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Protective effects of apigenin on altered lipid peroxidation, inflammation, and antioxidant factors in methotrexate-induced hepatotoxicity

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Abstract

Methotrexate (MTX) is used as an effective chemotherapeutic agent against autoimmune diseases and tumors. Oxidative stress and inflammation are involved in the pathogenesis of MTX-induced damage. This study aimed at examining the ameliorating effects of apigenin (API) as a natural antioxidant on MTX-induced hepatotoxicity. The rats were classified into four groups: group I: normal saline-treated, group II: MTX-treated (20 mg/kg, ip, single dose at day 7), group III: MTX + API–treated (20 mg/kg, po), and group IV: API-treated. API was administrated for 9 days. Alanine aminotransferase (ALT), alkaline phosphatase (ALP), and aspartate aminotransferase (AST) were used as biochemical factors of MTX-induced hepatic injury. In hepatic tissues, the levels of malondialdehyde (MDA), nitric oxide (NO), glutathione (GSH), and activities of antioxidant enzymes such as catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) as oxidative stress markers along with inflammatory factors such as tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta (IL-1β) were assessed. Our results showed that MTX administration significantly increased ALP, ASP, ALT, MDA, NO, TNF-α, and IL-1β levels and significantly decreased antioxidant factors such as GSH, CAT, GPx, and SOD. The API pretreatment group showed a significant rise in hepatic antioxidant markers, besides significant reductions in the serum levels of AST, ALT, and ALP and hepatic content of MDA, TNF-α, NO, and IL-1β. In addition, the hepatoprotective effect of API was confirmed by histological evaluation of the liver. API can prevent MTX-induced hepatotoxicity through mitigation of oxidative stress and inflammation.

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Funding

This experiment was kindly supported by the Medicinal Plant Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran (Grant No: MPRC-9614).

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Authors and Affiliations

  1. Medicinal Plant Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Mehdi Goudarzi & Hadi Kalantar

  2. Faculty of Medicine, Shoushtar University of Medical Sciences, Shoushtar, Iran

    Mojtaba Kalantar & Mojtaba Haghi Karamallah

  3. Toxicology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Elahe Sadeghi

  4. Department of Toxicology, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Hadi Kalantar

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HK and MG conceived and designed the study. MK and MHK performed experiments. HK, MG, and ES analyzed data. HK and ES wrote the manuscript. All authors read and approved the manuscript. All data were generated in-house and that no paper mill was used.

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Correspondence to Hadi Kalantar.

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Goudarzi, M., Kalantar, M., Sadeghi, E. et al. Protective effects of apigenin on altered lipid peroxidation, inflammation, and antioxidant factors in methotrexate-induced hepatotoxicity. Naunyn-Schmiedeberg's Arch Pharmacol 394, 523–531 (2021). https://doi.org/10.1007/s00210-020-01991-2

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