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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MDPI AG
2025-03-01
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| author | Hanan Abdelmawgoud Atia Hemat A. Elariny Marwa H. Abdallah Amany M. Khalifa Remon S. Estfanous Maaly A. Abd Elmaaboud Ahmed M. Kabel |
| author_facet | Hanan Abdelmawgoud Atia Hemat A. Elariny Marwa H. Abdallah Amany M. Khalifa Remon S. Estfanous Maaly A. Abd Elmaaboud Ahmed M. Kabel |
| author_sort | Hanan Abdelmawgoud Atia |
| collection | DOAJ |
| description | <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. |
| format | Article |
| id | doaj-art-1381d3c8f8114060ae85a22fedc7fb65 |
| institution | DOAJ |
| issn | 1424-8247 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj-art-1381d3c8f8114060ae85a22fedc7fb652025-08-20T02:42:24ZengMDPI AGPharmaceuticals1424-82472025-03-0118335810.3390/ph18030358Repositioning Perindopril for Mitigation of Methotrexate-Induced Hepatotoxicity in RatsHanan Abdelmawgoud Atia0Hemat A. Elariny1Marwa H. Abdallah2Amany M. Khalifa3Remon S. Estfanous4Maaly A. Abd Elmaaboud5Ahmed M. Kabel6Department of Pharmacology and Toxicology, College of Pharmacy, University of Ha’il, Ha’il 81442, Saudi ArabiaDepartment of Pharmacology and Toxicology, College of Pharmacy, University of Ha’il, Ha’il 81442, Saudi ArabiaDepartment of Pharmaceutics, College of Pharmacy, University of Ha’il, Ha’il 81442, Saudi ArabiaDepartment of Pathology, College of Medicine, University of Ha’il, Ha’il 81442, Saudi ArabiaAnatomy and Embryology Department, Faculty of Medicine, Tanta University, Tanta 31527, EgyptDepartment of Pharmacology, Faculty of Medicine, Tanta University, Tanta 31527, EgyptDepartment of Pharmacology, Faculty of Medicine, Tanta University, Tanta 31527, Egypt<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.https://www.mdpi.com/1424-8247/18/3/358perindoprilmethotrexatehepatotoxicityinflammatory cascadeHMGB1rats |
| spellingShingle | Hanan Abdelmawgoud Atia Hemat A. Elariny Marwa H. Abdallah Amany M. Khalifa Remon S. Estfanous Maaly A. Abd Elmaaboud Ahmed M. Kabel Repositioning Perindopril for Mitigation of Methotrexate-Induced Hepatotoxicity in Rats Pharmaceuticals perindopril methotrexate hepatotoxicity inflammatory cascade HMGB1 rats |
| title | Repositioning Perindopril for Mitigation of Methotrexate-Induced Hepatotoxicity in Rats |
| title_full | Repositioning Perindopril for Mitigation of Methotrexate-Induced Hepatotoxicity in Rats |
| title_fullStr | Repositioning Perindopril for Mitigation of Methotrexate-Induced Hepatotoxicity in Rats |
| title_full_unstemmed | Repositioning Perindopril for Mitigation of Methotrexate-Induced Hepatotoxicity in Rats |
| title_short | Repositioning Perindopril for Mitigation of Methotrexate-Induced Hepatotoxicity in Rats |
| title_sort | repositioning perindopril for mitigation of methotrexate induced hepatotoxicity in rats |
| topic | perindopril methotrexate hepatotoxicity inflammatory cascade HMGB1 rats |
| url | https://www.mdpi.com/1424-8247/18/3/358 |
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