Abstract
BACKGROUND: 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. METHODS: With the aid of patch clamp technology, we investigated the effects of TPM on the amplitude, gating, and hysteresis of plasmalemmal ionic currents from GH(3) lactotrophs. RESULTS: We observed that TPM exhibited a concentration-dependent inhibition of both transient (I(Na(T))) and late (I(Na(L))) components of I(Na), activated by brief depolarizing stimuli. At low concentration, TPM did not show any noticeable effect on I(Na(T)); however, it was effective in reducing I(Na(L)) amplitude. TPM caused a leftward shift in the midpoint of the steady-state inactivation curve of I(Na(T)) without altering the gating charge. Importantly, the overall current density versus voltage relationship of I(Na(T)) remained unaltered during TPM exposure. Intriguingly, the reduction in I(Na(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 (I(h)). Simultaneously, the activation time course of I(h) 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. CONCLUSIONS: Collectively, these findings strongly suggest that TPM's effects on I(Na) and I(h) have the potential to impact the functional activities and electrical behaviors of excitable cells.