Dimethyl Fumarate Attenuates Methotrexate Hepatotoxicity in Mice Via the Nrf2/HO-1/Anti-Apoptotic Signaling Pathway
| Author | Mohammad Ali Karimi | en |
| Author | Maryam Salehcheh | en |
| Author | Mohammad Rashno | en |
| Author | Layasadat Khorsandi | en |
| Author | Heibatullah Kalantari | en |
| Author | Mohammad Javad Khodayar | en |
| Orcid | Mohammad Ali Karimi [0000-0001-8282-5994] | en |
| Orcid | Maryam Salehcheh [0000-0003-1406-4120] | en |
| Orcid | Mohammad Rashno [0000-0001-5473-1384] | en |
| Orcid | Layasadat Khorsandi [0000-0002-3391-3055] | en |
| Orcid | Mohammad Javad Khodayar [0000-0001-9518-1286] | en |
| Issued Date | 2023-11-30 | en |
| Abstract | Background: Methotrexate (MTX), a folate antagonist used to treat cancer and inflammatory diseases, is known to generate reactive oxygen species. Objectives: The research investigates the impact of dimethyl fumarate (DMF), a nuclear factor erythroid 2-related factor 2 (Nrf2) activator, on an MTX-induced mouse hepatotoxicity model. Methods: Forty-two mice were divided into 6 groups: Control, MTX, DMF 120, and 3 groups of MTX co-treated with DMF 30, 60, and 120 mg/kg. Dimethyl fumarate was gavaged once daily for 10 days. On the fifth day, the animals received MTX 20 mg/kg intraperitoneally. On the eleventh day, the animals were sacrificed, and serum and liver samples were collected to assess the level of oxidative/anti-oxidative and apoptotic/anti-apoptotic markers. Results: Dimethyl fumarate prevented the increase of liver function enzymes, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) induced by MTX (P < 0.001). It prevented the increase in AST and ALT levels, indicating liver recovery (P < 0.001). Furthermore, DMF restored antioxidant markers superoxide dismutase, catalase, glutathione peroxidase, and total thiol while reducing the level of thiobarbituric acid reactive substances (P < 0.001). Dimethyl fumarate also downregulated hepatic mRNA expression of caspase 3 and upregulated Bcl-2, heme oxygenase 1, and Nrf2 genes in MTX co-treated DMF groups. Conclusions: Dimethyl fumarate alleviates oxidative stress and apoptosis, which may be achieved by the Nrf2/HO-1 pathway. Therefore, DMF may be clinically effective in preventing or treating MTX-induced hepatotoxicity. | en |
| DOI | https://doi.org/10.5812/jjnpp-139411 | en |
| Keyword | Methotrexate | en |
| Keyword | Hepatotoxicity | en |
| Keyword | Dimethyl Fumarate | en |
| Keyword | Anti-oxidative | en |
| Keyword | Anti-apoptotic | en |
| Publisher | Brieflands | en |
| Title | Dimethyl Fumarate Attenuates Methotrexate Hepatotoxicity in Mice Via the Nrf2/HO-1/Anti-Apoptotic Signaling Pathway | en |
| Type | Research Article | en |