Concerted suppressive effects of carisbamate, an anti-epileptic alkyl-carbamate drug, on voltage-gated Na+ and hyperpolarization-activated cation currents

Te-Yu Hung; Sheng-Nan Wu; Chin-Wei Huang

doi:10.3389/fncel.2023.1159067

Concerted suppressive effects of carisbamate, an anti-epileptic alkyl-carbamate drug, on voltage-gated Na⁺ and hyperpolarization-activated cation currents

Front Cell Neurosci. 2023 May 24:17:1159067. doi: 10.3389/fncel.2023.1159067. eCollection 2023.

Authors

Te-Yu Hung¹, Sheng-Nan Wu^{2

3

4}, Chin-Wei Huang⁵

Affiliations

¹ Department of Pediatrics, Chi Mei Medical Center, Tainan, Taiwan.
² Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
³ College of Medicine, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan.
⁴ School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung City, Taiwan.
⁵ Department of Neurology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Abstract

Carisbamate (CRS, RWJ-333369) is a new anti-seizure medication. It remains unclear whether and how CRS can perturb the magnitude and/or gating kinetics of membrane ionic currents, despite a few reports demonstrating its ability to suppress voltage-gated Na⁺ currents. In this study, we observed a set of whole-cell current recordings and found that CRS effectively suppressed the voltage-gated Na⁺ (I_Na) and hyperpolarization-activated cation currents (I_h) intrinsically in electrically excitable cells (GH₃ cells). The effective IC₅₀ values of CRS for the differential suppression of transient (I_Na(T)) and late I_Na (I_Na(L)) were 56.4 and 11.4 μM, respectively. However, CRS strongly decreased the strength (i.e., Δarea) of the nonlinear window component of I_Na (I_Na(W)), which was activated by a short ascending ramp voltage (V_ramp); the subsequent addition of deltamethrin (DLT, 10 μM) counteracted the ability of CRS (100 μM, continuous exposure) to suppress I_Na(W). CRS strikingly decreased the decay time constant of I_Na(T) evoked during pulse train stimulation; however, the addition of telmisartan (10 μM) effectively attenuated the CRS (30 μM, continuous exposure)-mediated decrease in the decay time constant of the current. During continued exposure to deltamethrin (10 μM), known to be a pyrethroid insecticide, the addition of CRS resulted in differential suppression of the amplitudes of I_Na(T) and I_Na(L). The amplitude of I_h activated by a 2-s membrane hyperpolarization was diminished by CRS in a concentration-dependent manner, with an IC₅₀ value of 38 μM. For I_h, CRS altered the steady-state I-V relationship and attenuated the strength of voltage-dependent hysteresis (Hys_(V)) activated by an inverted isosceles-triangular V_ramp. Moreover, the addition of oxaliplatin effectively reversed the CRS-mediated suppression of Hys_(V). The predicted docking interaction between CRS and with a model of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel or between CRS and the hNa_V1.7 channel reflects the ability of CRS to bind to amino acid residues in HCN or hNa_V1.7 channel via hydrogen bonds and hydrophobic interactions. These findings reveal the propensity of CRS to modify I_Na(T) and I_Na(L) differentially and to effectively suppress the magnitude of I_h. I_Na and I_h are thus potential targets of the actions of CRS in terms of modulating cellular excitability.

Keywords: antiepileptic drug; carisbamate (RWJ-333369); current kinetics; hyperpolarization-activated cation current; late Na+ current; voltage-gated Na+ current; window Na+ current.

Grants and funding

This research described in this manuscript was partly supported by grants from the National Science and Technology Council (MOST-111-2320-B-006-028, MOST-110-2314-B-006-056, and 111-2314-B-006-103-MY2) and National Cheng Kung University Hospital (NCKUH-11201005). The funders of this research were not involved in the study design, data collection, analyses, or interpretation.