Voltage gated sodium channels and epilepsy

Year 2019, Cilt 11 Supp 1 (BRS), 7 - 7, 21.06.2019

Simon Hebeısen

https://doi.org/10.37212/jcnos.584668

Abstract

Epilepsy is the fourth most common neurological disorder and affects people of all ages. Medication for epilepsy is often life-long and has a major impact on the quality of life - mostly being related to substantial adverse effects. Therefore, over 30% of people with epilepsy do not achieve sufficient seizure control whilst effective medication being available.  Ion channels are often primary targets of anticonvulsant drugs. They can either act as blockers for voltage gated sodium and calcium channels or as activators for potassium or chloride channels. Additionally, modulators of ligand gated ion channels (GABA or Glutamate receptors) are frequently used to treat epilepsy.  Employing a panel of functional electrophysiological assays using fluorescence based methods and patch-clamping on a broad range of voltage and ligand gated ion channels, we were able to successfully screen for drugs with a beneficial action profile. In successful leads we found drugs that selectively interacted with TTX sensitive, neuronal voltage gated sodium channels. Activation and fast inactivation were unchanged, while an increased affinity in the slow inactivated state was observed. This profile is in contrast to traditional anticonvulsant drugs which show their major effects on the fast inactivated state of voltage gated sodium channels. One drug showed substantial shifts of the voltage dependence of the slow inactivation only for NaV1.2 and 1.6. This favours this drug for treating patients with diseases with compromised NaV1.1 function in interneurons, such as Alzheimer's disease.

Keywords

Voltage gated sodium channel, Epilepsy, state dependent inactivation, Patch-clamp

References

• 1: Faleschini MT, Maier A, Fankhauser S, Thasis K, Hebeisen S, Hamburger M, Butterweck V. A FLIPR Assay for Discovery of GABAA Receptor Modulators of Natural Origin. Planta Med. 2019 May 24. doi: 10.1055/a-0921-7602. [Epub ahead of print]
• 2: Holtkamp D, Opitz T, Hebeisen S, Soares-da-Silva P, Beck H. Effects of eslicarbazepine on slow inactivation processes of sodium channels in dentate gyrus granule cells. Epilepsia. 2018;59(8):1492-1506.