RESUMEN

Phenobarbital (PHB, Luminal Sodium®) is a medication of the barbiturate and has long been recognized to be an anticonvulsant and a hypnotic because it can facilitate synaptic inhibition in the central nervous system through acting on the γ-aminobutyric acid (GABA) type A (GABAA) receptors. However, to what extent PHB could directly perturb the magnitude and gating of different plasmalemmal ionic currents is not thoroughly explored. In neuroblastoma Neuro-2a cells, we found that PHB effectively suppressed the magnitude of voltage-gated Na+ current (INa) in a concentration-dependent fashion, with an effective IC50 value of 83 µM. The cumulative inhibition of INa, evoked by pulse train stimulation, was enhanced by PHB. However, tefluthrin, an activator of INa, could attenuate PHB-induced reduction in the decaying time constant of INa inhibition evoked by pulse train stimuli. In addition, the erg (ether-à-go-go-related gene)-mediated K+ current (IK(erg)) was also blocked by PHB. The PHB-mediated inhibition on IK(erg) could not be overcome by flumazenil (GABA antagonist) or chlorotoxin (chloride channel blocker). The PHB reduced the recovery of IK(erg) by a two-step voltage protocol with a geometrics-based progression, but it increased the decaying rate of IK(erg), evoked by the envelope-of-tail method. About the M-type K+ currents (IK(M)), PHB caused a reduction of its amplitude, which could not be counteracted by flumazenil or chlorotoxin, and PHB could enhance its cumulative inhibition during pulse train stimulation. Moreover, the magnitude of delayed-rectifier K+ current (IK(DR)) was inhibited by PHB, while the cumulative inhibition of IK(DR) during 10 s of repetitive stimulation was enhanced. Multiple ionic currents during pulse train stimulation were subject to PHB, and neither GABA antagonist nor chloride channel blocker could counteract these PHB-induced reductions. It suggests that these actions might conceivably participate in different functional activities of excitable cells and be independent of GABAA receptors.

RESUMEN

Carbamazepine (CBZ, Tegretol®) is an anticonvulsant used in the treatment of epilepsy and neuropathic pain; however, several unwanted effects of this drug have been noticed. Therefore, the regulatory actions of CBZ on ionic currents in electrically excitable cells need to be reappraised, although its efficacy in suppressing voltage-gated Na+ current (INa) has been disclosed. This study was undertaken to explore the modifications produced by CBZ on ionic currents (e.g., INa and erg-mediated K+ current [IK(erg)]) measured from Neuro-2a (N2a) cells. In these cells, we found that this drug differentially suppressed the peak (transient, INa(T)) and sustained (late, INa(L)) components of INa in a concentration-dependent manner with effective IC50 of 56 and 18 µM, respectively. The overall current-voltage relationship of INa(T) with or without the addition of CBZ remained unchanged; however, the strength (i.e., ∆area) in the window component of INa (INa(W)) evoked by the short ascending ramp pulse (Vramp) was overly lessened in the CBZ presence. Tefluthrin (Tef), a synthetic pyrethroid, known to stimulate INa, augmented the strength of the voltage-dependent hysteresis (Hys(V)) of persistent INa (INa(P)) in response to the isosceles-triangular Vramp; moreover, further application of CBZ attenuated Tef-mediated accentuation of INa(P)'s Hys(V). With a two-step voltage protocol, the recovery of INa(T) inactivation seen in Neuro-2a cells became progressively slowed by adding CBZ; however, the cumulative inhibition of INa(T) evoked by pulse train stimulation was enhanced during exposure to this drug. Neuro-2a-cell exposure to CBZ (100 µM), the magnitude of erg-mediated K+ current measured throughout the entire voltage-clamp steps applied was mildly inhibited. The docking results regarding the interaction of CBZ and voltage-gate Na+ (NaV) channel predicted the ability of CBZ to bind to some amino-acid residues in NaV due to the existence of a hydrogen bond or hydrophobic contact. It is conceivable from the current investigations that the INa (INa(T), INa(L), INa(W), and INa(P)) residing in Neuro-2a cells are susceptible to being suppressed by CBZ, and that its block on INa(L) is larger than that on INa(T). Collectively, the magnitude and gating of NaV channels produced by the CBZ presence might have an impact on its anticonvulsant and analgesic effects occurring in vivo.

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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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OBJECTIVE: To assess the PTS method in neuromonitoring of thoracic pedicle screws in a young cohort of AIS patients. The accuracy of both PTS (Pulse-train stimulation) and SPS (Single-pulse stimulation) techniques in the detection of misplaced thoracic screws was compared with special reference to the screws placed at the concavity and the convexity of the curve. PATIENTS AND METHODS: A single-center prospective clinical cohort study. LEVEL OF EVIDENCE II: Twelve AIS patients who underwent elective surgery were included in this study. Screw stimulation using repetitive constant-current stimulus train of variable intensities was first performed after screw insertion. SPS was performed immediately after PTS. Postoperatively, CT scan was used to check the final position of the screws. A total of 246 thoracic pedicle screws were placed. Thresholds of screws placed in the convexity and the concavity were compared. RESULTS: Invasion of the spinal canal was postoperatively confirmed in 29 of the pedicle screws. The SPS technique detected three (10.3%) of these screws using a threshold limit of 12 mA. The PTS technique detected 25 (86.2%) of the 29 misplaced screws using threshold of 30 mA (negative predictive value, 93.1%). When using a PTS threshold of < 20 mA, the positive predictive value was 70%. SPS did not detect any of the misplaced screws at the apex level of the scoliotic curves, and PTS detected 10 out of 17 of these screws. Overall, area under the ROC curve was 0.82 for PTS and 0.61 for SPS. CONCLUSIONS: PTS is a reliable method for detecting medially misplaced screws among young AIS patients undergoing scoliosis surgery. PTS provides more accurate predictions than SPS and improves the identification of screws invading the spinal canal at the apex or near the apex levels.

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