Protective effect of erdosteine against methotrexateinduced hepatotoxicity in rats

Osama Abdelaziz Hassan,Rabab Ahmed Moussa,Entesar Farghally Amin

doi:10.4314/tjpr.v19i7.19

Osama Abdelaziz Hassan, Rabab Ahmed Moussa + Show 1 more

Open Access

https://doi.org/10.4314/tjpr.v19i7.19

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Abstract

Purpose: To study the possible mitigating effect of erdosteine (ERD) against methotrexate (MTX)-induced liver toxicity.Methods: Male albino Sprague-Dawley rats were randomly assigned to four groups of 8 rats each, viz, vehicle control, MTX (20 mg/kg i.p.), MTX (20 mg/kg i.p.) + ERD (300 mg/kg) and ERD (300 mg/kg) groups. Serum levels of alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were determined by enzymatic colorimetric commercial kits while Hepatic tissue content of malondialdehyde (MDA), reduced glutathione (GSH), SOD and catalase (CAT) were also evaluated. In addition, measurement of the inflammatory cytokine, TNF-α, as well as histopathological examination and histochemical assessment were carried out.Results: The results indicate that, compared to the control group, MTX group showed a remarkable elevation in oxidative stress as indicated by significantly lower levels of SOD, CAT and reduced glutathione, and increased tissue malondialdehyde (p < 0.05). MTX group exhibited significantly higher blood activities of ALT, AST and TNF-α, reflective of hepatocyte damage and inflammation (p < 0.05). In MTX group, significant hepatic degenerative changes were detected on histological examination, while marked apoptotic alternations were observed following immunohistochemical analysis of caspase-3 expression, when compared to control group. However, administration of ERD to rats ameliorated thechanges in these parameters (p < 0.05).Conclusion: Treatment with ERD in rats produced alleviation in hepatic oxidative stress, apoptosis, inflammation, and histological damage, when compared to MTX group. This study is the first to demonstrate the potentially protective effect of ERD-pretreatment against hepatotoxicity associated with MTX. Keywords: Erdosteine, Methotrexate, Hepatotoxicity, Oxidant, Anti-oxidant                                                                                                                                                                                                                                                                     

Highlights

Methotrexate (MTX) is an antineoplastic and immunosuppressive drug that is frequently used for the treatment of multiple types of leukemia and solid tumors [1], as well as rheumatoid arthritis and psoriasis [2]
A significant body of evidence has highlighted the antioxidant effects of ERD, in addition to its established mucolytic affect [9]
On day 7, the animals were subjected to 12 h fast, and blood was drawn from the neck vein of each rat under urethane anesthesia (1.5 g/kg, i.p.), and sera samples were obtained after centrifugation at 5000 rpm for 10 min

Summary

Introduction

Methotrexate (MTX) is an antineoplastic and immunosuppressive drug that is frequently used for the treatment of multiple types of leukemia and solid tumors [1], as well as rheumatoid arthritis and psoriasis [2]. In addition to the inhibitory effect on DNA and protein synthesis, the hepatotoxic effect of MTX significantly involves reductions in methionine synthesis and various enzyme antioxidants e.g. CAT, GPx and SOD. Reductions in the activities of these enzymes result in build-up of ROS, leading to deleterious effects on DNA, proteins, lipids and various cell organelles, and enhancing apoptosis [7]. It has been shown that erdosteine ameliorated oxidative tissue damage in various animal models of druginduced organ toxicity [10]. Based on these findings, it was felt that the potential mitigating influence of ERD pre-treatment against MTXmediated liver damage should be studied in a rat model of the disease.

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