Skip to main content

ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Gastrointestinal and Hepatic Pharmacology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1491249

Nitazoxanide mitigates methotrexate hepatotoxicity in rats: role in inhibiting apoptosis and regulating endoplasmic reticulum stress

Provisionally accepted
Nevertyty Mohamed Mahmoud Nevertyty Mohamed Mahmoud 1Shimaa Elshazly Shimaa Elshazly 2*Fatma El-Shaarawy Fatma El-Shaarawy 3Sawsan A Zaitone Sawsan A Zaitone 4Afaf Aldahish Afaf Aldahish 5Gehan A Ahmed Gehan A Ahmed 1Manal S Fawzy Manal S Fawzy 6Sheka Aloyouni Sheka Aloyouni 7Sally Abed Sally Abed 8Shaimaa S El-Sayed Shaimaa S El-Sayed 2
  • 1 Faculty of Medicine, Zagazig University, Zagazig, Al Sharqia, Egypt
  • 2 Zagazig University, Zagazig, Egypt
  • 3 Department of Pharmacy Practice, Faculty of Pharmacy, Sinai University, El Arish, North Sinai, Egypt
  • 4 Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
  • 5 Department of Clinical Pharmacy, College of Pharmacy, King Khalid University, Abha, Asir, Saudi Arabia
  • 6 Northern Border University, Arar, Northern Borders, Saudi Arabia
  • 7 Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
  • 8 Department of Respiratory Care, College of Applied Medical Science, Imam Abdulrahman Bin Faisal University, Damam, Saudi Arabia

The final, formatted version of the article will be published soon.

    Objectives: Hepatotoxicity is a severe outcome of methotrexate (MTX) therapy, limiting its clinical use and contributing to its related morbidity and mortality. This study investigated the hepatoprotective effects of nitazoxanide (NTZ), an antiprotozoal drug, against MTX-induced hepatotoxicity and whether endoplasmic reticulum (ER) stress-modulation underlies the expected beneficial effects of NTZ. Methods: Thirty-six rats were allocated to six groups, one control group and five MTX groups, where induction of hepatotoxicity was achieved via injecting MTX (20 mg/kg). Groups were assigned as MTX-vehicle, NTZ-100, and NTZ-200 groups (at 100 and 200 mg/kg/day, gavage, respectively), N-acetyl cysteine (NAC) group (500 mg/kg), and 4-phenyl butyric acid (4-PBA) group (150 mg/kg, i.p). Liver function enzymes in serum, hepatic oxidative stress, proinflammatory cytokines, apoptosis, and ER-stress biomarkers were assessed. A histopathological examination was performed. Results: Treatment with NTZ lessened the serum liver enzymes, reduced malondialdehyde (lipid peroxidation product), enhanced antioxidant capacity, attenuated proinflammatory cytokines, and suppressed apoptosis. The protective effect of NTZ was dose-dependent, and the findings observed with the high-dose NTZ were similar to those obtained with the ER-stress inhibitor (4-PBA). Conclusion: NTZ exerted a hepatoprotective effect in MTX-challenged rats that is mediated via modulation of ER stress and inhibiting apoptosis.

    Keywords: Nitazoxanide, Methotrexate, Hepatotoxicity, Endoplasmic Reticulum Stress, Rat 2

    Received: 04 Sep 2024; Accepted: 14 Nov 2024.

    Copyright: © 2024 Mahmoud, Elshazly, El-Shaarawy, Zaitone, Aldahish, Ahmed, Fawzy, Aloyouni, Abed and El-Sayed. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Shimaa Elshazly, Zagazig University, Zagazig, Egypt

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.