Nitazoxanide mitigates methotrexate hepatotoxicity in rats: role in inhibiting apoptosis and regulating endoplasmic reticulum stress
ObjectivesHepatotoxicity 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 whe...
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Frontiers Media S.A.
2024-12-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1491249/full |
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| author | Nevertyty Mohamed Mahmoud Shimaa M. Elshazly Fatma El-shaarawy Sawsan A. Zaitone Sawsan A. Zaitone Afaf A. Aldahish Gehan A. Ahmed Manal S. Fawzy Manal S. Fawzy Sheka Yagub Aloyouni Sally Y. Abed Tahani Saeedi Shaimaa S. El-Sayed |
| author_facet | Nevertyty Mohamed Mahmoud Shimaa M. Elshazly Fatma El-shaarawy Sawsan A. Zaitone Sawsan A. Zaitone Afaf A. Aldahish Gehan A. Ahmed Manal S. Fawzy Manal S. Fawzy Sheka Yagub Aloyouni Sally Y. Abed Tahani Saeedi Shaimaa S. El-Sayed |
| author_sort | Nevertyty Mohamed Mahmoud |
| collection | DOAJ |
| description | ObjectivesHepatotoxicity 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.MethodsThirty-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.ResultsTreatment 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).ConclusionNTZ exerted a hepatoprotective effect in MTX-challenged rats that is mediated via modulation of ER stress and inhibiting apoptosis. |
| format | Article |
| id | doaj-art-b38c16f06da1443e937e9ad8a0f27d30 |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-b38c16f06da1443e937e9ad8a0f27d302024-12-02T09:20:07ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122024-12-011510.3389/fphar.2024.14912491491249Nitazoxanide mitigates methotrexate hepatotoxicity in rats: role in inhibiting apoptosis and regulating endoplasmic reticulum stressNevertyty Mohamed Mahmoud0Shimaa M. Elshazly1Fatma El-shaarawy2Sawsan A. Zaitone3Sawsan A. Zaitone4Afaf A. Aldahish5Gehan A. Ahmed6Manal S. Fawzy7Manal S. Fawzy8Sheka Yagub Aloyouni9Sally Y. Abed10Tahani Saeedi11Shaimaa S. El-Sayed12Department of Clinical Pharmacology, Faculty of Medicine, Zagazig University, Zagazig, EgyptDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, EgyptDepartment of Biochemistry, Faculty of Pharmacy, Sinai University, Arish, EgyptDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, EgyptDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi ArabiaDepartment of Pharmacology, College of Pharmacy, King Khalid University, Abha, Saudi ArabiaForensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Zagazig University, Zagazig, EgyptDepartment of Biochemistry, Faculty of Medicine, Northern Border University, Arar, Saudi ArabiaCenter for Health Research, Northern Border University, Arar, Saudi Arabia0Research Department, Natural and Health Sciences Research Center, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia1Department of Respiratory Care, College of Applied Medical Science in Jubail, Imam Abdulrahman Bin Faisal University, Jubail, Saudi Arabia2Department of Pharmacology and Toxicology, School of Pharmacy, Taibah University, Medina, Saudi ArabiaDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, EgyptObjectivesHepatotoxicity 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.MethodsThirty-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.ResultsTreatment 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).ConclusionNTZ exerted a hepatoprotective effect in MTX-challenged rats that is mediated via modulation of ER stress and inhibiting apoptosis.https://www.frontiersin.org/articles/10.3389/fphar.2024.1491249/fullnitazoxanidemethotrexatehepatotoxicityendoplasmic reticulum stressrat |
| spellingShingle | Nevertyty Mohamed Mahmoud Shimaa M. Elshazly Fatma El-shaarawy Sawsan A. Zaitone Sawsan A. Zaitone Afaf A. Aldahish Gehan A. Ahmed Manal S. Fawzy Manal S. Fawzy Sheka Yagub Aloyouni Sally Y. Abed Tahani Saeedi Shaimaa S. El-Sayed Nitazoxanide mitigates methotrexate hepatotoxicity in rats: role in inhibiting apoptosis and regulating endoplasmic reticulum stress Frontiers in Pharmacology nitazoxanide methotrexate hepatotoxicity endoplasmic reticulum stress rat |
| title | Nitazoxanide mitigates methotrexate hepatotoxicity in rats: role in inhibiting apoptosis and regulating endoplasmic reticulum stress |
| title_full | Nitazoxanide mitigates methotrexate hepatotoxicity in rats: role in inhibiting apoptosis and regulating endoplasmic reticulum stress |
| title_fullStr | Nitazoxanide mitigates methotrexate hepatotoxicity in rats: role in inhibiting apoptosis and regulating endoplasmic reticulum stress |
| title_full_unstemmed | Nitazoxanide mitigates methotrexate hepatotoxicity in rats: role in inhibiting apoptosis and regulating endoplasmic reticulum stress |
| title_short | Nitazoxanide mitigates methotrexate hepatotoxicity in rats: role in inhibiting apoptosis and regulating endoplasmic reticulum stress |
| title_sort | nitazoxanide mitigates methotrexate hepatotoxicity in rats role in inhibiting apoptosis and regulating endoplasmic reticulum stress |
| topic | nitazoxanide methotrexate hepatotoxicity endoplasmic reticulum stress rat |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1491249/full |
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