Effect of valproic acid on sodium currents in cortical neurons from patients with pharmaco-resistant temporal lobe epilepsy

Abstract

In a selected group of temporal lobe epilepsy patients with seizures refractory to pharmacological treatment, pharmacological seizure control can be attained by surgical resection of the epileptic zone. We investigated to what extent pharmaco-resistance is reflected in a reduced response at the cellular level, in neurons acutely isolated from the temporal cortex resected in 20 patients. We studied the effect of valproic acid (VPA) on the transient sodium current, measured under whole-cell voltage-clamp conditions. We compared neurons from patients with temporal lobe sclerosis (S) with neurons from patients without hippocampal sclerosis (nS) and compared hippocampal CA1 neurons (CA) with neocortical neurons (NC). We could not detect differences in the voltage dependence and kinetics of sodium current activation and inactivation in any of the group comparisons. VPA shifted the voltage dependence of steady-state inactivation (expressed as V(h,i) in a Boltzmann fit) to more hyperpolarized levels. The shift induced by 2 mM VPA was -5.1 +/- 0.7 mV in CA-S (n = 13), -5.1 +/- 0.7 mV in CA-nS (n = 25), -4.3 +/- 0.5 mV in NC-S (n = 17) and -4.9 +/- 0.5 mV in NC-nS (n = 16) The relation between concentration and voltage shift had an EC50 of 1.4 +/- 0.2 mM VPA (n = 16) and a maximal shift of 9.6 +/- 0.9 mV. We conclude that pharmaco-resistance in these patients is not associated with a changed modulation of the sodium current by VPA. Results are discussed in the light of a reduced sodium current modulation by carbamazepine in CA1 neurons of patients with hippocampal sclerosis and of similar observations in the kindling model of epileptogenesis.