(725): Lacosamide has a dual mode of action: Selective enhancement of sodium channel slow inactivation

Abstract

Lacosamide is a functionalized amino acid which showed analgesic and anticonvulsant effects in a variety of animal models. This analgesic activity 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. Lacosamide bound to collapsin response mediator protein 2 (CRMP-2, see corresponding poster) and displayed low binding affinity to binding site 2 of the sodium ion channel. The aim of the present experiments was to assess the effect of lacosamide on Na-currents in detailed electrophysiological studies. 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 to remove Na-channel fast inactivation, whereas inhibition by carbamazepine (CBZ), phenytoin (PHT) and lamotrigine (LTG) was almost completely abolished by this hyperpolarizing prepulse. Lacosamide did not influence the steady state fast inactivation curve. In contrast, CBZ, PHT and LTG shifted this curve to more hyperpolarized potentials. Lacosamide shifted the availability curve of steady state slow inactivation to more negative potentials and increased the number of slow inactivated Na-channels. In neuroblastoma cells it enhanced entry of Na-channels into slow inactivation without influencing recovery from slow inactivation or Na-channel activation. Enhanced slow inactivation by lacosamide was also detected in TTX-resistant Na-channels of rat dorsal root ganglia in vitro. When compared to the fast inactivation Na-channel modifier lamotrigine in animal models of neuropathic pain, lacosamide showed clear antinociceptive effects under conditions where lamotrigine was without effect. Since slow inactivation of Na-channels is an endogenous mechanism by which neurons reduce stimulated or ectopic hyperactivity, this modulation represents one molecular mechanism involved in the pharmacological activity of lacosamide. In summary, these experiments (see also corresponding abstract) demonstrate a dual mode of action for lacosamide.