Therapeutic potential of Na(V)1.1 activators

Abstract

Sodium channel inhibitors have been developed and approved as drugs to treat a variety of indications. By contrast, sodium channel activators have not previously been considered relevant in a therapeutic setting owing to their high risk of toxicity and side effects. Here we present an opinion that selective activators of the Na(V)1.1 sodium channel may hold therapeutic potential for diseases such as epilepsy, schizophrenia, and Alzheimer's disease. Central to this novel avenue of sodium channel drug discovery is that fact that Na(V)1.1 comprises the majority of the sodium current in specific inhibitory interneurons. Conversely, it plays only a modest role in excitatory neurons owing to the high redundancy of other types of sodium channels in these cells. We discuss the biological background and rationale and present reflections on how to identify activators of Na(V)1.1.

Keywords: SCN1A mutations; cognition; connectivity; epilepsy; interneurons; oscillations; schizophrenia.