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Trimetazidine counteracts the hepatic injury associated with ischemia-reperfusion by preserving mitochondrial
1Département de Pharmacologie, IM3, Faculté de Médecine de Paris XII, France. elimadi@univ-paris12.fr
Abstract:
Recent studies suggest a crucial role played by mitochondria in the pathogenesis of ischemia-reperfusion injury. This study was conducted to clarify the role of trimetazidine, a cellular anti-ischemic agent, on mitochondria isolated from rat liver subjected to 120-min normothermic ischemia followed by 30-min reperfusion. Rats were divided into groups, pretreated with different doses of trimetazidine (5, 10 and 20 mg/kg/day) or saline and subjected to the ischemia-reperfusion process; another group served as the sham-operated controls. Alanine aminotransferase and aspartate aminotransferase activities and hepatocyte ATP content, bile flow and mitochondrial functions were assessed. Ischemia-reperfusion caused membrane leakage from hepatocytes and a decrease in ATP content and in bile flow. These effects were well correlated with alterations in mitochondrial function, namely, decrease in ATP synthesis, NAD(P)H level and mitochondrial membrane potential and generation of mitochondrial permeability transition. The pretreatment of rats with trimetazidine prevented these ischemia-reperfusion deleterious effects at both the cellular and mitochondrial level in a dose-dependent manner. It is concluded that trimetazidine at an optimal dosage of 10 mg/kg/day protects mitochondria against the deleterious effects of ischemia-reperfusion. This protective effect appears to be the key factor through which this drug exerts its cytoprotective activity.
Insights
Trimetazidine protects liver mitochondria from ischemia-reperfusion injury. This anti-ischemic agent preserves mitochondrial function and ATP levels, demonstrating significant cytoprotective effects.
Area of Science:
- Mitochondrial biology
- Hepatology
- Pharmacology
Background:
- Mitochondria play a key role in ischemia-reperfusion (I/R) injury pathogenesis.
- I/R injury significantly impacts liver function and cellular integrity.
Purpose of the Study:
- To investigate the protective effects of trimetazidine on mitochondria isolated from rat liver subjected to I/R.
- To determine the optimal dosage of trimetazidine for mitigating I/R-induced damage.
Main Methods:
- Rats were pretreated with varying doses of trimetazidine (5, 10, 20 mg/kg/day) or saline before undergoing 120-min ischemia and 30-min reperfusion.
- Assessed liver injury markers (ALT, AST), hepatocyte ATP content, bile flow, and mitochondrial functions (ATP synthesis, NAD(P)H level, membrane potential, mitochondrial permeability transition).
Main Results:
- I/R caused significant hepatocyte membrane leakage, decreased ATP content and bile flow.
- I/R induced mitochondrial dysfunction, including reduced ATP synthesis, NAD(P)H levels, and membrane potential, alongside increased mitochondrial permeability transition.
- Trimetazidine pretreatment dose-dependently prevented these cellular and mitochondrial damages, with 10 mg/kg/day being optimal.
Conclusions:
- Trimetazidine effectively protects liver mitochondria against I/R-induced damage.
- The optimal dose of 10 mg/kg/day highlights trimetazidine's potential as a cytoprotective agent against I/R injury.
- Mitochondrial protection is the primary mechanism underlying trimetazidine's cytoprotective activity in I/R injury.