Slow Sodium Channel Research Articles

Short Lysine-Containing Tripeptide as Analgesic Substance: The Possible Mechanism of Ligand–Receptor Binding to the Slow Sodium Channel

A possible molecular mechanism of the ligand–receptor binding of Ac-Lys-Lys-Lys-NH2 (Ac-KKK-NH2) to the NaV1.8 channel that is responsible for nociceptive signal coding in the peripheral nervous system is investigated by a number of experimental and theoretical techniques. Upon Ac-KKK-NH2 application at 100 nM, a significant decrease in the effective charge carried by the NaV1.8 channel activation gating system Zeff is demonstrated in the patch-clamp experiments. A strong Ac-KKK-NH2 analgesic effect at both the spinal and supraspinal levels is detected in vivo in the formalin test. The distances between the positively charged amino groups in the Ac-KKK-NH2 molecule upon binding to the NaV1.8 channel are 11–12 Å, as revealed by the conformational analysis. The blind docking with the NaV1.8 channel has made it possible to locate the Ac-KKK-NH2 binding site on the extracellular side of the voltage-sensing domain VSDI. The Ac-KKK-NH2 amino groups are shown to form ionic bonds with Asp151 and Glu157 and a hydrogen bond with Thr161, which affects the coordinated movement of the voltage sensor up and down, thus modulating the Zeff value. According to the results presented, Ac-KKK-NH2 is a promising candidate for the role of an analgesic medicinal substance that can be applied for pain relief in humans.

Favorable combinations of antiseizure medication with vagus nerve stimulation to improve health-related quality of life in patients with epilepsy

BackgroundVagus nerve stimulation (VNS) is a non-pharmacological treatment of refractory epilepsy, which also has an antidepressive effect. The favorable combinations of VNS with specific mechanisms of action of antiseizure medication (ASM) on mood and health-related quality of life (HrQol) have not yet been studied. The objective was to identify favourable combinations of specific ASMs with VNS for the HrQoL and depression in refractory epilepsy. MethodsWe performed an observational study including patients with refractory epilepsy and an implanted VNS (N = 151). In the first 24 months after VNS implantation, all patients were on stable ASM therapy. We used the standardized questionnaires QOLIE10, EQVAS and EQ5D to evaluate HrQoL as well as the Beck Depression Inventory (BDI). Multiple regression analysis was performed to evaluate the synergistic combinations of ASM with VNS for HrQoL. ResultsAt the year-two follow-up (N = 151, age 45.2 ± 17.0 years), significant improvement (p < 0.05) in BDI scores was found for combination of VNS with SV2A modulators (58.4 %) or AMPA antagonists (44.4 %). A significant increase of HrQoL by at least 30 % (p < 0.05) was measured for a combination of VNS with SV2A modulators (brivaracetam, levetiracetam) or slow sodium channel inhibitors (eslicarbazepine, lacosamide). ConclusionThe results of our study suggests a favorable effect of the combination of SV2A modulators or slow sodium channel inhibitors with VNS on the HrQoL in comparison to other ASMs. Besides the possible synergistic effects on the seizure frequency, the amelioration of behavioral side effects of SV2A modulators by VNS is an important factor of HrQoL-improvement in these combinations.

Synergistic effects of vagus nerve stimulation and antiseizure medication

IntroductionVagus nerve stimulation (VNS) is an effective, non-pharmacological therapy for epileptic seizures. Until now, favorable combinations of different groups of antiseizure medication (ASM) and VNS have not been sufficiently addressed. The aim of this study was to identify the synergistic effects between VNS and different ASMs.MethodsWe performed an observational study of patients with epilepsy who were implanted with VNS and had a stable ASM therapy during the first 2 years after the VNS implantation. Data were collected from the Mainz Epilepsy Registry. The efficacy of VNS depending on the concomitantly used ASM group/individual ASMs was assessed by quantifying the responder rate (≥ 50% seizure reduction compared to the time of VNS implantation) and seizure freedom (absence of seizures during the last 6 months of the observation period).ResultsOne hundred fifty one patients (mean age 45.2 ± 17.0 years, 78 females) were included in the study. Regardless of the used ASM, the responder rate in the whole cohort was 50.3% and the seizure freedom was 13.9%. Multiple regression analysis showed that combination of VNS with synaptic vesicle glycoprotein (SV2A) modulators (responder rate 64.0%, seizure freedom 19.8%) or slow sodium channel inhibitors (responder rate 61.8%, seizure freedom 19.7%) was associated with a statistically significant better responder rate and seizure freedom than combinations of VNS and ASM with other mechanism of action. Within these ASM groups, brivaracetam showed a more favorable effect than levetiracetam, whereas lacosamide and eslicarbazepine were comparable in their effects.ConclusionOur data suggest that the combination of VNS with ASMs belonging to either SV2A modulators or slow sodium channel inhibitors could be optimal to achieve a better seizure control following VNS. However, these preliminary data require further validation under controlled conditions.

Physiological role of slow sodium channels in primary sensory coding

Nav1.8 sodium channels of nociceptors participate in encoding signals generated by polymodal nociceptors and only the high-frequency component of this impulse response alerts the brain to tissue damage and provides information about the location and type of pain. Specific reduction of the functional activity of these channels should help in “switching off” this high-frequency component, hence, the possibility of retaining the normal functioning of polymodal mechanoreceptors, thermoreceptors, and chemoreceptors in case of chronic pain. From general medical practice, it is known that in the treatment of pain, there are no safe analgesics, the use of which as a long-term therapy would be completely safe. Mathematical modeling based on the Hodkgin and Nuxley formulation describing the flow of ionic currents was used to understand the mechanism of specific modulation of the functional activity of Nav1.8 channels and its role in primary sensory encoding of nociceptive information. This mechanism is based on a reduction in the potential sensitivity of these channels due to a decrease in the effective charge transferred by their activation gating structure. It is shown for the first time that this leads to a complete restoration of the normal function of the stimulus-response of the nociceptive neuron. At the same time, only the high-frequency component of its membrane response is specifically eliminated. The same effect can be achieved by reducing the density of slow sodium channels. However, it is obvious that in the second case, the action of pharmacological substances which are supposed to be called analgesics will be less specific since the interaction with other representatives of the superfamily of sodium channels might turn out to be feasible.

Physiological Role of Slow Sodium Channels in Primary Sensory Coding of Nociceptive Information

Physiological Role of Slow Sodium Channels in Primary Sensory Coding of Nociceptive Information

Role of the Guanidinium Groups in Ligand-Receptor Binding of Arginine-Containing Short Peptides to the Slow Sodium Channel: Quantitative Approach to Drug Design of Peptide Analgesics.

Several arginine-containing short peptides have been shown by the patch-clamp method to effectively modulate the NaV1.8 channel activation gating system, which makes them promising candidates for the role of a novel analgesic medicinal substance. As demonstrated by the organotypic tissue culture method, all active and inactive peptides studied do not trigger the downstream signaling cascades controlling neurite outgrowth and should not be expected to evoke adverse side effects on the tissue level upon their medicinal administration. The conformational analysis of Ac-RAR-NH2, Ac-RER-NH2, Ac-RAAR-NH2, Ac-REAR-NH2, Ac-RERR-NH2, Ac-REAAR-NH2, Ac-PRERRA-NH2, and Ac-PRARRA-NH2 has made it possible to find the structural parameter, the value of which is correlated with the target physiological effect of arginine-containing short peptides. The distances between the positively charged guanidinium groups of the arginine side chains involved in intermolecular ligand–receptor ion–ion bonds between the attacking peptide molecules and the NaV1.8 channel molecule should fall within a certain range, the lower threshold of which is estimated to be around 9 Å. The distance values have been calculated to be below 9 Å in the inactive peptide molecules, except for Ac-RER-NH2, and in the range of 9–12 Å in the active peptide molecules.

Arginine-Containing Tripeptides as Analgesic Substances: The Possible Mechanism of Ligand-Receptor Binding to the Slow Sodium Channel.

Two short arginine-containing tripeptides, H-Arg-Arg-Arg-OH (TP1) and Ac-Arg-Arg-Arg-NH2 (TP2), have been shown by the patch-clamp method to modulate the NaV1.8 channels of DRG primary sensory neurons, which are responsible for the generation of nociceptive signals. Conformational analysis of the tripeptides indicates that the key role in the ligand-receptor binding of TP1 and TP2 to the NaV1.8 channel is played by two positively charged guanidinium groups of the arginine side chains located at the characteristic distance of ~9 Å from each other. The tripeptide effect on the NaV1.8 channel activation gating device has been retained when the N- and C-terminal groups of TP1 were structurally modified to TP2 to protect the attacking peptide from proteolytic cleavage by exopeptidases during its delivery to the molecular target, the NaV1.8 channel. As demonstrated by the organotypic tissue culture method, the agents do not affect the DRG neurite growth, which makes it possible to expect the absence of adverse side effects at the tissue level upon administration of TP1 and TP2. The data obtained indicate that both tripeptides can have great therapeutic potential as novel analgesic medicinal substances.

Modulation of Voltage Sensitivity of Slow Sodium Channels by a Synthetic Cyclic Peptide

Modulation of Voltage Sensitivity of Slow Sodium Channels by a Synthetic Cyclic Peptide

The Role of Slow Sodium Channels in GABAergic and NOergic Modulation of Nociceptive Neuron Excitability

The Role of Slow Sodium Channels in GABAergic and NOergic Modulation of Nociceptive Neuron Excitability

A Possible Mechanism of Modulation of Slow Sodium Channels in the Sensory Neuron Membrane by Short Peptides

A Possible Mechanism of Modulation of Slow Sodium Channels in the Sensory Neuron Membrane by Short Peptides

Nonlinear Dynamics of Firing Activity Patterns of Nociceptive Neurons during Management of Damaging Pain Stimulation

A bifurcation analysis of a nociceptive neuron model was performed to study how the firing activity pattern changes when an antinociceptive response to damaging pain stimulation arises in rat dorsal ganglia. Ectopic train activity was found to arise in the model. Suppression of train activity was demonstrated to proceed solely through modification of the activation gating structure of the NaV1.8 slow sodium channel in response to comenic acid, which exerts an analgesic effect and is an active ingredient of the new nonopioid analgesic Anoceptin.

Нелинейная динамика паттернов импульсной активности ноцицептивных нейронов при коррекции повреждающего болевого воздействия

AbstractA bifurcation analysis of a nociceptive neuron model was performed to study how the firing activity pattern changes when an antinociceptive response to damaging pain stimulation arises in rat dorsal ganglia. Ectopic train activity was found to arise in the model. Suppression of train activity was demonstrated to proceed solely through modification of the activation gating structure of the Na _ V 1.8 slow sodium channel in response to comenic acid, which exerts an analgesic effect and is an active ingredient of the new nonopioid analgesic Anoceptin.

Abstract 519: Mitochondrial-mediated Oxidative CaMKII Activation Induces Early Afterdepolarizations in Guinea Pig Cardiomyocytes: An in Silico Study

Background: Oxidative stress-mediated CaMKII phosphorylation of cardiac ion channels has emerged as a critical contributor to arrhythmogenesis in cardiac pathology. However, the link between mitochondrial-derived reactive oxygen species (mdROS) and increased CaMKII activity in the context of cardiac arrhythmias has not been fully elucidated and is difficult to establish experimentally. Methods: We hypothesize that pathological mdROS can cause erratic action potentials through the oxidation-dependent CaMKII activation pathway. We further propose that CaMKII dependent phosphorylation of sarcolemmal slow sodium channels alone is sufficient to elicit early afterdepolarizations. To test the hypotheses, we expanded our well-established guinea pig cardiomyocyte e xcitation- c ontraction coupling, m itochondrial e nergetics and R OS- i nduced- R OS- r elease model by incorporating oxidative CaMKII activation and CaMKII-dependent Na + channel phosphorylation in silico . Results: Simulations show that mdROS mediated-CaMKII activation elicits early afterdepolarizations (EADs) by augmenting the late Na + currents ( I Na,L ), which can be suppressed by blocking L-type Ca 2+ channels or Na + /Ca 2+ exchangers. Interestingly, we found that oxidative CaMKII activation-induced EADs sustain even after mdROS has returned to its physiological levels. Moreover, mitochondrial-targeting antioxidant treatment can suppress the EADs, but only if given in an appropriate time window. Incorporating concurrent mdROS-induced RyRs activation further exacerbates the proarrhythmogenic effect of oxidative CaMKII activation. Conclusions: We conclude that oxidative CaMKII activation-dependent Na channel phosphorylation is a critical pathway in mitochondria mediated cardiac arrhythmogenesis.

Lacosamide protects striatal and hippocampal neurons from in vitro ischemia without altering physiological synaptic plasticity

Lacosamide ([(R)-2-acetamido-N-benzyl-3-methoxypropanamide], LCM), is an antiepileptic that exerts anticonvulsant activity by selectively enhancing slow sodium channel inactivation. By inhibiting seizures and neuronal excitability it might therefore be a good candidate to stabilize neurons and protect them from energetic insults. Using electrophysiological analyses, we have investigated in mice the possible neuroprotective effect of LCM against in vitro ischemia obtained by oxygen and glucose deprivation (ODG), in striatal and hippocampal tissues, two brain structures particularly susceptible to ischemic injury and of pivotal importance for different form of learning and memory. We also explored in these regions the influence of LCM on firing discharge and on long-term synaptic plasticity. We found that in both areas LCM reduced the neuronal firing activity in a use-dependent manner without influencing the physiological synaptic transmission, confirming its anticonvulsant effects. Moreover, we found that this AED is able to protect, in a dose dependent manner, striatal and hippocampal neurons from energy metabolism failure produced by OGD. This neuroprotective effect does not imply impairment of long-term potentiation of striatal and hippocampal synapses and suggests that LCM might exert additional beneficial therapeutic effects beyond its use as antiepileptic.

Modelling the impulse distribution, delay and block in the electrical conduction system of the heart bundles

In the article the excitatory irradiation in the electrical conduction system was numerically modeled. The overview of transmembrane potential of electrical conduction system was given. The Luo-Rudi model (2011) was chosen for the investigation. A finite element model of the electrical conduction system was built in which the latter was regarded as a one-dimensional sequence of cells connected at the edges. Based on the elaborated model one of the mechanisms of a bundle branch block was investigated. A Y-shaped structure which models the move from the common trunk of the bundle of His to the bundle branches was investigated. The results show that depending on the conductivity of certain parts of the electrical conduction system of the heart three regimes might occur: excitation advancing through branching, complete block or excitation advancing with delay. Conductivity Value Domains for the common trunk of the bundle of His and the bundle branches in which each of the regimes occurs were obtained. The role of quick and slow sodium channels when the regime with delay occurs is considered

Na+-H+ exchanger and proton channel in heart failure associated with Becker and Duchenne muscular dystrophies.

Cardiomyopathy is found in patients with Duchenne (DMD) and Becker (BMD) muscular dystrophies, which are linked muscle diseases caused by mutations in the dystrophin gene. Dystrophin defects are not limited to DMD but are also present in mild BMD. The hereditary cardiomyopathic hamster of the UM-X7.1 strain is a particular experimental model of heart failure (HF) leading to early death in muscular dystrophy (dystrophin deficiency and sarcoglycan mutation) and heart disease (δ-sarcoglycan deficiency and dystrophin mutation) in human DMD. Using this model, our previous work showed a defect in intracellular sodium homeostasis before the appearance of any apparent biochemical and histological defects. This was attributed to the continual presence of the fetal slow sodium channel, which was also found to be active in human DMD. Due to muscular intracellular acidosis, the intracellular sodium overload in DMD and BMD was also due to sodium influx through the sodium-hydrogen exchanger NHE-1. Lifetime treatment with an NHE-1 inhibitor prevented intracellular Na+ overload and early death due to HF. Our previous work also showed that another proton transporter, the voltage-gated proton channel (Hv1), exists in many cell types including heart cells and skeletal muscle fibers. The Hv1 could be indirectly implicated in the beneficial effect of blocking NHE-1.

Possible mechanism of bursting suppression in nociceptive neurons.

The use of the mathematical model of rat nociceptive neuron membrane allowed us to predict a new mechanism of suppression of ectopic bursting discharges, which arise in neurons of dorsal root ganglia and are one of the causes of neuropathic pain. The treatment with comenic acid leads to switching off the ectopic bursting discharges due to a decrease in the effective charge transferring via the activation gating structure of the slow sodium channels (Na V1.8a). Comenic acid is a drug substance of a new non-opioid analgesic [1] Thus, this analgesic not only reduces the frequency of rhythmic discharges of nociceptive neuron membrane [2] but also it suppresses its ectopic bursting discharges.

Possible molecular effect related to the reception of low-intensity IR radiation: Role of Src-kinase

The patch-clamp technique has been used to demonstrate that low-intensity IR irradiation affects the effective charge of the activation gating system of slow sodium channels in the nociceptive neuron membrane. IR photons are absorbed by ATP molecules bound to Na+,K+-ATPase at their hydrolysis site. Na+,K+-ATPase is a transducer of signal that is further delivered to slow sodium channels and cell genome. It is demonstrated that the irradiation does not modulate the response of a sensory neuron in the presence of PP2, an inhibitor of Src-kinase. The results show that Src-kinase is a series unit involved in the intracellular cascade processes triggered by low-intensity radiation of CO2 laser.

Ab initio conformational analysis of marinobufagenin molecule and molecular targets of the action of cardiotonic steroids

Complete conformational analysis of marinobufagenin molecule was fulfilled by ab initio calculations. The comparison of results obtained with analogous calculations of ouabain and ouabagenin molecules made it possible to understand the effect of decrease in the effective charge on the voltage-gated slow sodium channels Nav1.8 experimentally detected by the local fixation of potential. A mechanism is suggested of the interaction between the mentioned cardiotonic steroids with the membrane of the sensor neuron.

Application of bifurcation analysis for determining the mechanism of coding of nociceptive signals

The patch clamp method is used for studying the characteristics of slow sodium channels responsible for coding of nociceptive signals. Quantitative estimates of rate constants of transitions of “normal” and pharmacologically modified activation gating mechanisms of these channels are obtained. A mathematical model of the type of Hogdkin–Huxley nociceptive neuron membrane is constructed. Cometic acid, which is a drug substance of a new nonopioid analgesic, is used as a pharmacological agent. The application of bifurcation analysis makes it possible to outline the boundaries of the region in which a periodic impulse activity is generated. This boundary separates the set of values of the model parameter for which periodic pulsation is observed from the values for which such pulsations are absent or damped. The results show that the finest effect of modulation of physical characteristic of a part of a protein molecule and its effective charge suppresses the excitability of the nociceptive neuron membrane and, hence, leads to rapid reduction of pain.