The effects of meldonium on the acute ischemia/reperfusion liver injury in rats

Siniša Đurašević,Slađan Pavlović,Jelena Sopta,Saša Đurović,Anđelija Ivanović,Tomislav Tosti,Maja Stojković,Zoran Todorović,Jelena Đorđević,Nebojša Jasnić,Slavica Borković-Mitić

doi:10.1038/s41598-020-80011-y

Abstract

Acute ischemia/reperfusion (I/R) liver injury is a clinical condition challenging to treat. Meldonium is an anti-ischemic agent that shifts energy production from fatty acid oxidation to less oxygen-consuming glycolysis. Thus, we investigated the effects of a 4-week meldonium pre-treatment (300 mg/kg b.m./day) on the acute I/R liver injury in Wistar strain male rats. Our results showed that meldonium ameliorates I/R-induced liver inflammation and injury, as confirmed by liver histology, and by attenuation of serum alanine- and aspartate aminotransferase activity, serum and liver high mobility group box 1 protein expression, and liver expression of Bax/Bcl2, haptoglobin, and the phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells. Through the increased hepatic activation of the nuclear factor erythroid 2-related factor 2, meldonium improves the antioxidative defence in the liver of animals subjected to I/R, as proved by an increase in serum and liver ascorbic/dehydroascorbic acid ratio, hepatic haem oxygenase 1 expression, glutathione and free thiol groups content, and hepatic copper-zinc superoxide dismutase, manganese superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activity. Based on our results, it can be concluded that meldonium represent a protective agent against I/R-induced liver injury, with a clinical significance in surgical procedures.

Highlights

Acute ischemia/reperfusion (I/R) liver injury is a clinical condition challenging to treat
Meldonium protects mitochondria against the accumulation of toxic long-chain fatty acids (FAs) intermediates[13], and shifts energy production to glycolysis, which is less oxygen-demanding in comparison with the FAs oxidation, and more favourable under ischemic conditions
The liver antioxidant defence was investigated by monitoring the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) by phosphorylation, and expression of Nrf2-regulated antioxidative enzyme haem oxygenase 1 (HO-1), and by measuring the activity of the copper-zinc superoxide dismutase (CuZnSOD), manganese superoxide dismutase (MnSOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase (GR), and glutathione S-transferase (GST), free sulfhydryl groups (SH) and glutathione (GSH) concentration, and the level of lipid peroxidation

Summary

Introduction

Acute ischemia/reperfusion (I/R) liver injury is a clinical condition challenging to treat. In our previous work in the model of renal I/R, we showed that meldonium, a clinical drug used to treat myocardial and cerebral ischemic conditions[10], exhibits anti-inflammatory properties[11] It inhibits synthesis and transport of carnitine, disturbing transport of cytosolic long-chain fatty acids (FAs) into mitochondria, and redirecting it to peroxisomes[12]. Meldonium protects mitochondria against the accumulation of toxic long-chain FAs intermediates[13], and shifts energy production to glycolysis, which is less oxygen-demanding in comparison with the FAs oxidation, and more favourable under ischemic conditions For these reasons, the protective effect of a four-week meldonium pre-treatment in a dose of 300 mg/kg b.m./day was investigated in a model of rat hepatic I/R. Since the link between ascorbic acid and catecholamine production in the adrenal glands is well k nown[17,18], we determined the noradrenaline (NA) and adrenaline (AD) concentrations in the adrenal glands

Methods

Results

Conclusion