Protective Effect of Mito-TEMPO on Sodium Valproate-Induced Hepatotoxicity in Mice

Valproic acid is a broad-spectrum anticonvulsant drug that is also useful for other diseases such as bipolar disorder and migraine. The most important side effect of this drug is hepatotoxicity. Oxidative stress and mitochondrial dysfunction play a role in the pathogenesis of liver toxicity of valproic acid. Mito-TEMPO is an antioxidant-based compound, which is selectively accumulated in mitochondria. The effects of its mitochondrial protection against oxidative damage in various pathologies, such as liver damage, have been observed. The aim of this study was to evaluate the protective effect of mito-TEMPO on liver toxicity induced by sodium valproate in mice.

Animals were divided into five groups and treated intraperitonealy over a 4-week period. Group 1 received normal saline, served as vehicle control, group 2 treated with 12.5 mg/kg of sodium valproate, group 3 was treated with 1 mg/kg of Mito-TEMPO, group 4 received both sodium valproate (12.5 mg/kg) and Mito-TEMPO (1mg/kg), and group 5 received sodium valproate (12.5 mg/kg) and vitamin E (5mg/kg) served as positive control. At the end of the experiment, blood samples collected by cardiac puncture and all the animals were killed under ether anesthesia. Biochemical parameters including AST, ALT, ALP and GGT in serum samples and glutathione (GSH) and malondialdehyde (MDA) contents in liver homogenates were determined.

Findings of this study showed that activity of AST and ALT were significantly lower in the sodium valproate + mito-TEMPO treated animals as compared to sodium valproate group (group 2). Furthermore, mito-TEMPO was able to recover glutathione content (GSH) of liver tissue. Effect of mito-TEMPO on the activity of ALP and GGT and serum level of MDA was not significant.

Taken collectively, mito-TEMPO has a protective role in sodium valproate hepatotoxicity. Considering the present results, further studies, in view of the potential therapeutic properties of mito-TEMPO in improving liver damage caused by the use of valproic acid, may lead to the clinical applications of mito-TEMPO in the treatment of liver disease.