Long-lasting antiseizure effects of chronic intrasubthalamic convection-enhanced delivery of valproate

Abstract

Intracerebral drug delivery is an experimental approach for the treatment of drug-resistant epilepsies that allows for pharmacological intervention in targeted brain regions. Previous studies have shown that targeted pharmacological inhibition of the subthalamic nucleus (STN) via modulators of the GABAergic system produces antiseizure effects. However, with chronic treatment, antiseizure effects are lost as tolerance develops. Here, we report that chronic intrasubthalamic microinfusion of valproate (VPA), an antiseizure medication known for its wide range of mechanisms of action, can produce long-lasting antiseizure effects over three weeks in rats. In the intravenous pentylenetetrazole seizure-threshold test, seizure thresholds were determined before and during chronic VPA application (480 μg/d, 720 μg/d, 960 μg/d) to the bilateral STN. Results indicate a dose-dependent variation in VPA-induced antiseizure effects with mean increases in seizure threshold of up to 33%, and individual increases of up to 150%. The lowest VPA dose showed a complete lack of tolerance development with long-lasting antiseizure effects. Behavioral testing with all doses revealed few, acceptable adverse effects. VPA concentrations were high in STN and low in plasma and liver. In vitro electrophysiology with bath applied VPA revealed a reduction in spontaneous firing rate, increased background membrane potential, decreased input resistance and a significant reduction in peak NMDA, but not AMPA, receptor currents in STN neurons. Our results suggest an advantage of VPA over purely GABAergic modulators in preventing tolerance development with chronic intrasubthalamic drug delivery and provide first mechanistic insights in intracerebral pharmacotherapy targeting the STN.