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Benzimidazole Derivative (N-{4-[2-(4-Methoxyphenyl)-1H-Benzimidazole-1-Sulfonyl] Phenyl} Acetamide) Ameliorates Methotrexate-Induced Intestinal Mucositis by Suppressing Oxidative Stress and Inflammatory Markers in Mice

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Abstract

Methotrexate (MTX)-induced intestinal mucositis (IM) is a common side effect in cancer treatment that impairs the immune system and gut microbes, resulting in loss of mucosal integrity and gut barrier dysfunction. The quality of life and outcomes of treatment are compromised by IM. The present study was designed to investigate the mucoprotective potential of the benzimidazole derivative N-{4-[2-(4-methoxyphenyl)-1H-benzimidazole-1-sulfonyl] phenyl} acetamide (B8) on MTX-induced IM in mice. IM was induced by a single dose of MTX in mice and assessed by physical manifestations as well as biochemical, oxidative, histological, and inflammatory parameters. B8 (1, 3, 9 mg/kg) significantly reduced diarrhea score, mitigated weight loss, increased feed intake and, survival rate in a dose-dependent manner. Notably, B8 exhibited a mucoprotective effect evident through the mitigation of villus atrophy, crypt hypoplasia, diminished crypt mitotic figures, mucin depletion, and oxidative stress markers (GSH, SOD, MDA, and catalase concentration). Gene expression analysis revealed that B8 downregulated the mRNA expression of tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), IL-1β, and nuclear factor-κB (NF-κB) and concurrently upregulated IL-10 expression in contrast to the MTX group. Further, B8 significantly improved the luminal microflora profile by augmenting the growth of Lactobacillus spp. and reducing the number of pathogenic bacteria (E. coli). Additionally, the enzyme-linked immunoassay showed that B8 decreased the levels of pro-inflammatory cytokines. Our findings suggest that B8 had mucoprotective effects against MTX-induced IM and could be used as an adjunct in chemotherapy to deter this side effect.

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Availability of Data and Materials

Data is available from the corresponding author upon reasonable request.

Abbreviations

B8:

(N-{4-[2-(4-methoxyphenyl)-1H-benzimidazole-1-sulfonyl] phenyl} acetamide)

IM:

Intestinal mucositis

MTX:

Methotrexate

MSZ:

Mesalazine

DMSO:

Dimethyl sulfoxide

CBC:

Complete blood count

NO :

Nitrite

NF-κB :

Nuclear factor-κB

TNF-α :

Tumor necrosis factor-α

COX-2 :

Cyclooxygenase-2

IL-6 :

Interleukin-6

IL-1β :

Interleukin-1β

i.p:

Intraperitoneal

ROS:

Reactive oxygen species

GSH:

Glutathione

SOD:

Superoxide dismutase

CAT:

Catalase

MDA:

Malondialdehyde

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Acknowledgements

All authors thank and acknowledge their respective universities and institutes.

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Authors and Affiliations

  1. Faculty of Pharmacy, The University of Lahore, Lahore, Pakistan

    Muhammad Awais, Hafiz Muhammad Zubair & Rabia Asghar

  2. Post-Graduate Medical College, Faculty of Medicine and Allied Health Sciences, The Islamia University of Bahawalpur, Bahawalpur, 63100, Pakistan

    Hafiz Muhammad Zubair

  3. Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan

    Humaira Nadeem

  4. Department of Physiology and Pharmacology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, 43614, USA

    Jennifer W. Hill & Muhammad Naveed

  5. Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan

    Jawad Ali

  6. Department of Pharmacology, Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Faisalabad, 38000, Pakistan

    Ammara Saleem

  7. Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan

    Samiullah Khan & Tahir Maqbool

  8. Riphah Institute of Pharmaceutical Sciences, Riphah International University, Lahore, Pakistan

    Muhammad Furqan Akhtar

  9. Department of Pharmacology, Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur, 63100, Pakistan

    Muhammad Asif

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Contributions

M.A., investigation, methodology, and writing, original draft; H.N., synthesis of the compound; M.F.A., J.A., M.N., and A.S., review and editing; R.A., M.A., and S.K., data analysis; T.M., J.W.H., review and editing; H.M.Z., research idea, conceptualization, staining analysis, review editing, and supervision. All the authors read and approved the final manuscript.

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Correspondence to Hafiz Muhammad Zubair.

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Awais, M., Zubair, H.M., Nadeem, H. et al. Benzimidazole Derivative (N-{4-[2-(4-Methoxyphenyl)-1H-Benzimidazole-1-Sulfonyl] Phenyl} Acetamide) Ameliorates Methotrexate-Induced Intestinal Mucositis by Suppressing Oxidative Stress and Inflammatory Markers in Mice. Inflammation (2024). https://doi.org/10.1007/s10753-024-01969-9

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