Sodium Channel Slow Inactivation Research Articles

A Reinterpretation of the Relationship between Persistent and Resurgent Sodium Currents.

The resurgent sodium current (INaR) activates on membrane repolarization, such as during the downstroke of neuronal action potentials. Due to its unique activation properties, INaR is thought to drive high rates of repetitive neuronal firing. However, INaR is often studied in combination with the persistent or noninactivating portion of sodium currents (INaP). We used dynamic clamp to test how INaR and INaP individually affect repetitive firing in adult cerebellar Purkinje neurons from male and female mice. We learned INaR does not scale repetitive firing rates due to its rapid decay at subthreshold voltages and that subthreshold INaP is critical in regulating neuronal firing rate. Adjustments to the voltage-gated sodium conductance model used in these studies revealed INaP and INaR can be inversely scaled by adjusting occupancy in the slow-inactivated kinetic state. Together with additional dynamic clamp experiments, these data suggest the regulation of sodium channel slow inactivation can fine-tune INaP and Purkinje neuron repetitive firing rates.

A Reinterpretation of the Relationship Between Persistent and Resurgent Sodium Currents.

The resurgent sodium current (INaR) activates on membrane repolarization, such as during the downstroke of neuronal action potentials. Due to its unique activation properties, INaR is thought to drive high rates of repetitive neuronal firing. However, INaR is often studied in combination with the persistent or non-inactivating portion of sodium currents (INaP). We used dynamic clamp to test how INaR and INaP individually affect repetitive firing in adult cerebellar Purkinje neurons from male and female mice. We learned INaR does not scale repetitive firing rates due to its rapid decay at subthreshold voltages, and that subthreshold INaP is critical in regulating neuronal firing rate. Adjustments to the Nav conductance model used in these studies revealed INaP and INaR can be inversely scaled by adjusting occupancy in the slow inactivated kinetic state. Together with additional dynamic clamp experiments, these data suggest the regulation of sodium channel slow inactivation can fine-tune INaP and Purkinje neuron repetitive firing rates.

Structural mechanism of voltage-gated sodium channel slow inactivation

Voltage-gated sodium (NaV) channels mediate a plethora of electrical activities. NaV channels govern cellular excitability in response to depolarizing stimuli. Inactivation is an intrinsic property of NaV channels that regulates cellular excitability by controlling the channel availability. The fast inactivation, mediated by the Ile-Phe-Met (IFM) motif and the N-terminal helix (N-helix), has been well-characterized. However, the molecular mechanism underlying NaV channel slow inactivation remains elusive. Here, we demonstrate that the removal of the N-helix of NaVEh (NaVEhΔN) results in a slow-inactivated channel, and present cryo-EM structure of NaVEhΔN in a potential slow-inactivated state. The structure features a closed activation gate and a dilated selectivity filter (SF), indicating that the upper SF and the inner gate could serve as a gate for slow inactivation. In comparison to the NaVEh structure, NaVEhΔN undergoes marked conformational shifts on the intracellular side. Together, our results provide important mechanistic insights into NaV channel slow inactivation.

Efficacy of Lacosamide and Rufinamide as Adjuncts to Midazolam-Ketamine Treatment Against Cholinergic-Induced Status Epilepticus in Rats.

Benzodiazepine pharmacoresistance develops when treatment of status epilepticus (SE) is delayed. This response may result from gamma-aminobutyric acid A receptors (GABAAR) internalization that follows prolonged SE; this receptor trafficking results in fewer GABAAR in the synapse to restore inhibition. Increase in synaptic N-methyl-D-aspartate receptors (NMDAR) also occurs in rodent models of SE. Lacosamide, a third-generation antiseizure medication (ASM), acts on the slow inactivation of voltage-gated sodium channels. Another ASM, rufinamide, similarly acts on sodium channels by extending the duration of time spent in the inactivation stage. Combination therapy of the benzodiazepine midazolam, NMDAR antagonist ketamine, and ASMs lacosamide (or rufinamide) was investigated for efficacy against soman (GD)-induced SE and neuropathology. Adult male rats implanted with telemetry transmitters for monitoring electroencephalographic (EEG) activity were exposed to a seizure-inducing dose of GD and treated with an admix of atropine sulfate and HI-6 1 minute later and with midazolam monotherapy or combination therapy 40 minutes after EEG seizure onset. Rats were monitored continuously for seizure activity for two weeks, after which brains were processed for assessment of neurodegeneration, neuronal loss, and neuroinflammatory responses. Simultaneous administration of midazolam, ketamine, and lacosamide (or rufinamide) was more protective against GD-induced SE compared with midazolam monotherapy. In general, lacosamide triple therapy had more positive outcomes on measures of epileptogenesis, EEG power integral, and the number of brain regions protected from neuropathology compared with rats treated with rufinamide triple therapy. Overall, both drugs were well tolerated in these combination models. SIGNIFICANCE STATEMENT: We currently report on improved efficacy of antiseizure medications lacosamide and rufinamide, each administered in combination with ketamine (NMDAR antagonist) and midazolam (benzodiazepine), in combatting soman (GD)-induced seizure, epileptogenesis, and brain pathology over that provided by midazolam monotherapy, or dual therapy of midazolam and lacosamide (or rufinamide) in rats. Administration of lacosamide as adjunct to midazolam and ketamine was particularly effective against GD-induced toxicity. However, protection was incomplete, suggesting the need for further study.

Third-Generation Antiseizure Medication in the Treatment of Benzodiazepine-Refractory Status Epilepticus in Poststroke Epilepsy: A Retrospective Observational Register-Based Study.

Status epilepticus in poststroke epilepsy is a challenging condition because of multiple vascular comorbidities and the advanced age of patients. Data on third-generation antiseizure medication (ASM) in this condition are limited. The aim of this study was to evaluate the efficacy of third-generation ASMs in the second- or third-line therapy of benzodiazepine-refractory status epilepticus in poststroke epilepsy following acute ischemic stroke. Data on the effectiveness of third-generation ASMs in patients with status epilepticus in poststroke epilepsy were gathered from two German Stroke Registries and the Mainz Epilepsy Registry. We included only cases with epilepsy remote to the ischemic event. No patients with acute symptomatic seizures were included. The following third-generation ASMs were included: brivaracetam, lacosamide, eslicarbazepine, perampanel, topiramate, and zonisamide. The assessment of effectiveness was based on seizure freedom within 48 h since the start of therapy with the respective ASM. Seizure freedom was evaluated both clinically (clinical evaluation at least three times per day) and by daily electroencephalogram records. Of the 138 patients aged 70.8 ± 8.1 years with benzodiazepine-refractory status epilepticus in ischemic poststroke epilepsy, 33 (23.9%) were treated with lacosamide, 24 (17.4%) with brivaracetam, 23 (16.7%) with eslicarbazepine, 21 (15.2%) with perampanel, 20 (14.5%) with topiramate, and 17 (12.3%) with zonisamide. Seizure freedom within 48 h was achieved in 66.7% of patients with lacosamide, 65.2% with eslicarbazepine, 38.1% with perampanel, 37.5% with brivaracetam, 35.0% with topiramate, and 35.3% with zonisamide (p < 0.05 for comparison of lacosamide or eslicarbazepine to other ASMs). Based on these data, lacosamide and eslicarbazepine might be more favorable in the treatment of refractory status epilepticus in poststroke epilepsy, when administered as second- or third-line ASMs before anesthesia. Because of the fact that these ASMs share the same mechanism of action (slow inactivation of sodium channels), our findings could motivate further research on the role that this pharmaceutical mechanism of action has in the treatment of poststroke epilepsy. This study was registered at ClinicalTrials.gov (NCT05267405).

Anticonvulsant effects of cenobamate in chemically and electrically induced seizure models in rodents

BackgroundCenobamate is an antiseizure medication used to treat partial-onset (focal) seizures. It is a molecule with one chiral center and a unique dual mechanism of action: enhancement of fast and slow inactivation of sodium channels with preferential inhibition of the persistent current and positive allosteric modulation of GABAA receptor-mediated ion channels. Aims/MethodsAnticonvulsant effects of cenobamate (YKP3089; R-enantiomer), YKP3090 (S-enantiomer), and YKP1983 (racemate) were evaluated in chemically and electrically induced focal and generalized seizure models in rodents. The Genetic Absence Epilepsy Rat from Strasbourg (GAERS) model examined the effect of cenobamate on spike-wave seizures. Motor coordination was assessed with rotarod tests and minimal motor impairment exams. ResultsEarly in development, cenobamate was found to have activity in focal and generalized seizure models in animals and was selected for continued development. Cenobamate prevented seizures in a dose-dependent manner, prevented seizure spread, and increased seizure threshold without potentiating seizure initiation or the development of tolerance to its anticonvulsant effects. In contrast, YKP3090 and YKP1983 were only effective against generalized tonic-clonic seizures. Cenobamate also protected mice from 6 Hz psychomotor-induced seizures. Cenobamate showed significant dose-dependent reductions in the number and cumulative duration of spike-and-wave discharges in the GAERS model. DiscussionCenobamate showed efficacy or efficacy signals in all animal models of epilepsy tested with a favorable risk-versus-benefit ratio, supporting its clinical use in the treatment of partial-onset (focal) seizures in adults and warranting further clinical research in generalized seizures and absence seizures.

Sodium channel slow inactivation normalizes firing in axons with uneven conductance distributions

The Na+ channels that are important for action potentials show rapid inactivation, a state in which they do not conduct, although the membrane potential remains depolarized.1,2 Rapid inactivation is a determinant of millisecond-scale phenomena, such as spike shape and refractory period. Na+ channels also inactivate orders of magnitude more slowly, and this slow inactivation has impacts on excitability over much longer timescales than those of a single spike or a single inter-spike interval.3,4,5,6,7,8,9,10 Here, we focus on the contribution of slow inactivation to the resilience of axonal excitability11,12 when ion channels are unevenly distributed along the axon. We study models in which the voltage-gated Na+ and K+ channels are unevenly distributed along axons with different variances, capturing the heterogeneity that biological axons display.13,14 In the absence of slow inactivation, many conductance distributions result in spontaneous tonic activity. Faithful axonal propagation is achieved with the introduction of Na+ channel slow inactivation. This "normalization" effect depends on relations between the kinetics of slow inactivation and the firing frequency. Consequently, neurons with characteristically different firing frequencies will need to implement different sets of channel properties to achieve resilience. The results of this study demonstrate the importance of the intrinsic biophysical properties of ion channels in normalizing axonal function.

Depolarization block in olfactory sensory neurons expands the dimensionality of odor encoding.

Upon strong and prolonged excitation, neurons can undergo a silent state called depolarization block that is often associated with disorders such as epileptic seizures. Here, we show that neurons in the peripheral olfactory system undergo depolarization block as part of their normal physiological function. Typically, olfactory sensory neurons enter depolarization block at odor concentrations three orders of magnitude above their detection threshold, thereby defining receptive fields over concentration bands. The silencing of high-affinity olfactory sensory neurons produces sparser peripheral odor representations at high-odor concentrations, which might facilitate perceptual discrimination. Using a conductance-based model of the olfactory transduction cascade paired with spike generation, we provide numerical and experimental evidence that depolarization block arises from the slow inactivation of sodium channels-a process that could affect a variety of sensory neurons. The existence of ethologically relevant depolarization block in olfactory sensory neurons creates an additional dimension that expands the peripheral encoding of odors.

Efficacy and safety of antiseizure medication in post-stroke epilepsy

BackgroundSpecific antiseizure medications (ASM) would improve the outcome in post-stroke epilepsy (PSE). The aim of this multicenter observational study was to compare different antiseizure monotherapies in PSE. MethodsWe collected the data from 207 patients with PSE who did not change their initial antiseizure monotherapy during the period of 12 months. Efficacy was assessed by a standardized three month seizure frequency and seizure freedom. Safety was estimated by the reported side effects. ResultsThe mean three month seizure frequency was 1.9 ± 3.1 on eslicarbazepine, 2.1 ± 3.2 on lacosamide, 3.4 ± 4.4 on levetiracetam, 4.3 ± 6.8 on lamotrigine, and 5.1 ± 7.3 on valproate (p < 0.05 for eslicarbazepine or lacosamide in comparison with levetiracetam, lamotrigine and valproate, respectively). The lowest seizure frequency and the highest seizure freedom was observed on ASMs acting via the slow inactivation of sodium channels in comparison to other mechanisms of action (0.7 ± 0.9 vs 2.2 ± 2.4, p < 0.01). Among side effects, the most frequently reported were vertigo (25%) and tiredness (15.9%). They were similar in all investigated groups of ASM. The independent factors increasing seizure frequency that were identified in multiple regression analyses were increased size of infarction, cortical involvement, hemorrhagic transformation, neurological deficits at admission and functional impairment. Administration of ASM with the mechanism of action via the slow inactivation of sodium channels was an independent factor decreasing the seizure frequency. ConclusionOur data show that antiseizure medications acting via the slow inactivation of sodium channels, such as lacosamide and eslicarbazepine, are well tolerated and might be associated with better seizure control in PSE.

Slow Inactivation of Sodium Channels Contributes to Short-Term Adaptation in Vomeronasal Sensory Neurons.

Adaptation plays an important role in sensory systems as it dynamically modifies sensitivity to allow the detection of stimulus changes. The vomeronasal system controls many social behaviors in most mammals by detecting pheromones released by conspecifics. Stimuli activate a transduction cascade in vomeronasal neurons that leads to spiking activity. Whether and how these neurons adapt to stimuli is still debated and largely unknown. Here, we measured short-term adaptation performing current-clamp whole-cell recordings by using diluted urine as a stimulus, as it contains many pheromones. We measured spike frequency adaptation in response to repeated identical stimuli of 2–10 s duration that was dependent on the time interval between stimuli. Responses to paired current steps, bypassing the signal transduction cascade, also showed spike frequency adaptation. We found that voltage-gated Na+ channels in VSNs undergo slow inactivation processes. Furthermore, recovery from slow inactivation of voltage-gated Na+ channels occurs in several seconds, a time scale similar to that measured during paired-pulse adaptation protocols, suggesting that it partially contributes to short-term spike frequency adaptation. We conclude that vomeronasal neurons do exhibit a time-dependent short-term spike frequency adaptation to repeated natural stimuli and that slow inactivation of Na+ channels contributes to this form of adaptation. These findings not only increase our knowledge about adaptation in the vomeronasal system, but also raise the question of whether slow inactivation of Na+ channels may play a role in other sensory systems.

The effect of chronic treatment with sodium channel blocker lacosamide on early development of absence seizures in genetic absence epilepsy rats

ObjectiveLacosamide (LCM) is a new generation antiepileptic drug that affects the slow inactivation of voltage-gated sodium channels. We studied whether chronic LCM treatment prior to onset of absence seizures was able to prevent/reduce the development of absence seizures in GAERS rats, a well-validated animal model of absence epilepsy and epileptogenesis. Drug effects on the duration, mean duration, number and spectral characteristics of spike-wave discharges (SWDs) were measured both 1 and 2 months after treatment withdrawal and compared with the ethosuximide (ETX) that has anti-epileptogenic activity in GAERS. Furthermore, the acute effects of LCM on SWDs in adult GAERS were evaluated. MethodsGAERS rats were administered either with LCM (10 mg/kg/day or 30 mg/kg/day, i.p) or ETX (25 mg/kg/day, i.p) or saline (%0.9 NaCl) until PN60 for 40 consecutive days starting from PN20. Animals were stereotaxically implanted with cortical screw electrodes under ketamine/xylazine anesthesia at PN53. Following recovery period, EEG were recorded at PN60 (last day of drug administration)− 61–62, PN90–91–92 and PN120–121–122 time periods for 3 consecutive days. ResultsThe chronic treatment with both LCM and ETX led to an ∼50% reduction in the development of spontaneous absence seizures in GAERS at PN90 and PN120 after the treatment withdrawal at PN60. The spectral analysis of EEG data revealed significant slowing of the peak frequency of SWDs in LCM treated animals at PN62. ConclusionThese results confirm that chronic LCM treatment modifies the development of absence seizures in GAERS and suggest that LCM exerts beneficial effects on absence seizure epileptogenesis.

Lacosamide-Related Arrhythmias: A Systematic Analysis and Review of the Literature.

Lacosamide (LCM) is a new antiepileptic drug used as an adjunctive treatment for partial seizures with and without secondary generalization. One of the modes of action is the enhancement of slow inactivation of voltage-gated sodium channels. Experimental studies and clinical trials suggest that LCM acts upon both neurons and the heart and may increase the risk of cardiac arrhythmias. A systematic review was conducted to investigate characteristics of arrhythmias related to the use of LCM for the treatment of seizures. The search terms “lacosamide”, “arrhythmias”, “AV block”, “atrial fibrillations/flutter”, “cardiac conductions defects”, “ventricular tachycardia”, “ventricular fibrillation were used. Case reports and retrospective studies were gathered by searching Medline/PubMed, Google Scholar, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Cochrane CENTRAL (Cochrane Central Register of Controlled Trials), and Web of Science databases. Seventeen articles were selected for review. Ventricular tachycardia was the most reported LCM related arrhythmia (29.4%), followed by new-onset atrial fibrillation (17.6%), complete heart block (17.6%), Mobitz type 1 Atrio-ventricular block (11.8%), sinus pauses (11.8%), pulseless electrical activity (5.9%) and widening QRS complex (5.9%). Further research and clinical trials are needed to explore the etiopathogenesis and causative relationship between the use of LCM and arrhythmias.

The insecticide deltamethrin enhances sodium channel slow inactivation of human Nav1.9, Nav1.8 and Nav1.7

The insecticide deltamethrin of the pyrethroid class mainly targets voltage-gated sodium channels (Navs). Deltamethrin prolongs the opening of Navs by slowing down fast inactivation and deactivation. Pyrethroids are supposedly safe for humans, however, they have also been linked to the gulf-war syndrome, a neuropathic pain condition that can develop following exposure to certain chemicals. Inherited neuropathic pain conditions have been linked to mutations in the Nav subtypes Nav1.7, Nav1.8, and Nav1.9. Here, we examined the effect of deltamethrin on the human isoforms Nav1.7, Nav1.8, and Nav1.9_C4 (chimera containing the C-terminus of rat Nav1.4) heterologously expressed in HEK293T and ND7/23 cells using whole-cell patch-clamp electrophysiology. For all three Nav subtypes, we observed increased persistent and tail currents that are typical for Nav channels modified by deltamethrin. The most surprising finding was an enhanced slow inactivation induced by deltamethrin in all three Nav subtypes. An enhanced slow inactivation is contrary to the prolonged opening caused by pyrethroids and has not been described for deltamethrin or any other pyrethroid before. Furthermore, we found that the fraction of deltamethrin-modified channels increased use-dependently. However, for Nav1.8, the use-dependent potentiation occurred only when the holding potential was increased to −90 mV, a potential at which the tail currents decay more slowly. This indicates that use-dependent modification is due to an accumulation of tail currents. In summary, our findings support a novel mechanism whereby deltamethrin enhances slow inactivation of voltage-gated sodium channels, which may, depending on the cellular resting membrane potential, reduce neuronal excitability and counteract the well-described pyrethroid effects of prolonging channel opening.

Autonomic functions in focal epilepsy: A comparison between lacosamide and carbamazepine monotherapy

ObjectiveSome antiepileptic drugs (AEDs), like sodium channel blockers are significantly associated with autonomic dysfunction in patients with epilepsy. Unlike other sodium-blockers AEDs, lacosamide (LCM) is a third generation AEDs which enhances the slow inactivation of voltage-gated sodium channels. So far, data about LCM on autonomic nervous system are still unknown. This study was designed to investigate cardiovascular autonomic and sudomotor function in patients affected by focal epilepsy on LCM monotherapy, compared to patients treated with carbamazepine (CBZ) monotherapy and healthy subjects. MethodsPatients on LCM underwent autonomic function tests including head up tilt test (HUTT), Valsalva maneuver, deep breathing, hand grip, and cold face. Heart rate variability (HRV) analysis was performed in rest condition and during HUTT. Sudomotor function was assessed through Sudoscan. All results were compared with patients on carbamazepine (CBZ) monotherapy and with healthy subjects. ResultsFourteen patients on LCM monotherapy, 12 patients on CBZ monotherapy and 16 healthy controls were studied. At cardiovascular function tests, delta systolic blood pressure (∆SBP) at 3 min of HUTT and ∆SBP early phase II-late phase II at Valsalva maneuver were significantly lower in CBZ group compared to LCM patients. Spectral analysis of HRV showed no significant differences among LCM, CBZ and control groups. No difference in sudomotor function was found in all three groups. ConclusionsIn conclusion, our findings suggest that LCM and CBZ on monotherapy do not affect autonomic cardiovascular and sudomotor functions compared to controls. Nevertheless, patients on CBZ showed a lower sympathetic reactivity with respect to LCM.

Role of Lacosamide in Preventing Pentylenetetrazole Kindling-Induced Alterations in the Expression of the Gamma-2 Subunit of the GABAA Receptor in Rats.

Epilepsy remains challenging to treat still no etiologic treatment has been identified, however, some antiepileptic drugs (AEDs) are able to modify the pathogenesis of the disease. Lacosamide (LCM) has been shown to possess complex anticonvulsant and neuroprotective actions, being an enhancer of the slow inactivation of voltage-gated sodium channels, and it has the potential to prevent epileptogenesis. Recent evidence has shown that LCM indirectly improves the function of GABAA receptors. Receptors at most GABAergic synapses involve the gamma-2 subunit, which contributes to both phasic and tonic inhibition, and its presence assures benzodiazepine sensitivity. Moreover, mutant gamma-2 subunits were associated with generalized epilepsy syndromes. In animal models, the expression of the gamma-2 subunit of the gamma-aminobutyric acid A receptor (GABAAg2) was shown to be increased in pentylenetetrazole (PTZ)-induced chemical kindling in Wistar rats. This study hypothesized that LCM might affect the kindling process by influencing the expression of GABAA receptors in the hippocampus. The gene and protein expression levels of the GABAAg2 were studied using RT-qPCR and immunofluorescent staining. It was found that LCM treatment (10 mg/kg i.p. daily for 57 days) reduced the maximal intensity of the PTZ-induced seizures but did not prevent kindling. On the other hand, LCM treatment reverted the increase of mRNA expression of GABAAg2 in the hippocampus and prevented the decrease of GABAAg2 protein in the hippocampal CA1 region. LCM could exhibit modulatory effects on the GABAergic system of the hippocampus that may be independent of the anticonvulsant action.

Re] Mathematical analysis of depolarization block mediated by slow inactivation of fast sodium channels in midbrain dopamine neurons

Re] Mathematical analysis of depolarization block mediated by slow inactivation of fast sodium channels in midbrain dopamine neurons

Therapeutic Monitoring of Lacosamide in Japanese Patients With Epilepsy: Clinical Response, Tolerability, and Optimal Therapeutic Range.

Lacosamide is a novel anticonvulsant that acts by enhancing sodium channel slow inactivation. The aims of this study were to evaluate the influence of concomitant antiepileptic drugs (AEDs) on serum lacosamide concentration and explore the relationship between lacosamide serum concentration and both clinical response and adverse effects. The authors analyzed 649 serum samples from 426 Japanese patients with epilepsy. The concentration-to-dose (CD) ratio of lacosamide was compared among patients on various AED regimens. Clinical information about seizure frequency and adverse events was obtained from clinical records. In patients who did not receive enzyme-inducing AEDs, the CD ratio (mean ± SD) of lacosamide was 1.84 ± 0.68. By contrast, the CD ratio in patients who received phenytoin, carbamazepine, and phenobarbital was 1.42 ± 0.66 (22.8% lower), 1.46 ± 0.40 (20.7% lower), and 1.36 ± 0.38 (26.1% lower), respectively. Seventy-four patients (17.3%) achieved >50% seizure reduction. The median lacosamide concentration in patients who received and did not receive a sodium channel blocker was 6.6 mcg/mL (26.4 μmol/L) and 8.4 mcg/mL (33.6 μmol/L), respectively. Adverse events, including dizziness, somnolence, diplopia, and anorexia, were reported by 70 patients (16.4%). The incidence rate in patients treated with sodium channel blockers was significantly higher than that in patients not treated with these drugs (21.1% vs. 10.3%; P < 0.005), and the median lacosamide concentration in these patient groups was 5.1 (20.4 μmol/L) and 7.5 mcg/mL (30 μmol/L), respectively. Therapeutic drug monitoring of lacosamide is clinically useful because it allows physicians to estimate the extent of drug interactions and adjust the dose in individual AED regimens.

Open-label trial of ranolazine for the treatment of paramyotonia congenita.

Paramyotonia congenita (PMC) is a nondystrophic myotonic disorder that is believed to be caused by a defect in Nav 1.4 sodium channel inactivation. Ranolazine, which acts by enhancing slow inactivation of sodium channels, has been proposed as a therapeutic option, but in vivo studies are lacking. We conducted an open-label, single-center trial of ranolazine to evaluate efficacy and tolerability in patients with PMC. Subjective symptoms of stiffness, weakness, and pain as well as clinical and electrical myotonia were evaluated. Baseline measures were compared with those after 4 weeks of treatment with ranolazine. Ranolazine was tolerated well without any serious adverse events. Both subjective symptoms and clinical myotonia were significantly improved. Duration of myotonia was reduced according to electromyography, but this change was not statistically significant in all tested muscles. Our findings support the use of ranolazine as a treatment for myotonia in PMC and suggest that a randomized, placebo-controlled trial is warranted. Muscle Nerve 59:240-243, 2019.

Electroencephalographic and Electrocardiographic Effect of Intravenous Lacosamide in Refractory Focal Epilepsy.

Lacosamide selectively enhances slow inactivation of voltage-gated sodium channels to achieve seizure reduction. We studied the effect of intravenous lacosamide given as one of three single doses on EEG and electrocardiogram, as well as its tolerability in patients with drug-resistant epilepsy. This Canadian, investigator-initiated, multicenter, double-blind study recruited patients with refractory focal epilepsy admitted to a seizure monitoring unit. Participants received a loading dose of 100, 200, or 400 mg lacosamide over 30 minutes during continuous monitoring by video-EEG and 12-lead electrocardiogram. The number of interictal spikes, frequency and quantity of background EEG rhythms, corrected QT interval (QTc), PR interval, heart rate (HR), blood pressure, and respiration rate during 60 minutes before the administration were compared with 60 minutes after the infusion. We documented any adverse event during and after the infusion. Seventy-one patients completed the study. There was a significant decrease in interictal spikes (P = 0.039) and decreased frequency of the alpha rhythm (P = 0.003). No significant difference in beta, theta, and delta frequency or amount was noted. There were significant increases in PR interval (153.4-155.8 ms, P = 0.031) and HR (73.4-75.5 bpm, P = 0.022), but QTc, blood pressure, and respiration rate were not affected. Twelve patients (16.9%) experienced transient and mild adverse events, mainly dizziness and leg tingling. More adverse events occurred with 400 mg lacosamide than with the lower doses (P = 0.048). Intravenous lacosamide is effective in decreasing interictal spikes. Despite a small effect on EEG and electrocardiogram rhythms, it is well tolerated with no serious adverse events.

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.