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. 2025 Mar 2;18(3):358.
doi: 10.3390/ph18030358.

Repositioning Perindopril for Mitigation of Methotrexate-Induced Hepatotoxicity in Rats

Hanan Abdelmawgoud Atia  1 , Hemat A Elariny  1 , Marwa H Abdallah  2 , Amany M Khalifa  3 , Remon S Estfanous  4 , Maaly A Abd Elmaaboud  5 , Ahmed M Kabel  5
Affiliations

Repositioning Perindopril for Mitigation of Methotrexate-Induced Hepatotoxicity in Rats

Hanan Abdelmawgoud Atia et al. Pharmaceuticals (Basel). .

Abstract

Background/Objectives: 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 VSports手机版. 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. Methods: 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. Results: 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. Conclusions: This study presents perindopril as a promising remedy for mitigation of the hepatotoxic effects that occur as a consequence of treatment with methotrexate. .

Keywords: HMGB1; hepatotoxicity; inflammatory cascade; methotrexate; perindopril; rats. V体育安卓版.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Effect of the different treatments on the daily food intake throughout the whole study (mean ± SD). a Significant compared to the control group; b Significant relative to the untreated methotrexate group; c Significant relative to methotrexate group treated with perindopril 0.5 mg/kg/day; d Significant relative to methotrexate group treated with perindopril 1 mg/kg/day. MTX: methotrexate; PNP: perindopril.
Figure 2
Figure 2
Effect of the different doses of perindopril on the liver function tests in the animal groups treated with methotrexate (mean ± SD); * = p < 0.05, ** = p < 0.01, *** = p < 0.001; MTX: methotrexate; PNP: perindopril; ALT: alanine transaminase; AST: aspartate transaminase; ALP: alkaline phosphatase.
Figure 3
Figure 3
Effect of the different doses of perindopril on the redox status of the hepatic tissues of the animal groups treated with methotrexate (mean ± SD); * = p < 0.05, ** = p < 0.01, *** = p < 0.001; MTX: methotrexate; PNP: perindopril; MDA: malondialdehyde; SOD: superoxide dismutase; TAC: total antioxidant capacity.
Figure 4
Figure 4
Effect of the different doses of perindopril on sirtuin-1 and peroxisome proliferator-activated receptor gamma levels in the hepatic tissues of the animal groups treated with methotrexate (mean ± SD); ** = p < 0.01, *** = p < 0.001; MTX: methotrexate; PNP: perindopril; SIRT1: sirtuin-1; PPAR-γ: peroxisome proliferator-activated receptor gamma.
Figure 5
Figure 5
Effect of the different doses of perindopril on KEAP1, Nrf2, and HO-1 content of the hepatic tissues of the animal groups treated with methotrexate (mean ± SD); * = p < 0.05, ** = p < 0.01, *** = p < 0.001; MTX: methotrexate; PNP: perindopril; KEAP1: Kelch-like ECH-associated protein 1; Nrf2: nuclear factor erythroid 2-related factor 2; HO-1: heme oxygenase-1.
Figure 6
Figure 6
Effect of the different doses of perindopril on IL-1β, IL-6, MCP-1, and TNF-α levels in the hepatic tissues of the animal groups treated with methotrexate (mean ± SD); *** = p < 0.001; MTX: methotrexate; PNP: perindopril; IL-1β: interleukin 1-beta; MCP-1: monocyte chemoattractant protein 1; TNF-α: tumor necrosis factor-alpha.
Figure 7
Figure 7
Effect of the different doses of perindopril on HMGB1/RAGE/NF-κB axis in the hepatic tissues of the animal groups treated with methotrexate (mean ± SD); ns = non-significant, ** = p < 0.01, *** = p < 0.001; MTX: methotrexate; PNP: perindopril; HMGB1: High-Mobility Group Box 1; RAGE: receptors for advanced glycation end products; NF-κB: nuclear factor kappa B.
Figure 8
Figure 8
Effect of the different doses of perindopril on phospho-mTOR, total AMPK, and LC3-II levels in the hepatic tissues of the animal groups treated with methotrexate (mean ± SD); ns = non-significant, * = p < 0.05, ** = p < 0.01, *** = p < 0.001; MTX: methotrexate; PNP: perindopril; phospho-mTOR: phosphorylated mammalian target of rapamycin; AMPK: adenosine monophosphate-activated protein kinase; LC3-II: microtubule-associated protein light chain 3.
Figure 9
Figure 9
Effect of the different doses of perindopril on hydroxyproline, MMP-3, and MMP-9 in the hepatic tissues of the animal groups treated with methotrexate (mean ± SD); ns = non-significant, ** = p < 0.01, *** = p < 0.001; MTX: methotrexate; PNP: perindopril; MMP: matrix metalloproteinase.
Figure 10
Figure 10
Hematoxylin and eosin-stained sections of the liver from (A) the control group showing the characteristic hexagonal classic hepatic lobules with central veins (CV) at the center and portal tracts (PT) at the periphery. The polygonal hepatocytes are arranged in cords separated by blood sinusoids (S) (×100); (B) methotrexate group exhibiting loss of normal hepatic architecture with dilated and markedly congested central vein (CV) and portal venules (PV) with diffuse perivascular, periportal, and interstitial inflammatory cellular infiltration (I). The central parts of the blood sinusoids (S) appear dilated in some regions with focal areas of hepatic necrosis (Thin arrows) (×100); (C) Portal tract of methotrexate group showing dilated congested portal venules (PV) and hepatic arterioles (HA) with proliferation of bile ductules (BD) (Thick arrows). Also, scattered areas of inflammatory cellular infiltration (I) are seen in the portal area (×400); (D) methotrexate group treated with a small dose of perindopril revealing a significant improvement in the hepatic architecture with cords of normal hepatocytes that surround a mildly dilated central vein (CV). Some hepatic sinusoids appear mildly dilated (S) with scanty areas of hepatic necrosis (Thin arrows) and inflammatory cellular infiltration (I) (×100); (E) methotrexate group treated with a moderate dose of perindopril showing minimal dilatation of the central veins which are surrounded by cords of hepatocytes with acidophilic cytoplasm and vesicular nuclei. Some of the blood sinusoids (S) appear dilated with minimal inflammatory cellular infiltration (I) (×100); (F) methotrexate group treated with a large dose of perindopril exhibiting restoration of the normal hepatic histomorphic structure with appearance of the classic hexagonal hepatic lobules with apparently normal central veins (CV) and portal tracts with minimal congestion of the portal venules (PV) (×100).
Figure 11
Figure 11
Hepatic tissue sections of immunohistochemical staining of cleaved caspase 3 in (A) The control group clarifying minimal positive immunostaining for cleaved caspase 3; (B) The group that received methotrexate alone exhibiting strongly positive immunostaining for cleaved caspase 3; (C–E) Methotrexate-injected groups treated with small, moderate, and large doses of perindopril, respectively, showing mild positive immunostaining for cleaved caspase 3; (F) Quantitative representation of the percentage of cleaved caspase 3 immune expression in the different studied groups (% of the control); * = p < 0.05, *** = p < 0.001; MTX: methotrexate; PNP: perindopril.
Figure 12
Figure 12
Electron micrographs of ultrathin sections in the liver from animals of (A) the control group showing normal architecture of the hepatic tissues. The nuclei (N) appeared spherical with regular outlines with a small amount of heterochromatin in the peripheral regions and a large central amount of euchromatin and prominent nucleolus. The cytoplasm of the hepatocytes contains abundant mitochondria (Arrow) with well-developed cristae and the rough endoplasmic reticulum (RER) consists of closely packed parallel and flattened cisternae (Arrowhead); (B,C) methotrexate-treated group showing shrunken irregular nucleus with dispersed chromatin (N) and reduced number of the mitochondria with disrupted cristae (Arrow). The cisternae of the rough endoplasmic reticulum (RER) of the hepatocytes are fragmented (Arrowhead) with extensive fat droplets (F) and marked cytoplasmic vacuolation (V); (D) methotrexate group treated with a small dose of perindopril revealing irregular nucleus with preserved nucleolus (N). There is a mild increase in the number of the viable mitochondria with mild disrupted cristae (Arrow), partly preserved cisternae of the rough endoplasmic reticulum (Arrowhead), and small number of fat droplets could be observed (F); (E) methotrexate group treated with a moderate dose of perindopril exhibiting a spherical nucleus with regular wall and preserved nucleolus (N). There is moderate increase in the number of the mitochondria with mild disrupted cristae (Arrow) with mild disruption and wide separation of the cisternae of the rough endoplasmic reticulum (Arrowhead); (F) methotrexate group treated with a large dose of perindopril showing a normal spherical nucleus with intact regular walls and preserved nucleolus (N). The mitochondria are abundant with preserved cristae (Arrow) and the rough endoplasmic reticulum cisternae appear nearly normal with mild dilatation (Arrowhead).
Figure 13
Figure 13
The mechanisms by which perindopril mitigates methotrexate-induced hepatotoxicity (This artwork was constructed using Reactome icon library and Smart Art Servier items).
Figure 14
Figure 14
A representative diagram of the experimental protocol of the present study.
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