The Evidence for Effective Inhibition of INa Produced by Mirogabalin ((1R,5S,6S)-6-(aminomethyl)-3-ethyl-bicyclo [3.2.0] hept-3-ene-6-acetic acid), a Known Blocker of CaV Channels

Abstract

Mirogabalin (MGB, Tarlige®), an inhibitor of the α2δ-1 subunit of voltage-gated Ca2+ (CaV) channels, is used as a way to alleviate peripheral neuropathic pain and diabetic neuropathy. However, to what extent MGB modifies the magnitude, gating, and/or hysteresis of various types of plasmalemmal ionic currents remains largely unexplored. In pituitary tumor (GH3) cells, we found that MGB was effective at suppressing the peak (transient, INa(T)) and sustained (late, INa(L)) components of the voltage-gated Na+ current (INa) in a concentration-dependent manner, with an effective IC50 of 19.5 and 7.3 μM, respectively, while the KD value calculated on the basis of minimum reaction scheme was 8.2 μM. The recovery of INa(T) inactivation slowed in the presence of MGB, although the overall current–voltage relation of INa(T) was unaltered; however, there was a leftward shift in the inactivation curve of the current. The magnitude of the window (INa(W)) or resurgent INa (INa(R)) evoked by the respective ascending or descending ramp pulse (Vramp) was reduced during cell exposure to MGB. MGB-induced attenuation in INa(W) or INa(R) was reversed by the further addition of tefluthrin, a pyrethroid insecticide known to stimulate INa. MGB also effectively lessened the strength of voltage-dependent hysteresis of persistent INa in response to the isosceles triangular Vramp. The cumulative inhibition of INa(T), evoked by pulse train stimulation, was enhanced in its presence. Taken together, in addition to the inhibition of CaV channels, the NaV channel attenuation produced by MGB might have an impact in its analgesic effects occurring in vivo.

Characterization in Inhibitory Effectiveness of Carbamazepine in Voltage-Gated Na+ and Erg-Mediated K+ Currents in a Mouse Neural Crest-Derived (Neuro-2a) Cell Line

“…The presence of instantaneous I Na(W) evoked in response to the upsloping (or ascending) ramp voltage (V ramp ) was demonstrated earlier in different types of electrically excitable cells [ 48 , 50 ]. We next continued to explore whether the CBZ existence could modify the magnitude of I Na(W) evoked by rapid ascending V ramp .…”

“…With Neuro-2a cell exposure to 1 μM, the amplitude of I Na measured at the beginning of the short depolarizing pulse decreased from 813 ± 23 to 52 ± 4 pA (n = 8, t value = 3.7, p < 0.01). It was hence identified as a TTX-sensitive voltage-gated Na + current (I Na ) [ 38 , 40 , 42 , 43 , 44 , 45 , 48 , 49 ].…”

“…In the continued presence of 30 μM CBZ, subsequent addition of tefluthrin (10 μM, Tef) attenuated CBZ-mediated decrease of ∆area, as demonstrated by an increase of ∆area value to 5.41 ± 0.86 mV·nA (n = 8; t value = 3.2; p < 0.05). Tef has been shown to be an activator of I Na [ 43 , 44 , 45 , 48 ].…”

“…The background Na + currents have been growingly demonstrated in different types of excitable cells [ 37 , 43 , 51 , 52 , 53 , 54 , 55 ]. Earlier investigations have also shown the effectiveness of voltage-dependent hysteresis (Hys (V) ) of I Na(P) in modifying electrical behaviors in many types of excitable cells [ 48 , 49 ]. Therefore, we wanted to determine whether and how CBZ could modify the strength of I Na(P) ’s Hys (V) activated by an upright isosceles-triangular V ramp .…”

“…The I Na(T) inactivation could be accumulated during repetitive short pulses [ 48 , 56 , 57 , 58 ]. Thus, additional measurements were taken to see whether CBZ could modify the inactivation process of I Na(T) evoked in a train of depolarizing stimuli.…”