Topiramate (TPM), a sulfamate-substituted monosaccharide, is a broad-spectrum anticonvulsant widely prescribed for epilepsy, migraine prophylaxis, and neuropathic pain. Its therapeutic efficacy stems from multifaceted interactions with ion channels, neurotransmitter receptors, and enzymes; however, the precise mechanisms governing its modulation of plasmalemmal ionic currents—particularly voltage-gated sodium currents (I_Na) and hyperpolarization-activated cation currents (I_h)—remain incompletely characterized. Prior studies have implicated TPM in sodium channel blockade, yet inconsistencies persist regarding concentration-dependent effects, gating kinetics, and interactions with other currents. This study employs patch-clamp techniques in GH₃ rat lactotrophs, an established model for excitable cells, to provide comprehensive evidence of TPM’s “dual block” on I_Na and I_h, elucidating potential contributions to its neuromodulatory profile.
Whole-cell patch-clamp recordings were performed on GH₃ cells cultured under standard conditions. Transient (I_Na(T)) and late (I_Na(L)) sodium currents were elicited by depolarizing voltage steps from a holding potential of -80 mV. Steady-state inactivation and current-voltage relationships were assessed via protocols with varying prepulses and ramps. I_h was activated by hyperpolarizing steps to -120 mV. Hysteresis was evaluated using double triangular ramp waveforms. TPM was bath-applied at concentrations ranging from 1–30 μM, with reversibility tested using flumazenil (1 μM), chlorotoxin (200 nM), and oxaliplatin (10 μM). Current-clamp mode recorded spontaneous action potentials. Data were analyzed with ANOVA and fitted to Boltzmann or exponential functions, with significance at p < 0.05.
TPM induced a concentration-dependent inhibition of I_Na, reducing peak I_Na(T) by 25% at 3 μM and 60% at 30 μM (IC₅₀ ≈ 10 μM), while selectively suppressing I_Na(L) at low doses (1 μM) without affecting I_Na(T). The steady-state inactivation curve of I_Na(T) shifted leftward by -8 mV (V₁/₂ from -52 to -60 mV), with no change in slope factor or gating charge, preserving the I-V relationship. Blockade persisted post-washout and was insensitive to flumazenil or chlorotoxin. For I_h, TPM decreased current density by 40% at 10 μM, prolonging activation τ from 150 to 250 ms, and reduced hysteresis area under ramp protocols by 35%, an effect partially reversed (20%) by oxaliplatin. In current-clamp, TPM (10 μM) abolished spontaneous firing within 5 min, hyperpolarizing the membrane by -5 mV.
These findings demonstrate TPM’s dual, non-overlapping blockade of I_Na and I_h, altering gating and hysteresis to dampen excitability. Such mechanisms likely underpin TPM’s antiepileptic and analgesic actions, with implications for optimizing dosing in clinical settings. Future studies should explore isoform specificity in neurons.
Link: https://link.springer.com/article/10.1186/s40360-025-01043-6
