Repositioning Perindopril for Mitigation of Methotrexate-Induced Hepatotoxicity in Rats
<b>Background/Objectives:</b> Methotrexate is a folate antagonist that has proven efficacy as an anticancer and immunomodulatory agent. However, the possible incidence of overt hepatotoxicity represents a challenge for its clinical use. Up till now, no single remedy has been considered a...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-03-01
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| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/18/3/358 |
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| Summary: | <b>Background/Objectives:</b> Methotrexate is a folate antagonist that has proven efficacy as an anticancer and immunomodulatory agent. However, the possible incidence of overt hepatotoxicity represents a challenge for its clinical use. Up till now, no single remedy has been considered an effective solution to this important adverse effect. Perindopril is an angiotensin-converting enzyme inhibitor that is widely used for the treatment of hypertension. Due to the involvement of the renin–angiotensin system in the pathogenesis of methotrexate-elicited hepatotoxicity, investigating the efficacy of perindopril in this condition may be of particular interest. The current work aimed at an evaluation of the potential effects of perindopril in a rat model of methotrexate-induced hepatotoxicity and tried to precisely determine the molecular mechanisms that may represent the basis of these effects. <b>Methods:</b> In a model of methotrexate-elicited hepatotoxicity in male Wistar rats, the effects of different doses of perindopril were evaluated at the level of the biochemical measurements and the morphological examination. <b>Results:</b> Oral administration of perindopril to methotrexate-injected rats exhibited a dose-dependent significant improvement in daily food intake; the restoration of the functions of hepatocytes; the potentiation of antioxidant defense mechanisms; the abrogation of the different signaling pathways involved in liver inflammation, apoptosis, and fibrosis; and an enhancement in AMPK/mTOR-driven autophagy when compared to animals that received only a methotrexate injection. These events were reflected in the morphological appearance of the different studied groups. <b>Conclusions:</b> This study presents perindopril as a promising remedy for mitigation of the hepatotoxic effects that occur as a consequence of treatment with methotrexate. |
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| ISSN: | 1424-8247 |