Abstracts

Rationale: Lacosamide is a functionalized amino acid which showed analgesic and anticonvulsant effects in a large variety of animal models. Lacosamide is currently being evaluated in Phase III clinical trials. Lacosamide did not bind with significant affinity to any of more than 100 receptors, enzymes, transporters or ion-channels tested, except for collapsin response mediator protein 2 (see corresponding abstract) and showed a low binding affinity to binding site 2 of the sodium channel. The aim of the present experiments was to assess the potential effects of lacosamide on Na-currents.Methods: Patch-clamp electrophysiology studies were performed in isolated neuronal cells in order to determine the influence of lacosamide on fast and slow inactivation of voltage-gated sodium channels (VGSCs).Results: In neuroblastoma cells held at a potential of -60 mV lacosamide inhibited Na-current by about 30%. This inhibition was not affected by a prepulse to -100 mV that removes Na-channel fast inactivation. Carbamazepine, phenytoin and lamotrigine produced a similar inhibition at -60mV but in contrast to lacosamide this inhibition was almost completely abolished by the hyperpolarizing prepulse. Lacosamide did not influence the steady state fast inactivation curve but shifted the availability curve of steady state slow inactivation to more negative potentials and increased the number of slow inactivated Na-channels. When compared to the fast inactivation Na-channel modifier lamotrigine in animal models of epilepsy and neuropathic pain lacosamide showed clear effects under conditions where lamotrigine was without effect. Conclusions: Lacosamide is the only anticonvulsant drug that reduces VGSC availability by selective enhancement of slow inactivation but without any apparent interaction with fast inactivation gating. Slow inactivation of Na-channels is an endogenous mechanism by which neurons reduce stimulated or ectopic hyperactivity. Enhancement of slow inactivation thus represents an effective mechanism to selectively reduce pathophysiological activity without major influence on physiological activity. Together with the findings that CRMP-2 is a molecular target of lacosamide (see corresponding abstract), these results suggest that lacosamide has a dual and novel mode of action.