# Dual block evidence of the effects of topiramate, a sulfamate-substituted monosaccharide, on voltage-gated sodium current and hyperpolarization-activated cation current

## TL;DR

This study investigates how topiramate affects sodium and cation currents in excitable cells, revealing its dual inhibitory effects.

## Contribution

The study provides new evidence on TPM's dual block of voltage-gated sodium and hyperpolarization-activated cation currents in GH3 lactotrophs.

## Key findings

- TPM inhibits both transient and late components of voltage-gated sodium current in a concentration-dependent manner.
- TPM suppresses hyperpolarization-activated cation current and alters its activation time course.
- TPM-induced changes in ionic currents are not fully reversible by flumazenil or chlorotoxin.

## Abstract

Topiramate (TPM) is a sulfamate-substituted monosaccharide known for its wide-ranging effects on epilepsy, neuropathic pain, and migraines. However, its precise influence on plasmalemmal ionic currents, including their magnitude and gating kinetics, remains uncertain. Therefore, a reassessment of the regulatory effect of TPM on ionic currents in electrically excitable cells is warranted.

With the aid of patch clamp technology, we investigated the effects of TPM on the amplitude, gating, and hysteresis of plasmalemmal ionic currents from GH3 lactotrophs.

We observed that TPM exhibited a concentration-dependent inhibition of both transient (INa(T)) and late (INa(L)) components of INa, activated by brief depolarizing stimuli. At low concentration, TPM did not show any noticeable effect on INa(T); however, it was effective in reducing INa(L) amplitude. TPM caused a leftward shift in the midpoint of the steady-state inactivation curve of INa(T) without altering the gating charge. Importantly, the overall current density versus voltage relationship of INa(T) remained unaltered during TPM exposure. Intriguingly, the reduction in INa(T) induced by TPM could not be reversed by subsequent additions of flumazenil or chlorotoxin. Furthermore, TPM suppressed the density of the hyperpolarization-activated cation current (Ih). Simultaneously, the activation time course of Ih slowed in the presence of TPM. Moreover, TPM exposure decreased the hysteretic strength activated by double triangular ramp voltage, a change partially reversed by oxaliplatin. In current-clamp potential recordings, spontaneous action potentials were susceptible to suppression in the presence of TPM.

Collectively, these findings strongly suggest that TPM’s effects on INa and Ih have the potential to impact the functional activities and electrical behaviors of excitable cells.