Valproic Acid I: Time Course of Lipid Peroxidation Biomarkers, Liver Toxicity, and Valproic Acid Metabolite Levels in Rats

Abstract

A single dose of valproic acid (VPA), which is a widely used antiepileptic drug, is associated with oxidative stress in rats, as recently demonstrated by elevated levels of 15-F(2t)-isoprostane (15-F(2t)-IsoP). To determine whether there was a temporal relationship between VPA-associated oxidative stress and hepatotoxicity, adult male Sprague-Dawley rats were treated ip with VPA (500 mg/kg) or 0.9% saline (vehicle) once daily for 2, 4, 7, 10, or 14 days. Oxidative stress was assessed by determining plasma and liver levels of 15-F(2t)-IsoP, lipid hydroperoxides (LPO), and thiobarbituric acid reactive substances (TBARs). Plasma and liver 15-F(2t)-IsoP were elevated and reached a plateau after day 2 of VPA treatment compared to control. Liver LPO levels were not elevated until day 7 of treatment (1.8-fold versus control, p < 0.05). Liver and plasma TBARs were not increased until 14 days (2-fold vs. control, p < 0.05). Liver toxicity was evaluated based on serum levels of alpha-glutathione S-transferase (alpha-GST) and by histology. Serum alpha-GST levels were significantly elevated by day 4, which corresponded to hepatotoxicity as shown by the increasing incidence of inflammation of the liver capsule, necrosis, and steatosis throughout the study. The liver levels of beta-oxidation metabolites of VPA were decreased by day 14, while the levels of 4-ene-VPA and (E)-2,4-diene-VPA were not elevated throughout the study. Overall, these findings indicate that VPA treatment results in oxidative stress, as measured by levels of 15-F(2t)-IsoP, which precedes the onset of necrosis, steatosis, and elevated levels of serum alpha-GST.

Oxidative stress in children receiving valproic acid

“…10 VPA increases oxidative stress in the rat model as measured by serum and liver levels of 15-F 2t -IsoP, which increased in a time-and dose-dependent manner after single and multiple VPA doses. 32,38 These results suggest that VPA treatment increases ROS levels and that the liver may be the source of lipid peroxidation. Our data show that children receiving VPA have significantly higher levels of urine 15-F 2t -IsoP than those treated with CBZ or CLB or control subjects receiving no medications.…”

Combined effects of a high-fat diet and chronic valproic acid treatment on hepatic steatosis and hepatotoxicity in rats

“…VPA has broad applications. For this reason, the side effects associated with VPA, especially hepatotoxicity, have aroused widespread global concern [5,6] . Abdominal ultrasound studies showed the presence of non-alcoholic fatty liver disease (NAFLD) in 61% of VPA-treated patients [7] , which suggested a high frequency of changes in asymptomatic hepatic steatosis induced by VPA.…”

An in vitro approach to assess the neurotoxicity of valproic acid-induced oxidative stress in cerebellum and cerebral cortex of young rats

“…Several studies have reported the implication of an increased generation of free radicals and oxidative stress in the toxicity induction mechanism of VPA (Kiang et al, 2010;Zhang et al, 2010). Different mechanisms have been proposed to explain inhibition of mitochondrial function by VPA (Tong et al, 2005b;Chang and Abbott, 2006). CNS depression is the most common demonstration of toxicity, ranging in severity from mild drowsiness to profound coma and fatal cerebral oedema.…”