that all data supporting the findings of this study are available within the article.

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Acknowledgements

Dr. Pulkit Rastogi [Assistant Professor, Department of Haematology, Post Graduate Institute of Medical Education and Research (PGIMER)], for histopathological analysis of colon sections.

Funding

The work was supported by Senior Research Fellowship (SRF) sanctioned to Ms. Ramanpreet Kaur by Indian Council of Medical Research (ICMR) (No. 45/42/2019-BIO/BMS).

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Authors and Affiliations

  1. Department of Biophysics, Panjab University, BMS Block-2, South Campus, Sector-25, Chandigarh, 160015, India

    Ramanpreet Kaur & Naveen Kaushal

  2. Department of Pharmacology, The Pennsylvania State University, Hershey, PA, USA

    Dhimant Desai & Shantu Amin

  3. Department of Pharmacy, Central University of Rajasthan, Ajmer, Rajasthan, India

    Kaisar Raza

  4. Department of Chemistry, Panjab University, Chandigarh, India

    Aman Bhalla & Pooja Yadav

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  1. Ramanpreet Kaur
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  2. Dhimant Desai
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Correspondence to Naveen Kaushal.

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11010_2022_4532_MOESM1_ESM.tif

Supplementary file1 (TIF 450 KB)—Figure S1. a–c Shows comparison of in vitro cytotoxicity of Selenocoxib-3 and Celecoxib using MTT assay at a time interval of 12 h. The data are expressed as mean ± SD of at four independent observations and analyzed using one-way ANOVA (Tukey’s multiple comparison method). a Represents p < 0.05 when compared between Selenocoxib-3 vs Celecoxib at any time interval.

11010_2022_4532_MOESM2_ESM.tif

Supplementary file2 (TIF 464 KB)—Figure S2. a–c Shows comparison of in vitro cytotoxicity of Selenocoxib-3 and Celecoxib using MTT assay at a time interval of 24 h. The data are expressed as mean ± SD of at four independent observations and analyzed using one-way ANOVA (Tukey’s multiple comparison method). a Represents p < 0.05 when compared between Selenocoxib-3 vs Celecoxib at any time interval.

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Kaur, R., Desai, D., Amin, S. et al. Selenocoxib-3, a novel anti-inflammatory therapeutic effectively resolves colitis. Mol Cell Biochem 478, 621–636 (2023). https://doi.org/10.1007/s11010-022-04532-y

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