The Anticonvulsant Effect of Long-Term Valproate Might Be Attributable to Altered Expression of Selected Genes in Mice

In this study, we assessed the impact of repeated valproate administration on its anticonvulsant effects and side effects in mice. We measured the plasma and brain concentrations of valproate and examined changes in the expression of selected genes in the mouse hippocampus after both acute and chronic treatments. Electroconvulsions were induced using an alternating current (50 Hz, 25 mA, 0.2 s) through ear clip electrodes. Motor impairment and long-term memory deficits were assessed with the chimney test and passive avoidance task. Valproate concentrations in the brain and plasma were measured by a fluorescence polarization immunoassay. mRNA was isolated using a modified Chomczyński and Sacchi method, and RQ-PCR was performed with an Applied Biosystems 7900 using SDS and RQ Study software. The 50% effective dose (ED50) of valproate in the 14 × 2 protocol was significantly lower than the control. Despite no observed memory deficits in chronic protocols, the 50% toxic dose (TD50) for motor impairment was also significantly lower. Chronic valproate treatment did not alter the plasma and brain concentrations. However, the expression levels of three genes (CACNA1G, GAD1, SCN1A) were significantly higher in the chronic protocols with the higher dose of valproate compared to single protocols, suggesting a dose-dependent effect. The repeated administration of valproate resulted in both enhanced efficacy and increased toxicity in terms of motor impairment. The observed effect may be associated with transcriptional adaptations potentially mediated by epigenetic mechanisms rather than with pharmacokinetic events. To enhance the reliability of the results obtained in animal epilepsy models, antiepileptic drugs should be administered chronically.