Activity of the anticonvulsant lacosamide in experimental and human epilepsy via selective effects on slow Na⁺ channel inactivation

Abstract

SUMMARYObjective: In human epilepsy, pharmacoresistance to antiepileptic drug therapy is a major problem affecting~30% of patients with epilepsy. Many classical antiepileptic drugs target voltage-gated sodium channels, and their potent activity in inhibiting high-frequency firing has been attributed to their strong use-dependent blocking action. In chronic epilepsy, a loss of use-dependent block has emerged as a potential cellular mechanism of pharmacoresistance for anticonvulsants acting on voltage-gated sodium channels. The anticonvulsant drug lacosamide (LCM) also targets sodium channels, but has been shown to preferentially affect sodium channel slow inactivation processes, in contrast to most other anticonvulsants. Methods: We used whole-cell voltage clamp recordings in acutely isolated cells to investigate the effects of LCM on transient Na + currents. Furthermore, we used whole-cell current clamp recordings to assess effects on repetitive action potential firing in hippocampal slices. Results: We show here that LCM exerts its effects primarily via shifting the slow inactivation voltage dependence to more hyperpolarized potentials in hippocampal dentate granule cells from control and epileptic rats, and from patients with epilepsy. It is important to note that this activity of LCM was maintained in chronic experimental and human epilepsy. Furthermore, we demonstrate that the efficacy of LCM in inhibiting high-frequency firing is undiminished in chronic experimental and human epilepsy. Significance: Taken together, these results show that LCM exhibits maintained efficacy in chronic epilepsy, in contrast to conventional use-dependent sodium channel blockers such as carbamazepine. They also establish that targeting slow inactivation may be a promising strategy for overcoming target mechanisms of pharmacoresistance.

Effects of eslicarbazepine on slow inactivation processes of sodium channels in dentate gyrus granule cells

“…We observed quantitatively maintained effects of S‐Lic not only on slow inactivation in experimental epilepsy, but also on sodium channels in granule cells obtained from epilepsy surgical specimens. This is similar to the maintained activity of lacosamide on slow inactivation and use‐dependent block in chronic experimental and human epilepsy that was observed in a previous study . In addition, we have shown that the maintained activity also extends to cortical areas, which also display pathological changes in chronic epilepsy models …”

“…Similar effects are shared by some other AEDs. Lacosamide also exerts effects on slow inactivation in different types of neurons . Moreover, as seen for S‐Lic, lacosamide also shifts the voltage dependence of slow inactivation in a hyperpolarizing direction as a major effect, whereas other effects on slow inactivation were small .…”

“…In contrast to those AEDs, the effects of CBZ on slow inactivation are virtually negligible, with well‐known pronounced effects on fast inactivation processes . Lacosamide does differ from S‐Lic in that effects on fast inactivation voltage dependence were undetectable or small, whereas S‐Lic does have significant effects on fast sodium channel gating in native neurons . Another study, however, did not find significant S‐Lic effects on fast inactivation in expression systems .…”

“…Lacosamide also exerts effects on slow inactivation in different types of neurons . Moreover, as seen for S‐Lic, lacosamide also shifts the voltage dependence of slow inactivation in a hyperpolarizing direction as a major effect, whereas other effects on slow inactivation were small . In contrast to those AEDs, the effects of CBZ on slow inactivation are virtually negligible, with well‐known pronounced effects on fast inactivation processes .…”

“…Epileptic rats were generated as described previously . Briefly, male Wistar rats (∼200 g) obtained from Charles River (Wilmington, MA, USA) were housed under a 12‐hour light/dark cycle and received food and water ad libitum.…”