A Possible Explanation for a Neurotoxic Effect of the Anticancer Agent Oxaliplatin on Neuronal Voltage-Gated Sodium Channels

2001 ◽  
Vol 85 (5) ◽  
pp. 2293-2297 ◽  
Author(s):  
Françoise Grolleau ◽  
Laurence Gamelin ◽  
Michèle Boisdron-Celle ◽  
Bruno Lapied ◽  
Marcel Pelhate ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Calcium Ions ◽  
Periplaneta Americana ◽  
Sodium Current ◽  
Current Amplitude ◽  
Patch Clamp Technique ◽  
Electrophysiological Properties ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Whole Cell Patch Clamp

Oxaliplatin, a new widely used anticancer drug, displays frequent, sometimes severe, acute sensory neurotoxicity accompanied by neuromuscular signs that look like the symptoms observed in tetany and myotonia. The whole cell patch-clamp technique was employed to investigate the oxaliplatin effects on the electrophysiological properties of short-term cultured dorsal unpaired median (DUM) neurons isolated from the CNS of the cockroach Periplaneta americana. Within the clinical concentration range, oxaliplatin (40–500 μM), applied intracellularly, decreased the amplitude of the voltage-gated sodium current resulting in a reduction of half the amplitude of the action potential. For comparison, two other platinum derivatives, cisplatin and carboplatin, were found to be ineffective at reducing the sodium current amplitude. In addition, we compared the oxaliplatin action to those of its metabolites dichloro-diaminocyclohexane platinum (dach-Cl2-platin) and oxalate. Oxalate (500 μM) was found to be effective, like oxaliplatin, at reducing the inward sodium current amplitude, whereas dach-Cl2-platin (500 μM) failed to change the current amplitude. Interestingly, the effect of oxalate or oxaliplatin could be mimicked by using intracellularly applied 10 mM bis-( o-aminophenoxy)- N,N,N′,N′-tetraacetic acid (BAPTA), known as chelator of calcium ions. We concluded that oxaliplatin was capable of altering the voltage-gated sodium channels through a pathway involving calcium ions probably immobilized by its metabolite oxalate. The medical interest of preventing acute neurotoxic side effects of oxaliplatin by infusing Ca2+ and Mg2+ is discussed.

scholarly journals Block of Voltage-Gated Sodium Channels by Atomoxetine in a State- and Use-dependent Manner

2021 ◽  
Vol 12 ◽  
Author(s):  
Karl Josef Föhr ◽  
Ariadni Nastos ◽  
Michael Fauler ◽  
Thomas Zimmer ◽  
Bettina Jungwirth ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Heart Muscle ◽  
Brain Regions ◽  
Clinical Effects ◽  
Dependent Manner ◽  
Patch Clamp Technique ◽  
Human Embryonic Kidney Cells ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Slow Kinetics

Atomoxetine, a neuroactive drug, is approved for the treatment of attention-deficit/hyperactivity disorder (ADHD). It is primarily known as a high affinity blocker of the noradrenaline transporter, whereby its application leads to an increased level of the corresponding neurotransmitter in different brain regions. However, the concentrations used to obtain clinical effects are much higher than those which are required to block the transporter system. Thus, off-target effects are likely to occur. In this way, we previously identified atomoxetine as blocker of NMDA receptors. As many psychotropic drugs give rise to sudden death of cardiac origin, we now tested the hypothesis whether atomoxetine also interacts with voltage-gated sodium channels of heart muscle type in clinically relevant concentrations. Electrophysiological experiments were performed by means of the patch-clamp technique at human heart muscle sodium channels (hNav1.5) heterogeneously expressed in human embryonic kidney cells. Atomoxetine inhibited sodium channels in a state- and use-dependent manner. Atomoxetine had only a weak affinity for the resting state of the hNav1.5 (Kr: ∼ 120 µM). The efficacy of atomoxetine strongly increased with membrane depolarization, indicating that the inactivated state is an important target. A hallmark of this drug was its slow interaction. By use of different experimental settings, we concluded that the interaction occurs with the slow inactivated state as well as by slow kinetics with the fast-inactivated state. Half-maximal effective concentrations (2–3 µM) were well within the concentration range found in plasma of treated patients. Atomoxetine also interacted with the open channel. However, the interaction was not fast enough to accelerate the time constant of fast inactivation. Nevertheless, when using the inactivation-deficient hNav1.5_I408W_L409C_A410W mutant, we found that the persistent late current was blocked half maximal at about 3 µM atomoxetine. The interaction most probably occurred via the local anesthetic binding site. Atomoxetine inhibited sodium channels at a similar concentration as it is used for the treatment of ADHD. Due to its slow interaction and by inhibiting the late current, it potentially exerts antiarrhythmic properties.

scholarly journals Effect of Oxaliplatin on Voltage-Gated Sodium Channels in Peripheral Neuropathic Pain

Processes ◽  
2020 ◽  
Vol 8 (6) ◽  
pp. 680 ◽  
Author(s):  
Woojin Kim
Keyword(s):  
Neuropathic Pain ◽  
Action Potential ◽  
Sodium Channels ◽  
Sodium Current ◽  
Voltage Response ◽  
Treatment Schedule ◽  
Voltage Gated ◽  
Peripheral Neurons ◽  
Voltage Gated Sodium Channels ◽  
Current Voltage

Oxaliplatin is a chemotherapeutic drug widely used to treat various types of tumors. However, it can induce a serious peripheral neuropathy characterized by cold and mechanical allodynia that can even disrupt the treatment schedule. Since the approval of the agent, many laboratories, including ours, have focused their research on finding a drug or method to decrease this side effect. However, to date no drug that can effectively reduce the pain without causing any adverse events has been developed, and the mechanism of the action of oxaliplatin is not clearly understood. On the dorsal root ganglia (DRG) sensory neurons, oxaliplatin is reported to modify their functions, such as the propagation of the action potential and induction of neuropathic pain. Voltage-gated sodium channels in the DRG neurons are important, as they play a major role in the excitability of the cell by initiating the action potential. Thus, in this small review, eight studies that investigated the effect of oxaliplatin on sodium channels of peripheral neurons have been included. Its effects on the duration of the action potential, peak of the sodium current, voltage–response relationship, inactivation current, and sensitivity to tetrodotoxin (TTX) are discussed.

Effects of lactate on the voltage-gated sodium channels of rat skeletal muscle: modulating current opinion

2012 ◽  
Vol 112 (9) ◽  
pp. 1454-1465 ◽  
Author(s):  
F. Rannou ◽  
R. Leschiera ◽  
M. A. Giroux-Metges ◽  
J. P. Pennec
Keyword(s):  
Skeletal Muscle ◽  
Sodium Current ◽  
Lactate Production ◽  
Petri Dish ◽  
Potential Effect ◽  
Muscle Physiology ◽  
Membrane Area ◽  
Electrophysiological Properties ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels

During muscle contraction, lactate production and translocation across the membrane increase. While it has recently been shown that lactate anion acts on chloride channel, less is known regarding a potential effect on the voltage-gated sodium channel (Nav) of skeletal muscle. The electrophysiological properties of muscle Nav were studied in the absence and presence of lactate (10 mM) by using the macropatch-clamp method in dissociated fibers from rat peroneus longus (PL). Lactate in the external medium (petri dish + pipette) increases the maximal sodium current, while the voltage dependence of activation and fast inactivation are shifted toward the hyperpolarized potentials. Lactate induces a leftward shift in the relationship between the kinetic parameters and the imposed potentials, resulting in an earlier recruitment of muscle Nav. In addition, lactate significantly decreases the time constant of activation at voltages more negative than −10 mV, corresponding to an acceleration of Nav activation. The slow inactivation process is decreased by lactate, corresponding to an enhancement in the number of excitable Nav. In an additional series of experiments, lactate (10 mM) was only added to the petri dish, while the pipette remained sealed on the membrane area. With this approach, the electrophysiological properties of Nav were unaffected by lactate compared with the control condition. Altogether, these data indicate that lactate modulates muscle Nav properties by an extracellular pathway. These effects are consistent with an enhancement in excitability, providing new insights into the role of lactate in muscle physiology.

Voltage gating of ion channels

1994 ◽  
Vol 27 (1) ◽  
pp. 1-40 ◽  
Author(s):  
F. J. Sigworth
Keyword(s):  
Ion Channels ◽  
Action Potential ◽  
Sodium Channels ◽  
Calcium Ions ◽  
Neurotransmitter Release ◽  
Voltage Gating ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Voltage Gated Sodium Channels ◽  
Voltage Gated Ion Channels

Voltage-gated ion channels are membrane proteins that play a central role in the propagation and transduction of cellular signals (Hille, 1992). Calcium ions entering cells through voltage-gated calcium channels serve as the trigger for neurotransmitter release, muscle contraction, and the release of hormones. Voltage-gated sodium channels initiate the nerve action potential and provide for its rapid propagation because the ion fluxes through these channels regeneratively cause more channels to open.

scholarly journals Neurosteroids Allopregnanolone Sulfate and Pregnanolone Sulfate Have Diverse Effect on the α Subunit of the Neuronal Voltage-gated Sodium Channels Nav1.2, Nav1.6, Nav1.7, and Nav1.8 Expressed in Xenopus Oocytes

2014 ◽  
Vol 121 (3) ◽  
pp. 620-631 ◽  
Author(s):  
Takafumi Horishita ◽  
Nobuyuki Yanagihara ◽  
Susumu Ueno ◽  
Yuka Sudo ◽  
Yasuhito Uezono ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Xenopus Oocytes ◽  
Sodium Current ◽  
Dependent Manner ◽  
Sodium Currents ◽  
Concentration Dependent Manner ◽  
Α Subunit ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Α Subunits

Abstract Background: The neurosteroids allopregnanolone and pregnanolone are potent positive modulators of γ-aminobutyric acid type A receptors. Antinociceptive effects of allopregnanolone have attracted much attention because recent reports have indicated the potential of allopregnanolone as a therapeutic agent for refractory pain. However, the analgesic mechanisms of allopregnanolone are still unclear. Voltage-gated sodium channels (Nav) are thought to play important roles in inflammatory and neuropathic pain, but there have been few investigations on the effects of allopregnanolone on sodium channels. Methods: Using voltage-clamp techniques, the effects of allopregnanolone sulfate (APAS) and pregnanolone sulfate (PAS) on sodium current were examined in Xenopus oocytes expressing Nav1.2, Nav1.6, Nav1.7, and Nav1.8 α subunits. Results: APAS suppressed sodium currents of Nav1.2, Nav1.6, and Nav1.7 at a holding potential causing half-maximal current in a concentration-dependent manner, whereas it markedly enhanced sodium current of Nav1.8 at a holding potential causing maximal current. Half-maximal inhibitory concentration values for Nav1.2, Nav1.6, and Nav1.7 were 12 ± 4 (n = 6), 41 ± 2 (n = 7), and 131 ± 15 (n = 5) μmol/l (mean ± SEM), respectively. The effects of PAS were lower than those of APAS. From gating analysis, two compounds increased inactivation of all α subunits, while they showed different actions on activation of each α subunit. Moreover, two compounds showed a use-dependent block on Nav1.2, Nav1.6, and Nav1.7. Conclusion: APAS and PAS have diverse effects on sodium currents in oocytes expressing four α subunits. APAS inhibited the sodium currents of Nav1.2 most strongly.

scholarly journals Block of Voltage-Gated Sodium Channels as a Potential Novel Anti-cancer Mechanism of TIC10

2021 ◽  
Vol 12 ◽  
Author(s):  
Eva Fuchs ◽  
David Alexander Christian Messerer ◽  
Georg Karpel-Massler ◽  
Michael Fauler ◽  
Thomas Zimmer ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Sodium Channels ◽  
Tumor Therapy ◽  
Kinetic Studies ◽  
Dependent Manner ◽  
Patch Clamp Technique ◽  
Voltage Gated ◽  
Beneficial Effects ◽  
Voltage Gated Sodium Channels ◽  
Anti Cancer

Background: Tumor therapeutics are aimed to affect tumor cells selectively while sparing healthy ones. For this purpose, a huge variety of different drugs are in use. Recently, also blockers of voltage-gated sodium channels (VGSCs) have been recognized to possess potentially beneficial effects in tumor therapy. As these channels are a frequent target of numerous drugs, we hypothesized that currently used tumor therapeutics might have the potential to block VGSCs in addition to their classical anti-cancer activity. In the present work, we have analyzed the imipridone TIC10, which belongs to a novel class of anti-cancer compounds, for its potency to interact with VGSCs.Methods: Electrophysiological experiments were performed by means of the patch-clamp technique using heterologously expressed human heart muscle sodium channels (hNav1.5), which are among the most common subtypes of VGSCs occurring in tumor cells.Results: TIC10 angular inhibited the hNav1.5 channel in a state- but not use-dependent manner. The affinity for the resting state was weak with an extrapolated Kr of about 600 μM. TIC10 most probably did not interact with fast inactivation. In protocols for slow inactivation, a half-maximal inhibition occurred around 2 µM. This observation was confirmed by kinetic studies indicating that the interaction occurred with a slow time constant. Furthermore, TIC10 also interacted with the open channel with an affinity of approximately 4 µM. The binding site for local anesthetics or a closely related site is suggested as a possible target as the affinity for the well-characterized F1760K mutant was reduced more than 20-fold compared to wild type. Among the analyzed derivatives, ONC212 was similarly effective as TIC10 angular, while TIC10 linear more selectively interacted with the different states.Conclusion: The inhibition of VGSCs at low micromolar concentrations might add to the anti-tumor properties of TIC10.

Postnatal Changes in the Inactivation Properties of Voltage-Gated Sodium Channels Contribute to the Mature Firing Pattern of Spinal Motoneurons

2008 ◽  
Vol 99 (6) ◽  
pp. 2864-2876 ◽  
Author(s):  
K. P. Carlin ◽  
J. Liu ◽  
L. M. Jordan
Keyword(s):  
Sodium Channels ◽  
Firing Pattern ◽  
Sodium Current ◽  
Age Groups ◽  
Force Production ◽  
Postnatal Period ◽  
Spinal Motoneurons ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Age Related

Most mammals are born with the necessary spinal circuitry to produce a locomotor-like pattern of neural activity. However, rodents seldom demonstrate weight-supported locomotor behavior until the second or third postnatal week, possibly due to the inability of the neuromuscular system to produce sufficient force during this early postnatal period. As spinal motoneurons mature they are seen to fire an increasing number of action potentials at an increasing rate, which is a necessary component of greater force production. The mechanisms responsible for this enhanced ability of motoneurons are not completely defined. In the present study we assessed the biophysical properties of the developing voltage-gated sodium current to determine their role in the maturing firing pattern. Using dissociated postnatal lumbar motoneurons in short-term culture (18–24 h) we demonstrate that currents recorded from the most mature postnatal age group (P10–P12) were significantly better able to maintain channels in an available state during repetitive stimulation than were the younger age groups (P1–P3, P4–P6, P7–P9). This ability correlated with the ability of channels to recover more quickly and more completely from an inactivated state. These age-related differences were seen in the absence of changes in the voltage dependence of channel gating. Differences in both closed-state inactivation and slow inactivation were also noted between the age groups. The results indicate that changes in the inactivation properties of voltage-gated sodium channels are important for the development of a mature firing pattern in spinal motoneurons.

scholarly journals N58A Exerts Analgesic Effect on Trigeminal Neuralgia by Regulating the MAPK Pathway and Tetrodotoxin-Resistant Sodium Channel

Toxins ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 357
Author(s):  
Chun-Li Li ◽  
Ran Yang ◽  
Yang Sun ◽  
Yuan Feng ◽  
Yong-Bo Song
Keyword(s):  
Trigeminal Neuralgia ◽  
Sodium Channels ◽  
Analgesic Effect ◽  
Mapk Pathway ◽  
Dependent Manner ◽  
Patch Clamp Technique ◽  
Inactivation Curve ◽  
Thermal Pain ◽  
Voltage Gated Sodium Channels ◽  
Whole Cell Patch Clamp

The primary studies have shown that scorpion analgesic peptide N58A has a significant effect on voltage-gated sodium channels (VGSCs) and plays an important role in neuropathic pain. The purpose of this study was to investigate the analgesic effect of N58A on trigeminal neuralgia (TN) and its possible mechanism. The results showed that N58A could significantly increase the threshold of mechanical pain and thermal pain and inhibit the spontaneous asymmetric scratching behavior of rats. Western blotting results showed that N58A could significantly reduce the protein phosphorylation level of ERK1/2, P38, JNK, and ERK5/CREB pathways and the expression of Nav1.8 and Nav1.9 proteins in a dose-dependent manner. The changes in current and kinetic characteristics of Nav1.8 and Nav1.9 channels in TG neurons were detected by the whole-cell patch clamp technique. The results showed that N58A significantly decreased the current density of Nav1.8 and Nav1.9 in model rats, and shifted the activation curve to hyperpolarization and the inactivation curve to depolarization. In conclusion, the analgesic effect of N58A on the chronic constriction injury of the infraorbital (IoN-CCI) model rats may be closely related to the regulation of the MAPK pathway and Nav1.8 and Nav1.9 sodium channels.

Sign in / Sign up

Export Citation Format

Share Document