Trimetazidine mitigates methotrexate-induced liver damage: Insights From biochemical, histological, and in silico analyses.

in Archiv der Pharmazie by Maha R A Abdollah, Mohamed H Aly, Maha E Wally, Nada K Sedky, Ahmed H Saadawy, Eman Badr, Mai F Tolba

TLDR

  • TMZ pretreatment significantly reduced MTX-induced liver damage and oxidative stress, suggesting its potential therapeutic utility in mitigating MTX-induced hepatotoxicity.
  • Key Insights: TMZ decreased p65/NF-κB levels, boosted antioxidant defenses, and increased ATP levels, highlighting its cytoprotective effects against MTX-induced damage.

Abstract

This study aimed at generating preliminary evidence for the potential utility of repurposing the clinically approved anti-ischemic drug trimetazidine (TMZ) against methotrexate (MTX)-induced hepatotoxicity. In this study, rats received MTX (30 mg/kg) with or without TMZ pretreatment (20 mg/kg). MTX caused a 2.7-3.6-fold increase in serum transaminases, while TMZ pretreatment caused a 37%-40% reduction. Regarding oxidative markers, MTX significantly suppressed the antioxidant glutathione (GSH) levels by 37% and elevated malondialdehyde (MDA) levels by 29%, while TMZ boosted GSH levels by 40% and reduced MDA levels by 20%. Next, we assessed nuclear factor kappa B (NF-κB) (p-65), nuclear factor erythroid 2-related factor 2 (Nrf2) and hemoxygenase-1 (HO-1) to find that MTX significantly elevated the levels of the proinflammatory nuclear factor kappa B (NF-κB) (p65) by 2.4-fold, while TMZ pretreatment reduced its levels by 48%. Conversely, MTX decreased the levels of Nrf2, HO-1, and adenosine triphosphate (ATP) by 55%-71%, while TMZ led to a threefold increase in their levels. Regarding apoptosis, MTX caused a five to sixfold elevation in B-cell lymphoma 2 associated X (Bax)/B-cell lymphoma 2 (BCL2) ratio and caspase-3, while TMZ pretreatment caused a threefold reduction in their levels. An in silico analysis of TMZ protein target-prediction revealed statistically enriched pathways related to oxidative stress, inflammation, and apoptosis. In conclusion, pretreatment with TMZ successfully ameliorated MTX-induced alterations in serum aminotransferases, liver histology, oxidative stress, and apoptosis. Pathway enrichment analysis (PEA) showed that TMZ is involved in multiple signaling and immune-related pathways that might be, at least partly, implicated in its cytoprotective effects.

Overview

  • The study aimed to evaluate the potential of repositioning the clinically approved anti-ischemic drug trimetazidine (TMZ) against methotrexate (MTX)-induced hepatotoxicity.
  • Rats received MTX with or without TMZ pretreatment, and the effects on serum transaminases, oxidative markers, and apoptotic damage were assessed.
  • The study aimed to identify the primary objective of investigating TMZ's potential in mitigating MTX-induced liver damage.

Comparative Analysis & Findings

  • TMZ pretreatment resulted in a 37%-40% reduction in MTX-induced increases in serum transaminases.
  • TMZ boosted glutathione levels by 40% and reduced malondialdehyde levels by 20%, while MTX suppressed glutathione levels by 37% and elevated malondialdehyde levels by 29%.
  • TMZ reduced p65/NF-κB levels by 48%, while MTX elevated p65/NF-κB levels by 2.4-fold, and TMZ increased Nrf2, HO-1, and ATP levels by a factor of three.

Implications and Future Directions

  • The study provides preliminary evidence for the potential utility of TMZ in mitigating MTX-induced hepatotoxicity, highlighting its cytoprotective effects.
  • Future studies should investigate the therapeutic potential of TMZ in humans and explore its combination with other treatments for comprehensive liver protection.
  • In silico analysis suggests that TMZ may interact with multiple signaling and immune-related pathways, warranting further investigation into its mechanisms of action.
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