Effects of meldonium on thioacetamide-induced hepatotoxicity in Wistar rats

Abstract

Introduction: Hepatotoxicity is a liver injury caused by various factors such as drug usage, alcohol intake, malnutrition, viral infections, and others. Previous studies demonstrated the anti-inflammatory, antioxidant, and anti-apoptotic effects of meldonium (M). Therefore, we aimed to examine the effects of meldonium on thioacetamide (TAA)-induced hepatotoxicity in rats. Methods: Female Wistar rats were randomly divided into three experimental groups. TAA and TAA+M groups were biweekly intraperitoneally (i.p.) injected with TAA (150 mg/kg) for 16 weeks. The control group received i.p. injections of saline. Simultaneously, the TAA+M group ingested meldonium (300 mg/kg) with drinking water. Blood samples were collected to measure AST and ALP serum activity. Using Western blot and RT-qPCR, we analyzed the hepatic expression of inflammatory markers, anti- and proapoptotic proteins, and oxidative stress parameters. Results: TAA alone did not induce mortality, but co-administration with meldonium increased the mortality by 42%. As expected, TAA increased ALP serum activity, hepatic BAX/Bcl-2 ratio, and NFkβ, IL-6, TNFα, HMGB1, and CAT levels. Surprisingly, compared to the TAA group, meldonium did not alter ALP serum activity, hepatic BAX/Bcl-2 ratio, and NFkβ, IL-6, TNFα, HMGB1, and CAT levels. However, we observed a significantly increased AST serum activity in the TAA+M but not in the TAA group. Hepatic NOX4 and NRF2 levels remained unchanged in both treated groups. Conclusion: Contrary to our expectations, meldonium not only failed to prevent hepatotoxicity but also significantly increased mortality. Despite the previously shown beneficial effects of meldonium, its potential application in other pathological conditions requires further investigation.