Positive Modulation of Human Nav Channels by Pyrethroids

Abstract

Voltage-gated sodium channels (Nav) are crucial to the initiation and propagation of action potentials in electrically excitable cells. Inhibitors of such ion channels have been developed and approved as drugs to treat a variety of indications. In contrast, sodium channel activators have not been considered relevant and safe in a therapeutic setting because of their high risk of toxicity and side effects. Nevertheless, there is a recent interest in activators of e.g. Nav1.1 (SCN1A) for the treatment of neurological indications, i.e. that selective positive modulation of the Nav1.1 sodium channel may hold therapeutic potential for epilepsy, schizophrenia, and Alzheimer's disease (Jensen et al., 2014). Research aimed at the identification of novel, selective Nav positive modulators, however, appears to be hampered by a deficit in suitable tool compounds with certain modulating features to initiate and validate screening assays. Although sodium channel modifying pyrethroids have been in use as important pest management tools in agriculture, public health, and a variety of household applications, their action on human Nav has not been studied in detail. Therefore we tested a set of Type 1 pyrethroids that have been described to have positive modulatory effects on insect and rodent sodium channels. Utilizing the Syncropatch 96 automated patch clamp system we were able to identify several pyrethroids activating human Nav 1.1 and/or Nav1.5. Confirmation and characterization by manual patch-clamp revealed pyrethroids with different types of positive modulation. Both, compounds acting via a delay of the inactivation time constant (similar to those published recently by Crestey et al., 2015) as well as such promoting a sustained channel opening (Veratridine-like) were identified for Nav1.1 and Nav1.5, respectively.