Response to Letter to the Editor: Reversal by Ranolazine of Doxorubicin-Induced Prolongation in the Inactivation of Late Sodium Current in Rat Dorsal Root Ganglion Neurons

Gould, Harry J.

doi:10.1111/pme.12730

Cited by 1 publication

(1 citation statement)

References 6 publications

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“…It needs to be emphasized that ranolazine, an inhibitor of I Na(L) , has been demonstrated to be of benefit for peripheral or diabetic neuropathy [ 56 , 57 , 58 , 59 ]. This drug has also been revealed to have modifications on changes in peripheral nerve excitability [ 24 , 57 , 58 , 60 , 61 , 62 ]. As a corollary, it is tempting to anticipate that MGB-mediated alleviation of painful sensation could be partly, if not entirely, attributable to the inhibitory action on different types of I Na .…”

Section: Discussionmentioning

confidence: 99%

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

Chuang

Cho

et al. 2022

IJMS

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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.

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