The Effects of Meldonium on the Renal Acute Ischemia/Reperfusion Injury in Rats

Abstract

Acute renal ischemia/reperfusion (I/R) injury is a clinical condition that is challenging to treat. Meldonium is an anti-ischemic agent that shifts energy production from fatty acid oxidation to less oxygen-consuming glycolysis. Thus, in this study we investigated the effects of a four-week meldonium pre-treatment (300 mg/kg b.m./day) on acute renal I/R in male rats (Wistar strain). Our results showed that meldonium decreased animal body mass gain, food and water intake, and carnitine, glucose, and lactic acid kidney content. In kidneys of animals subjected to I/R, meldonium increased phosphorylation of mitogen-activated protein kinase p38 and protein kinase B, and increased the expression of nuclear factor erythroid 2-related factor 2 and haeme oxygenase 1, causing manganese superoxide dismutase expression and activity to increase, as well as lipid peroxidation, cooper-zinc superoxide dismutase, glutathione peroxidase, and glutathione reductase activities to decrease. By decreasing the kidney Bax/Bcl2 expression ratio and kidney and serum high mobility group box 1 protein content, meldonium reduced apoptotic and necrotic events in I/R, as confirmed by kidney histology. Meldonium increased adrenal noradrenaline content and serum, adrenal, hepatic, and renal ascorbic/dehydroascorbic acid ratio, which caused complex changes in renal lipidomics. Taken together, our results have confirmed that meldonium pre-treatment protects against I/R-induced oxidative stress and apoptosis/necrosis.

The Effects of a Meldonium Pre-Treatment on the Course of the Faecal-Induced Sepsis in Rats

“…Intriguingly, this meldonium-induced metabolic shift was followed by a decrease in lactate concentration. This implicates ATP production through the substrate-level phosphorylation, as previously reported in both liver [19] and kidney [20] models of ischemia/reperfusion injury. The present results suggested that meldonium decreases lipolysis and fatty acids β oxidation, and stimulates aerobic oxidation of glucose as an oxygen-sparing mechanism for ATP production under septic conditions.…”

“…It should be noted that depression of the cardiac function in sepsis is quite common, with the pathogenesis of septic cardiomyopathy being complex and most likely multifactorial, including metabolic alterations such as decreased glucose uptake and increased lactate production [ 31 , 32 ]. Our previous studies show an increase of the glucose uptake and decreased lactate production as a result of the meldonium pre-treatment in both liver [ 19 ] and kidney [ 20 ] models of ischemia/reperfusion injury. Accordingly, we expected meldonium to exert protective effects in the present study as well.…”

“…In our previous work, we showed that meldonium, an anti-ischemic drug clinically used to treat myocardial and cerebral ischemia [ 18 ], also expresses strong anti-inflammatory effects in the liver [ 19 ] and renal [ 20 ] ischemia/reperfusion. By decreasing the long-chain FFAs displacement from the cytosol into mitochondria and redirecting them to peroxisomes, meldonium inhibits L-carnitine biosynthesis and transport [ 21 ].…”

Ferroptosis in Different Pathological Contexts Seen through the Eyes of Mitochondria

“…The list of pathologies that involve ferroptosis as an underlying mechanism of their aetiology and progression is growing, as is knowledge about the signalling pathways regulating this type of cell death. In this context, ferroptosis has been established as a contributing factor to tissue damage in ischemic injury of the kidney and in liver diseases [ 18 , 19 , 63 ], in addition to the previously described contribution of apoptosis and necrosis [ 116 – 119 ]. Ferroptosis is also involved in liver haemochromatosis [ 120 ] and mediates the activity of anticancer drugs commonly used in hepatocellular cancer therapy (for example, sorafenib) [ 121 ].…”

Lipids and Antiplatelet Therapy: Important Considerations and Future Perspectives

“…Such changes are specific and make it possible to find new drugs’ action targets. In a series of experiments in models of ischemia-reperfusion injury of the kidney and liver, we showed that the lipid profile differs depending on the tissue and that drugs that modulate lipid metabolism in mitochondria and peroxisomes have different effects on that profile [ 76 , 77 ]. Lipidomics became even more important because lipid mediators cannot be deposited in vesicles but are created “on-demand” at the site of action in the cell.…”