Abstracts

Rationale: In chronic epilepsy, a substantial proportion of patients remain refractory to anticonvulsant drugs. The development of novel compounds with novel mechanisms of action is therefore paramount in order to develop new treatment options. Lacosamide (LCM) is a novel Na⁺-channel acting anticonvulsant that appears to mediate effects primarily via interacting with slow inactivation of fast transient Na⁺-channels. Given the preferential activity of LCM on slow inactivation processes, the activity of LCM on the persistent Na⁺-current (I_Na,P) has been examined. Methods: Using patch-clamp recordings in intact hippocampal CA1 neurons in the slice preparation of C57/B6 mice, I_Na,P was recorded using slow voltage ramps. I_Na,P was isolated by pharmacological subtraction using the Na⁺-channel blocker tetrodotoxin (1 µM). Results: LCM blocks I_Na,P in hippocampal pyramidal cells in a dose-dependent manner (IC50 = 81µM) and at a concentration range that is close to the mean plasma concentration (9.35 µg/ml; ~38 µM) observed in patients after 12 weeks of treatment with LCM 400 mg/day. The current traces were converted to conductance and the voltage of half-maximal activation was derived by fitting with a Boltzmann equation. The voltage-dependence of activation of I_Na,P, however, was not significantly affected by LCM. This is in contrast to the anticonvulsant carbamazepine, for which a slight but significant hyperpolarizing shift of the voltage-dependence of activation was observed. The efficacy of LCM in blocking action potential firing of hippocampal CA1 neurons also was tested. Application of 300 µM LCM in current-clamp recordings obtained with sharp microelectrodes revealed that LCM significantly reduces the output gain in response to prolonged current injections of different amplitudes. Conclusions: Given the important role of persistent Na⁺ currents in intrinsic neuronal excitability and the generation of seizure discharges in vivo and in vitro, block of persistent Na⁺ currents may contribute to the therapeutic effects of LCM.