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Context: Spinal cord injury (SCI) presents significant challenges due to its debilitating nature and potential complications. While few medications have shown efficacy in improving neurological recovery, 4-Aminopyridine (4-AP), a voltage-gated potassium channel blocker, has been used clinically off-label to improve neurologic function in adults with spinal cord-related paralysis. However, evidence regarding its safety and effectiveness in the pediatric population remains scarce, as it is approved for use in older patients. Findings: This manuscript reports the case of a pediatric patient who sustained a traumatic cervical SCI. Initial neurological assessment indicated a C1 motor complete SCI. Surgical intervention for bullet removal and spinal fusion was carried out, followed by comprehensive inpatient rehabilitation. Conclusion/clinical relevance: 4-AP was introduced three months post-injury and was well-tolerated without obvious adverse effects. Notably, he exhibited neurological and functional improvement after four months of 4-AP use, though his improvement followed the expected trajectory of recovery. To date, this case represents the first case of 4-AP administration in a pediatric SCI patient, and therefore these findings contribute valuable clinical insight. By documenting the clinical trajectory of this case, this manuscript suggests 4-AP may be safe for use in pediatric patients.

Introduction: Fatigue is a highly prevalent debilitating symptom among patients with multiple sclerosis (PwMS), which markedly affects the quality of life. The present study aimed to evaluate the effect of extended-release fampridine on fatigue in PwMS., Methods: This was a randomized, double-blind clinical trial on 77 PwMS with a complaint of fatigue, aged over 18 years old, randomized to extended-release fampridine (n = 44) or placebo (n = 35) for 12 weeks. Fatigue and motor function were assessed at baseline and end point., Results: A total of 88 patients were recruited, of whom 77 were analyzed. 80.5% were female, with a median age of 38. 87% were diagnosed with relapsing-remitting MS (RRMS) with a median disease duration of 96 months. Fingolimod (37.7%) was considered the most frequently used DMT, followed by ani-CD20s (32.5%). The total median MFIS score was 43.5 and 37 in the fampridine and placebo groups which were not significantly different (p > 0.05). After 12 weeks, the total MFIS improved in both groups compared to the baseline, which was significant in the active group (p = 0.04). However, the final end point total MFIS was still comparable between the two groups (p = 0.11)., Conclusion: The present study revealed a positive short-term effect of extended-release fampridine on MFIS in PwMS. However, this effect was not significantly superior to the placebo., (© 2024. The Author(s) under exclusive licence to Belgian Neurological Society.)

Background: Congenital myasthenic syndromes (CMS) are a group of inherited neuromuscular junction (NMJ) disorders arising from gene variants encoding diverse NMJ proteins. Recently, the VAMP1 gene, responsible for encoding the vesicle-associated membrane protein 1 (VAMP1), has been associated with CMS., Methods: This study presents a characterization of five new individuals with VAMP1-related CMS, providing insights into the phenotype., Results: The individuals with VAMP1-related CMS exhibited early disease onset, presenting symptoms prenatally or during the neonatal period, alongside severe respiratory involvement and feeding difficulties. Generalized weakness at birth was a common feature, and none of the individuals achieved independent walking ability. Notably, all cases exhibited scoliosis. The clinical course remained stable, without typical exacerbations seen in other CMS types. The response to anticholinesterase inhibitors and salbutamol was only partial, but the addition of 3,4-diaminopyridine (3,4-DAP) led to significant and substantial improvements, suggesting therapeutic benefits of 3,4-DAP for managing VAMP1-related CMS symptoms. Noteworthy is the identification of the VAMP1 (NM_014231.5): c.340delA; p.Ile114SerfsTer72 as a founder variant in the Iberian Peninsula and Latin America., Conclusions: This study contributes valuable insights into VAMP1-related CMS, emphasizing their early onset, arthrogryposis, facial and generalized weakness, respiratory involvement, and feeding difficulties. Furthermore, the potential efficacy of 3,4-DAP as a useful therapeutic option warrants further exploration. The findings have implications for clinical management and genetic counseling in affected individuals. Additional research is necessary to elucidate the long-term outcomes of VAMP1-related CMS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Potassium channels have recently emerged as suitable target for the treatment of epileptic diseases. Among potassium channels, KCNT1 channels are the most widely characterized as responsible for several epileptic and developmental encephalopathies. Nevertheless, the medicinal chemistry of KCNT1 blockers is underdeveloped so far. In the present review, we describe and analyse the papers addressing the issue of KCNT1 blockers' development and identification, also evidencing the pros and the cons of the scientific approaches therein described. After a short introduction describing the epileptic diseases and the structure-function of potassium channels, we provide an extensive overview of the chemotypes described so far as KCNT1 blockers, and the scientific approaches used for their identification.

Recent literature reports highlight the importance of the renal outer medullary potassium (ROMK) channel in renal sodium and potassium homeostasis and emphasize the potential impact that ROMK inhibitors could have as a novel mechanism diuretic in heart failure patients. A series of piperazine-based ROMK inhibitors were designed and optimized to achieve excellent ROMK potency, hERG selectivity, and ADME properties, which led to the identification of compound 28 (BMS-986308). BMS-986308 demonstrated efficacy in the volume-loaded rat diuresis model as well as promising in vitro and in vivo profiles and was therefore advanced to clinical development.

Voltage-gated potassium channel 1.3 (Kv1.3) has emerged as a pivotal player in numerous biological processes and pathological conditions, sparking considerable interest as a potential therapeutic target across various diseases. In this review, we present a comprehensive examination of Kv1.3 channels, highlighting their fundamental characteristics and recent advancements in utilizing Kv1.3 inhibitors for treating autoimmune disorders, neuroinflammation, and cancers. Notably, Kv1.3 is prominently expressed in immune cells and implicated in immune responses and inflammation associated with autoimmune diseases and chronic inflammatory conditions. Moreover, its aberrant expression in certain tumors underscores its role in cancer progression. While preclinical studies have demonstrated the efficacy of Kv1.3 inhibitors, their clinical translation remains pending. Molecular imaging techniques offer promising avenues for tracking Kv1.3 inhibitors and assessing their therapeutic efficacy, thereby facilitating their development and clinical application. Challenges and future directions in Kv1.3 inhibitor research are also discussed, emphasizing the significant potential of targeting Kv1.3 as a promising therapeutic strategy across a spectrum of diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Senicapoc, a small molecule inhibitor of the calcium-activated potassium channel KCa3.1, was safe and well-tolerated in clinical trials for sickle cell anemia. We previously reported proof-of-concept data suggesting that both pharmacological inhibition and genetic deletion of KCa3.1 reduces infarction and improves neurologic recovery in rodents by attenuating neuroinflammation. Here we evaluated the potential of repurposing senicapoc for ischemic stroke. In cultured microglia, senicapoc inhibited KCa3.1 currents with an IC 50 of 7 nM, reduced Ca 2+ signaling induced by the purinergic agonist ATP, suppressed expression of pro-inflammatory cytokines and enzymes (iNOS and COX-2), and prevented induction of the inflammasome component NLRP3. When transient middle cerebral artery occlusion (tMCAO, 60 min) was induced in male C57BL/6 J mice, twice daily administration of senicapoc at 10 and 40 mg/kg starting 12 h after reperfusion dose-dependently reduced infarct area determined by T2-weighted magnetic resonance imaging (MRI) and improved neurological deficit on day 8. Ultra-high-performance liquid chromatography/mass spectrometry analysis of total and free brain concentrations demonstrated sufficient KCa3.1 target engagement. Senicapoc treatment significantly reduced microglia/macrophage and T cell infiltration and activation and attenuated neuronal death. A different treatment paradigm with senicapoc started at 3 h and MRI on day 3 and day 8 revealed that senicapoc reduces secondary infarct growth and suppresses expression of inflammation markers, including T cell cytokines in the brain. Lastly, we demonstrated that senicapoc does not impair the proteolytic activity of tissue plasminogen activator (tPA) in vitro. We suggest that senicapoc could be repurposed as an adjunctive immunocytoprotective agent for combination with reperfusion therapy for ischemic stroke., (© 2023. The Author(s).)

Peripheral cytokine levels may serve as biomarkers for treatment response and disease monitoring in patients with multiple sclerosis (pwMS). The objectives were to assess changes in plasma biomarkers in PwMS after 14 days of fampridine treatment and to explore correlations between changes in performance measures and plasma biomarkers. We included 27 PwMS, 14 women and 13 men, aged 52.0 ± 11.6 years, with a disease duration of 17 ± 8.5 years, and an Expanded Disability Status Scale of 6 [IQR 5.0/6.5]. Gait and hand function were assessed using performance tests completed prior to fampridine and after 14 days of treatment. Venous blood was obtained, and chemiluminescence analysis conducted to assess plasma cytokines and neurodegenerative markers. All performance measures demonstrated improvements. Biomarkers showed decreased tumor necrosis factor (TNF) receptor-2 levels. Associations were found between change scores in (i) Six Spot Step Test and Interleukin (IL)-2, IL-8, and IL-17 levels; (ii) timed 25-foot walk and interferon-γ, IL-2, IL-8, TNF-α, and neurofilament light levels, and (iii) 12-Item Multiple Sclerosis Walking Scale and IL-17 levels. The associations may reflect increased MS-related inflammatory activity rather than a fampridine-induced response or that a higher level of inflammation induces a better response to fampridine.

Introduction: Lambert-Eaton myasthenic syndrome (LEMS) is an ultrarare neuromuscular disease with a triad of symptoms: muscle paresis, dysautonomy, and areflexia. Amifampridine is the symptomatic treatment of LEMS., Aim of Study: To assess the effectiveness and safety of treatment in the real world., Material and Methods: 14 patients with non-neoplastic LEMS treated with amifampridine were enrolled in the study (female 42.9%, mean age 48.8 ± 11.4 years). The patients were assessed using the Quantitative Myasthenia Gravis (QMG) scale, QMG limb domain (LD) score, spirometry, Hand Grip Strength (GRIP) test, and repetitive nerve stimulation study (RNS) at baseline and at the end of follow-up. Diagnostic delay since first symptoms was from seven months up to 22 years. Treatment delay ranged from one to 26 years. The patients were treated and reevaluated after 21.1 ± 12.0 weeks (range 13-48)., Results: All of the patients improved in QMG score. Mean improvement was 5.1 ± 2.0 (range 1-8) points (p < 0.001) and this showed no correlation with the duration of the disease before treatment (p = 0.477). 85.7% of patients (N = 12) improved ≥ 3 points (clinically meaningful) in QMG. 78.6% of the patients improved in QMG LD (mean 2.2 ± 1.6 points (p < 0.001)). Also, forced vital capacity (FVC) improved after treatment (p = 0.031). Mean improvement in GRIP test was 7.0 ± 7.1 kg in the right hand and 5.2 ± 7.5 kg in the left hand (p < 0.001). In RNS before treatment, facilitation ( > 100%) was observed in 78.6% (N = 11) of patients, and was higher before treatment (p < 0.001). Compound muscle action potential (CMAP) amplitude was higher after treatment (p < 0.001). Mean increase of CMAP amplitude was 2.1 ± 1.6 times. In 64.3% (N = 9) of patients lowering of corticosteroid dose was achieved., Conclusions: Amifampridine is an effective treatment in non-neoplastic LEMS patients, regardless of disease duration. The treatment is well-tolerated and allows to reduce dose of corticosteroids in the majority of patients.

Modulation of the human Ether-à-go-go-Related Gene (hERG) channel, a crucial voltage-gated potassium channel in the repolarization of action potentials in ventricular myocytes of the heart, has significant implications on cardiac electrophysiology and can be either antiarrhythmic or proarrhythmic. For example, hERG channel blockade is a leading cause of long QT syndrome and potentially life-threatening arrhythmias, such as torsades de pointes . Conversely, hERG channel blockade is the mechanism of action of Class III antiarrhythmic agents in terminating ventricular tachycardia and fibrillation. In recent years, it has been recognized that less proarrhythmic hERG blockers with clinical potential or Class III antiarrhythmic agents exhibit, in addition to their hERG-blocking activity, a second action that facilitates the voltage-dependent activation of the hERG channel. This facilitation is believed to reduce the proarrhythmic potential by supporting the final repolarizing of action potentials. This review covers the pharmacological characteristics of hERG blockers/facilitators, the molecular mechanisms underlying facilitation, and their clinical significance, as well as unresolved issues and requirements for research in the fields of ion channel pharmacology and drug-induced arrhythmias.

Background: Gait imbalance is one of the frequent complications in subjects with multiple sclerosis (MS). Fampridine (4-aminopyridine) is a potassium-channel blocker that is administered for gait imbalance in MS. Different studies showed the effects of fampridine on gait status based on various tests in subjects with MS. Some showed significant improvement after treatment, and others did not. So, we designed this systematic review, and meta-analysis to estimate the pooled effects of fampridine on gait status in patients with MS., Methods: The main goal is the evaluation of times of different gait test pre and post fampridine treatment. Two independent expert researchers conducted a systematic and comprehensive search in PubMed, Scopus, EMBASE, Web of Science, and Google Scholar and also gray literature, including references of the references and conference abstracts. The search was done on September 16, 2022. Before-after studies trials reporting scores of the walking tests. We extracted data regarding the total number of participants, first author, publication year, country of origin, mean age, Expanded Disability Status Scale (EDSS), and the results of walking tests., Results: The literature search revealed 1963 studies; after deleting duplicates, 1098 studies remained. Seventy-seven full texts were evaluated. Finally, 18 studies were included for meta-analysis, while most of them were not placebo-controlled trials. The most frequent country of origin was Germany, and the mean age and EDSS ranged between 44 and 56 years and 4 and 6, respectively. The studies were published between 2013 and 2019. The pooled standardized mean difference (SMD) (after-before) of the MS Walking Scale (MSWS-12) was - 1.97 (95%CI: - 1.7, - 1.03) (I 2  = 93.1%, P < 0.001). The pooled SMD (after-before) of the six-minute walk test (6MWT) was 0.49 (95%CI: 0.22, - 0.76) (I 2  = 0%, P = 0.7). The pooled SMD (after-before) of T Timed 25-Foot Walk (T25FW) was - 0.99(95%CI: - 1.52, - 0.47) (I 2  = 97.5%, P < 0.001)., Conclusion: This systematic review and meta-analysis show that fampridine improves gait imbalance in patients with MS., (© 2023. Fondazione Società Italiana di Neurologia.)

Engineered microbes for the delivery of biologics are a promising avenue for the treatment of various conditions such as chronic inflammatory disorders and metabolic disease. In this study, we developed a genetically engineered probiotic delivery system that delivers a peptide to the intestinal tract with high efficacy. We constructed an inducible system in the probiotic Lactobacillus reuteri to secrete the Kv1.3 potassium blocker ShK-235 (LrS235). We show that LrS235 culture supernatants block Kv1.3 currents and preferentially inhibit human T effector memory (T EM ) lymphocyte proliferation in vitro. A single oral gavage of healthy rats with LrS235 resulted in sufficient functional ShK-235 in the circulation to reduce inflammation in a delayed-type hypersensitivity model of atopic dermatitis mediated by T EM cells. Furthermore, the daily oral gavage of LrS235 dramatically reduced clinical signs of disease and joint inflammation in rats with a model of rheumatoid arthritis without eliciting immunogenicity against ShK-235. This work demonstrates the efficacy of using the probiotic L. reuteri as a novel oral delivery platform for the peptide ShK-235 and provides an efficacious strategy to deliver other biologics with great translational potential.

Background: Fampridine is a potassium channel blocker drug used to improve walking ability in patients with multiple sclerosis (MS). We evaluated the effect of fampridine in patients with MS in the acute phase of transverse myelitis., Methods: In a randomized, placebo-controlled trial, 30 patients who had their first episode of cervical myelitis with quadriparesis presentation, with the final diagnosis of MS, were randomly divided into two equal groups. The intervention group received intravenous methylprednisolone (IVMP) for 7 days plus fampridine. The placebo group received IVMP for 7 days plus placebo. To compare the treatment results, we compared the Barthel index (BI) scores of the groups at the start of the trial and the 21st day after the start of treatment., Results: There was no significant difference in baseline characteristics between the intervention and placebo groups in terms of mean age, sex, and mean admission BI (p > 0.05). Mean (SD) admission BI in placebo and intervention groups was 27.20 (7.341) and 27.87(5.78), respectively (p = 0.784). The measured mean (SD) BI after treatment was 48.73 (15.54) in the placebo and 64.93 (11.81) in the intervention group (p = 0.003) after 3 weeks., Conclusion: Using fampridine plus IVMP in the acute phase of transverse myelitis in MS patients improved the disease's symptoms and increased the daily activity ability of patients., (© 2022. Fondazione Società Italiana di Neurologia.)

Potassium ion channels are expressed on the cell membranes, implicated in wide variety of cell functions and intimately linked to cancer cell behaviors. This work reports the first bioplatform described to date allowing simple and rapid detection of ion channel activity and the effect of their inhibitors in cancer cells. The methodology involves interrogation of the channel of interest from cells specifically captured on magnetic immunoconjugates using specific detection antibodies that are labeled with horseradish peroxidase enzyme. The channel activity is reflected by an amperometric signal transduction of the resulting magnetic bioconjugates onto screen-printed carbon electrodes. The bioplatform feasibility was proven for the detection of the Kv channels in U87 human glioblastoma cells and their blocking by scorpion venom KAaH1 and KAaH2 peptides. The obtained results confirm the high sensitivity (detection of 5 U87 cells⋅mL -1 and 0.06 μg mL -1 of KAaH2) of the proposed bioplatform and their versatility to detect both potassium channel activity and their potential inhibitors, in a given cancer cell line, with high sensitivity in a simple and fast way. This bioplatform presents potential applications in cancer and theranostic of channelopathies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Noureddine Raouafi reports financial support was provided by Tunisian Ministry of Higher Education and Scientific Research., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Slack channels are sodium-activated potassium channels that are encoded by the KCNT1 gene. Several KCNT1 gain of function mutations have been linked to malignant migrating partial seizures of infancy. Quinidine is an anti-arrhythmic drug that functions as a moderately potent inhibitor of Slack channels; however, quinidine use is limited by its poor selectivity, safety and pharmacokinetic profile. Slack channels represent an interesting target for developing novel therapeutics for the treatment of malignant migrating partial seizures of infancy and other childhood epilepsies; thus, ongoing efforts are directed toward the discovery of small-molecules that inhibit Slack currents. This review summarizes patent applications published in 2020-2021 that describe the discovery of novel small-molecule Slack inhibitors.

Background: People with multiple sclerosis have reduced walking speed and impaired gait pattern. Prolonged release-fampridine is a potassium channel blocker that improves nerve conduction in patients with multiple sclerosis, leading to walking benefits. Whether fampridine alters gait pattern is unknown., Methods: In this crossover, randomized controlled trial, patients with multiple sclerosis were tested for responder status during a 4-week run-in period. Patients were considered responders if they improved their 25-ft walk test by 10% and improved their perceived walking capacity. Responders were randomized to prolonged release-fampridine (10 mg b.i.d.) or placebo for a 6-week period. After a 2-week wash-out period, they were allocated to the other treatment for 6 weeks. Participants were assessed before and after both conditions. Three-dimensional gait analysis assessed kinematic, kinetic, mechanic and energetic variables while walking on a treadmill at comfortable speed. Six-minute walk test and 25-ft walk test were used to assess walking speed on middle and short-distances, respectively. Patient-reported outcome measures were also used. Repeated measures ANCOVAs were applied to assess the treatment effects., Findings: Out of 39 included patients, 24 responders (12 women; Expanded Disability Status Scale:4.25[4-5]; age:46 ± 10 years; maximal speed:0.93 ± 0.38 m·s -1 ) were identified. Among them, prolonged release-fampridine reduced the external mechanical work (-0.039 J·kg -1 ·m -1 ;p = 0.02), and improved knee flexion during swing phase (+5.3°; p = 0.02). No differences were found in other walking tests and patient-reported outcomes, at group-level., Interpretation: Prolonged release-fampridine increases knee flexion during swing phase and lowers mechanical external work. Whether these changes are related to clinically meaningful improvements in walking capacity and other functional variables should be further investigated., (Copyright © 2021. Published by Elsevier Ltd.)

The K ca 3.1 channels, previously designated as IK1 or SK4 channels and encoded by the KCNN4 gene, are activated by a rise of the intracellular Ca 2+ concentration. These K + channels are widely expressed in many organs and involved in many pathologies. In particular, K ca 3.1 channels have been studied intensively in the context of cancer. They are not only a marker and a valid prognostic tool for cancer patients, but have an important share in driving cancer progression. Their function is required for many characteristic features of the aggressive cancer cell behavior such as migration, invasion and metastasis as well as proliferation and therapy resistance. In the context of cancer, another property of K ca 3.1 is now emerging. These channels can be a target for novel small molecule-based imaging probes, as it has been validated in case of fluorescently labeled senicapoc-derivatives. The aim of this review is (i) to give an overview on the role of K ca 3.1 channels in cancer progression and in shaping the cancer microenvironment, (ii) discuss the potential of using K ca 3.1 targeting drugs for cancer imaging, (iii) and highlight the possibility of combining molecular dynamics simulations to image inhibitor binding to K ca 3.1 channels in order to provide a deeper understanding of K ca 3.1 channel pharmacology. Alltogether, K ca 3.1 is an attractive therapeutic target so that senicapoc, originally developed for the treatment of sickle cell anemia, should be repurposed for the treatment of cancer patients., Competing Interests: The authors declare no conflict of interest., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)

Drug-induced long QT syndrome (LQTS) is an established cardiac side effect of a wide range of medications and represents a significant concern for drug safety. The rapidly and slowly activating delayed rectifier K + currents, mediated by channels encoded by the human ether-a-go-go-related gene ( hERG ) and KCNQ1 + KCNE1, respectively, are two main currents responsible for ventricular repolarization. The common cause for drugs to induce LQTS is through impairing the hERG channel. For the recent emergence of COVID-19, caused by severe acute respiratory syndrome coronavirus 2, several drugs have been investigated as potential therapies; however, there are concerns about their QT prolongation risk. Here, we studied the effects of chloroquine, hydroxychloroquine, azithromycin, and remdesivir on hERG channels. Our results showed that although chloroquine acutely blocked hERG current (I hERG ), with an IC 50 of 3.0 µM, hydroxychloroquine acutely blocked I hERG 8-fold less potently, with an IC 50 of 23.4 µM. Azithromycin and remdesivir did not acutely affect I hERG When these drugs were added at 10 µM to the cell culture medium for 24 hours, remdesivir increased I hERG by 2-fold, which was associated with an increased mature hERG channel expression. In addition, these four drugs did not acutely or chronically affect KCNQ1 + KCNE1 channels. Our data provide insight into COVID-19 drug-associated LQTS and cardiac safety concerns. SIGNIFICANCE STATEMENT: This work demonstrates that, among off-label potential COVID-19 treatment drugs chloroquine, hydroxychloroquine, azithromycin, and remdesivir, the former two drugs block hERG potassium channels, whereas the latter two drugs do not. All four drugs do not affect KCNQ1 + KCNE1. As hERG and KCNQ1 + KCNE1 are two main K + channels responsible for ventricular repolarization, and most drugs that induce long QT syndrome (LQTS) do so by impairing hERG channels, these data provide insight into COVID-19 drug-associated LQTS and cardiac safety concerns., Competing Interests: The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Substance use disorders (SUDs) are ubiquitous throughout the world. However, much remains to be done to develop pharmacotherapies that are very efficacious because the focus has been mostly on using dopaminergic agents or opioid agonists. Herein we discuss the potential of using potassium channel activators in SUD treatment because evidence has accumulated to support a role of these channels in the effects of rewarding drugs. Potassium channels regulate neuronal action potential via effects on threshold, burst firing, and firing frequency. They are located in brain regions identified as important for the behavioral responses to rewarding drugs. In addition, their expression profiles are influenced by administration of rewarding substances. Genetic studies have also implicated variants in genes that encode potassium channels. Importantly, administration of potassium agonists have been shown to reduce alcohol intake and to augment the behavioral effects of opioid drugs. Potassium channel expression is also increased in animals with reduced intake of methamphetamine. Together, these results support the idea of further investing in studies that focus on elucidating the role of potassium channels as targets for therapeutic interventions against SUDs.

Dysfunction of neuronal circuits is an important determinant of neurodegenerative diseases. Synaptic dysfunction, death, and intrinsic activity of neurons are thought to contribute to the demise of normal behavior in the disease state. However, the interplay between these major pathogenic events during disease progression is poorly understood. Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by a deficiency in the ubiquitously expressed protein SMN and is characterized by motor neuron death, skeletal muscle atrophy, as well as dysfunction and loss of both central and peripheral excitatory synapses. These disease hallmarks result in an overall reduction of neuronal activity in the spinal sensory-motor circuit. Here, we show that increasing neuronal activity by chronic treatment with the FDA-approved potassium channel blocker 4-aminopyridine (4-AP) improves motor behavior in both sexes of a severe mouse model of SMA. 4-AP restores neurotransmission and number of proprioceptive synapses and neuromuscular junctions (NMJs), while having no effects on motor neuron death. In addition, 4-AP treatment with pharmacological inhibition of p53-dependent motor neuron death results in additive effects, leading to full correction of sensory-motor circuit pathology and enhanced phenotypic benefit in SMA mice. Our in vivo study reveals that 4-AP-induced increase of neuronal activity restores synaptic connectivity and function in the sensory-motor circuit to improve the SMA motor phenotype. SIGNIFICANCE STATEMENT Spinal muscular atrophy (SMA) is a neurodegenerative disease, characterized by synaptic loss, motor neuron death, and reduced neuronal activity in spinal sensory-motor circuits. However, whether these are parallel or dependent events is unclear. We show here that long-term increase of neuronal activity by the FDA-approved drug 4-aminopyridine (4-AP) rescues the number and function of central and peripheral synapses in a SMA mouse model, resulting in an improvement of the sensory-motor circuit and motor behavior. Combinatorial treatment of pharmacological inhibition of p53, which is responsible for motor neuron death and 4-AP, results in additive beneficial effects on the sensory-motor circuit in SMA. Thus, neuronal activity restores synaptic connections and improves significantly the severe SMA phenotype., (Copyright © 2021 the authors.)

Oxidative stress is one of the most important risk factors for cataractogenesis. Previous studies have indicated that BDS-II, a Kv3 channel blocker, plays pivotal roles in oxidative stress-related diseases. This study demonstrates that BDS-II exerts a protective effect on cataractogenesis. Specifically, BDS-II was observed to inhibit lens opacity induced by H 2 O 2 . BDS-II was also determined to inhibit cataract progression in a sodium selenite-induced in vivo cataract model by inhibiting reduction of the total GSH. In addition, BDS-II was demonstrated to protect human lens epithelial cells against H 2 O 2 -induced cell death. Our results suggest that BDS-II is a potential pharmacological candidate in cataract therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Symptomatic treatment has a great relevance for the management of patients with neurologic diseases, since it reduces disease burden and improves quality of life. Aminopyridines (APs) are a group of potassium (K+) channel blocking agents that exert their activity both at central nervous system level and on neuromuscular junction. This review describes the use of APs for the symptomatic treatment of neurological conditions. We will describe trials leading to the approval of the extended-release 4-aminopyridine for MS and evidence in support of the use in other neurological diseases.

The voltage-gated potassium channel K V 1.3 is a well-established therapeutic target for a range of autoimmune diseases, in addition to being the site of action of many venom-derived peptides. Numerous studies have documented the efficacy of venom peptides that target K V 1.3, in particular from sea anemones and scorpions, in animal models of autoimmune diseases such as rheumatoid arthritis, psoriasis and multiple sclerosis. Moreover, an analogue of the sea anemone peptide ShK (known as dalazatide) has successfully completed Phase 1 clinical trials in mild-to-moderate plaque psoriasis. In this article we consider other potential therapeutic applications of inhibitors of K V 1.3, including in inflammatory bowel disease and neuroinflammatory conditions such as Alzheimer's and Parkinson's diseases, as well as fibrotic diseases. We also summarise strategies for facilitating the entry of peptides to the central nervous system, given that this will be a pre-requisite for the treatment of most neuroinflammatory diseases. Venom-derived peptides that have been reported recently to target K V 1.3 are also described. The increasing number of autoimmune and other conditions in which K V 1.3 is upregulated and is therefore a potential therapeutic target, combined with the fact that many venom-derived peptides are potent inhibitors of K V 1.3, suggests that venoms are likely to continue to serve as a rich source of new pharmacological tools and therapeutic leads targeting this channel., (Copyright © 2020 Elsevier Inc. All rights reserved.)

After cerebral ischemia/reperfusion injury, pro-inflammatory M1-like and anti-inflammatory M2-like phenotypes of microglia are involved in neuroinflammation, in which NLRP3 inflammasome plays an essential role. Kv1.3 channel has been recognized as neuro-immunomodulatory target, but it is not clear as to its role in the neuroinflammation after cerebral ischemic injury. The current study aimed to investigate the issue. Middle cerebral artery occlusion/reperfusion (MCAO/R) model in rats and oxygen-glucose deprivation/ reoxygenation (OGD/R) in primary microglia were utilized to mimic disease state of ischemic stroke. Treatment with PAP-1, a Kv1.3 channel blocker, produced a significant improvement in neurological deficit scores and a decrease in infarct volume in MCAO/R model. An increased number of M2-like phenotypic microglia and a reduced number of M1-like phenotypic microglia were observed by immunofluorescent staining in the in vivo model, which was further validated by flow cytometry in vitro. Western blot showed that PAP-1 treatment profoundly reduced cleavage of caspase-1 and IL-1β in vivo and in vitro. Furthermore, PAP-1 administration reduced the number of NLRP3 + /Iba1 + cells and NLRP3 protein levels in vivo, while reduced mRNA and protein expression levels of NLRP3 in vitro. Reduced mRNA expression levels of IL-1β in vitro and protein level of IL-1β in vivo were also observed. Taken together, our findings suggested that Kv1.3 channel blockade effectively alleviated cerebral ischemic injury, possibly by reshaping microglial phenotypic response from M1 towards M2, compromising the activation of NLRP3 inflammasome in microglia, and inhibiting release of IL-1β., Competing Interests: Declaration of Competing Interest There are no conflicts to declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Fampridine is the only drug approved for the treatment of walking impairment in multiple sclerosis. Around a third of the patients on treatment obtained an improvement in walking speed during the development phase. The effects are clinically significant, appear soon after the start of the treatment and are long-lasting, but disappear soon after the drug is withdrawn. In the real-world setting, the number of patients with a significant response to the treatment seems to be higher (around 70%). The tolerance is good, with mild to moderate, and transient adverse events. The most commonly reported are insomnia, headache, fatigue, back pain, dizziness, nausea and balance disorders. The main contraindications are a history of seizures, renal impairment and concomitant treatment with OCT2 inhibitors.

Gait dysfunction is common in patients with multiple sclerosis (PwMS). Treatment with prolonged-release fampridine (PR-fampridine) improves walking ability in some PwMS. Associated fampridine-induced changes in the walking pattern are still poorly understood but may provide a better understanding of the mechanisms underlying the beneficial drug effects. 61 PwMS were treated with PR-fampridine in a randomized, monocentric, double-blind and placebo-controlled clinical trial with crossover design (FAMPKIN). Drug-induced improvements in walking speed (Timed-25-Foot Walk; T25FW) and endurance (6-Minute Walk Test; 6MWT) were quantified. In this sub-study of the FAMPKIN trial, fampridine-induced changes in kinetic gait patterns were analyzed by pressure-based foot print analysis during treadmill walking. Vertical ground reaction forces were analyzed during different gait phases. Kinetic data of 44 PwMS was eligible for analysis. During double-blind treatment with PR-fampridine, patients performed significantly better in the T25FW and 6MWT than during placebo treatment (p < 0.0001 for both). At the group level (n = 44), there were no significant changes of gait kinetics under PR-fampridine vs. placebo. However, we found relevant changes of walking kinetics regarding forces during loading, single limb and pre-swing phase in a patient sub-group (n = 8). Interestingly, this sub-group demonstrated superior responsiveness to PR-fampridine in the clinical walking tests compared to those patients without any fampridine-induced changes in kinetics (n = 36). Our results demonstrate fampridine-induced changes in gait kinetics in a sub-group of PwMS. These gait pattern changes were accompanied by improved clinical walking performance under PR-fampridine. These results shed some light on the biomechanical changes in walking patterns underlying enhanced fampridine-induced gait performance., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

SMA is a genetically determined motor system disorder that results in muscle weakness, selective motor neuron death, muscle atrophy, and impaired functional mobility. In SMA model systems, long-term treatment with 4-aminopyridine (4-AP) has been shown to improve motor function. To assess tolerability and preliminary efficacy of 4-AP on walking ability, endurance and EMG in adult ambulatory SMA patients, we conducted a double blind, placebo control, crossover pilot study with dalfampridine (4-AP, 10 mg BID). The study is comprised of a short-term (2 weeks) treatment arm with 1-week washout and a long-term (6 weeks) treatment arm with a 2-week washout. The primary outcome measure, for which the study was powered, was the 6 min walk test (6MWT, distance and percent fatigue); secondary outcome measures were the Hammersmith Functional Motor Scale Expanded (HFMSE), Manual Muscle Testing (MMT), Myometry with Hand held Dynamometry, HHD) and Quantitative Gait Analyses. We performed electrophysiology, including CMAP and H-reflex, during the short-term treatment trial. The mean age of the 11 participants enrolled was 37.7 ± 11.9 years; 54.5% were male. Dalfampridine was safe and well tolerated and no patient suffered a serious adverse event related to treatment. We observed no statistically significant positive effects of dalfampridine treatment on our primary functional motor outcome (6MWT distance, fatigue). Dalfampridine had a positive effects on H-reflex and H/M ratio but not on CMAP amplitude. The effect on the H-reflex is of interest, as it suggests dalfampridine may enhance neuronal activity, an effect observed in SMA Drosophila and mouse models at doses (mg/kg) not recommended for clinical use. Larger studies with dalfampridine in SMA patients are needed to confirm our findings, especially in light of studies in other populations showing drug effects in only a subset of patients., (Copyright © 2020. Published by Elsevier B.V.)

Zanthoxylum bungeanum pericarp is a commonly used herbal medicine in China with effects of anti-inflammatory and analgesic, improving learning and memory ability, while hydroxy- α -sanshool (HAS) is the most important active ingredient of Z. bungeanum pericarps. The purpose of this study was to investigate the neuroprotective effect of HAS and its related possible mechanisms using a H 2 O 2 -stimulated PC12 cell model. CCK-8 assay results showed that HAS had a significant protective effect on H 2 O 2 -stimulated PC12 cells without obvious cytotoxicity on normal PC12 cells. Flow cytometry and fluorescence microscope (DAPI staining and DCFH-DA staining) indicated that HAS could reduce the H 2 O 2 -induced apoptosis in PC12 cells via reduction of intracellular ROS and increase of mitochondrial membrane potential (MMP). Subsequently, results of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) determination suggested that HAS could increase the enzyme activities of SOD, CAT, and GSH-Px whereas it could decrease the MDA contents in H 2 O 2 -stimulated PC12 cells. Furthermore, the western blotting assays showed that HAS could upregulate the expressions of p-PI3k, Akt, p-Akt, and Bcl-2, while it could downregulate the expressions of cleaved caspase-3 and Bax in H 2 O 2 -stimulated PC12 cells. Collectively, it could be concluded according to our results that HAS possesses protective potentials on H 2 O 2 -stimulated PC12 cells through suppression of oxidative stress-induced apoptosis via regulation of PI3K/Akt signal pathway., Competing Interests: There are no conflicts of interest associated with this paper., (Copyright © 2020 Ruo-Lan Li et al.)

Parkinson's disease (PD) is the second most common neurodegenerative disorder, which is associated with a selective loss of dopaminergic neurons in the substantia nigra (SN) and a reduction of dopamine in the striatum. Recently, ion channel dysfunction has been considered a reason for the pathogenesis of PD. Potassium (K + ) channels are widespread in the central nervous system, and play key roles in modulating cellular excitability, synaptic transmission, and neurotransmitter release. Based on recent studies and data, we propose that K + channels may be new therapeutic targets for PD that slow the progressive loss of dopaminergic neurons and attenuate motor and non-motor symptoms. In this review, we mainly focus on: delayed rectifier, inwardly rectifying, and double-pore K + channels. We summarize the expression and function of these channels in PD-related brain regions. We also discuss the effects of pharmacological blockade or activation of K + channels in the progression and treatment of PD., Competing Interests: Declaration of Competing Interest All authors claim that there are no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

K + channels play a critical role in maintaining the normal electrical activity of excitable cells by setting the cell resting membrane potential and by determining the shape and duration of the action potential. In nonexcitable cells, K + channels establish electrochemical gradients necessary for maintaining salt and volume homeostasis of body fluids. Inward rectifier K + (Kir) channels typically conduct larger inward currents than outward currents, resulting in an inwardly rectifying current versus voltage relationship. This property of inward rectification results from the voltage-dependent block of the channels by intracellular polyvalent cations and makes these channels uniquely designed for maintaining the resting potential near the K + equilibrium potential (E K ). The Kir family of channels consist of seven subfamilies of channels (Kir1.x through Kir7.x) that include the classic inward rectifier (Kir2.x) channel, the G-protein-gated inward rectifier K + (GIRK) (Kir3.x), and the adenosine triphosphate (ATP)-sensitive (K ATP ) (Kir 6.x) channels as well as the renal Kir1.1 (ROMK), Kir4.1, and Kir7.1 channels. These channels not only function to regulate electrical/electrolyte transport activity, but also serve as effector molecules for G-protein-coupled receptors (GPCRs) and as molecular sensors for cell metabolism. Of significance, Kir channels represent promising pharmacological targets for treating a number of clinical conditions, including cardiac arrhythmias, anxiety, chronic pain, and hypertension. This review provides a brief background on the structure, function, and pharmacology of Kir channels and then focuses on describing and evaluating current high-throughput screening (HTS) technologies, such as membrane potential-sensitive fluorescent dye assays, ion flux measurements, and automated patch clamp systems used for Kir channel drug discovery.

Large (big)-conductance calcium-activated potassium (BK Ca ) channels are expressed in migraine-related structures such as the cranial arteries, trigeminal ganglion and trigeminal spinal nucleus, and they play a substantial role in vascular tonus and neuronal excitability. Using synthetic BK Ca channels openers was associated with headache as a frequent adverse effect in healthy volunteers. Additionally, BK Ca channels are downstream molecules in migraine signalling pathways that are activated by several compounds known to provoke migraine, including calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating polypeptide (PACAP) and glyceryl trinitrate (GTN). Also, there is a high affinity and a close coupling between BK Ca channels and ATP-sensitive potassium (K ATP ) channels, the role of which has recently been established in migraine pathophysiology. These observations raise the question as to whether direct BK Ca channel activation can provoke migraine in migraine patients, and whether the BK Ca channel could be a potential novel anti-migraine target. Hence, randomized and placebo-controlled clinical studies on BK Ca channel openers or blockers in migraine patients are needed.

This was a substudy of a randomized, double-blind, placebo-controlled trial originally designed to explore the effect of dalfampridine on information processing speed (2013-002558-64 EU Clinical Trials Register) in patients with multiple sclerosis (MS). A total of 120 patients were originally randomized in a 2:1 ratio to receive dalfampridine 10 mg or placebo twice daily for 12 weeks. Here, we sought to explore the effect of dalfampridine on static balance in single-task and dual-task conditions in a subgroup of 41 patients. They underwent static posturography in quiet standing (single-task) and while performing the Stroop test (dual-task) at randomization (baseline), after 12 weeks and after a 4-week wash-out period. Baseline characteristics of active group (n = 27) did not differ from those of placebo group (n = 14). Dalfampridine treatment was associated with better balance control than placebo in both single-task (F = 4.80, p = 0.034) and dual-task (F = 6.42, p = 0.015) conditions, with small-to-moderate effect sizes (Cohen's f 2 = 0.122-0.162). The beneficial effect of dalfampridine was not retained 4 weeks after its discontinuation. The rate of accidental falls per month did not differ between the two groups (p = 0.12). Our preliminary findings suggest that dalfampridine can be considered a potential option to treat balance impairment due to MS. Larger sample sizes are needed to verify if the beneficial effect of dalfampridine on balance can be translated into a reduced risk of accidental falls.

Toxins from marine animals provide molecular tools for the study of many ion channels, including mammalian voltage-gated potassium channels of the Kv1 family. Selectivity profiling and molecular investigation of these toxins have contributed to the development of novel drug leads with therapeutic potential for the treatment of ion channel-related diseases or channelopathies. Here, we review specific peptide and small-molecule marine toxins modulating Kv1 channels and thus cover recent findings of bioactives found in the venoms of marine Gastropod (cone snails), Cnidarian (sea anemones), and small compounds from cyanobacteria. Furthermore, we discuss pivotal advancements at exploiting the interaction of κM-conotoxin RIIIJ and heteromeric Kv1.1/1.2 channels as prevalent neuronal Kv complex. RIIIJ's exquisite Kv1 subtype selectivity underpins a novel and facile functional classification of large-diameter dorsal root ganglion neurons. The vast potential of marine toxins warrants further collaborative efforts and high-throughput approaches aimed at the discovery and profiling of Kv1-targeted bioactives, which will greatly accelerate the development of a thorough molecular toolbox and much-needed therapeutics.

Background: Electrocardiographic (ECG) markers of antiarrhythmic drug (AAD) activity could be used to optimize efficacy and minimize toxicity. Vectorcardiographic global electrical heterogeneity (GEH) is associated with ventricular arrhythmias and sudden death, but it is unclear how GEH measurements change in response to AADs., Objective: The purpose of this study was to characterize acute effects of AADs on GEH measurements., Methods: We analyzed double-blind placebo-controlled trial data from healthy volunteers given 1 dose of placebo, dofetilide, quinidine, ranolazine, or verapamil on subsequent visits. Serial ECGs and plasma drug concentrations were collected. Vectorcardiographic GEH parameters (spatial ventricular gradient [SVG], spatial QRST angle, sum absolute QRST integral, and SVG-QRS peak angle) were measured. Placebo-corrected change from baseline was regressed on drug concentration stratified by sex using linear mixed effects models., Results: Among 22 persons (11 (50%) male median age 27 ± 5 years), 5232 ECGs were analyzed. Dofetilide and quinidine were associated with significant changes in more GEH parameters (5) compared with verapamil (2) and ranolazine (1). The most notable change occurred in SVG azimuth, with largest changes (degrees per unit normalized drug concentration) in dofetilide (6.1; 95% confidence interval [CI] 4.2-8.0) and quinidine (9.4; 95% CI 6.7-12.0), and smaller effects in verapamil (4.4; 95% CI 2.9-5.9) and ranolazine (5.4; 95% CI 3.5-7.3). AAD-induced GEH changes significantly differed in men and women., Conclusion: AADs change GEH measurements. These changes, which differ by sex, are likely driven by alterations in ion channel function and dispersion of depolarization or repolarization. GEH measurement may allow early assessment of favorable or adverse AAD effects., (Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Botulinum neurotoxins (BoNTs) are potent neuroparalytic toxins that cause mortality through respiratory paralysis. The approved medical countermeasure for BoNT poisoning is infusion of antitoxin immunoglobulins. However, antitoxins have poor therapeutic efficacy in symptomatic patients; thus, there is an urgent need for treatments that reduce the need for artificial ventilation. We report that the US Food and Drug Administration-approved potassium channel blocker 3,4-diaminopyridine (3,4-DAP) reverses respiratory depression and neuromuscular weakness in murine models of acute and chronic botulism. In ex vivo studies, 3,4-DAP restored end-plate potentials and twitch contractions of diaphragms isolated from mice at terminal stages of BoNT serotype A (BoNT/A) botulism. In vivo, human-equivalent doses of 3,4-DAP reversed signs of severe respiratory depression and restored mobility in BoNT/A-intoxicated mice at terminal stages of respiratory collapse. Multiple-dosing administration of 3,4-DAP improved respiration and extended survival at up to 5 LD50 BoNT/A. Finally, 3,4-DAP reduced gastrocnemius muscle paralysis and reversed respiratory depression in sublethal models of serotype A-, B-, and E-induced botulism. These findings make a compelling argument for repurposing 3,4-DAP to symptomatically treat symptoms of muscle paralysis caused by botulism, independent of serotype. Furthermore, they suggest that 3,4-DAP is effective for a range of botulism symptoms at clinically relevant time points.

Gain-of-function of BK channels or knockout of their β4 subunit is associated with spontaneous epilepsy. Currently, efficacy of BK (α + β4) channel modulators in preventing epilepsy was never reported. Here, we show that martentoxin selectively inhibits BK (α + β4) channels by interaction with the extracellular loop of the BK β4 subunit (hβ4-loop) at a molar ratio 4:1 (hβ4-loop vs martentoxin). Residues Glu 104 , Glu 122 , Gln 124 , Lys 125 , and Glu 128 of the hβ4-loop form hydrogen bonds with residues Asp 5 , Glu 13 , Lys 20 , Ser 24 , Gln 26 , Lys 28 , and Arg 35 of martentoxin, by which martentoxin reduces the neuronal spiking frequency and increases interspike intervals. Intrahippocampal infusion of martentoxin significantly increases the latency time of seizure, reduces seizure duration and seizure numbers on pentylenetetrazole-induced presensitized rats, inhibits hippocampal hyperexcitability and c-Fos expression, and displays neuroprotective effects on hippocampal neurons. These results suggest that the BK (α + β4) channel is a novel therapeutic target of intractable epilepsy and martentoxin contributes to the rational drug design for epilepsy treatment.

Recently, we found cardioprotective effects of ischemic preconditioning (IPC), and from a blocker of KCNQ voltage-gated K + channels (K V 7), XE991 (10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone), in isolated rat hearts. The purpose of the present study was to investigate the cardiovascular effects of IPC and XE991 and whether they are cardioprotective in intact rats. In conscious rats, we measured the effect of the K V 7 channel blocker XE991 on heart rate and blood pressure by use of telemetry. In anesthetized rats, cardiac ischemia was induced by occluding the left coronary artery, and the animals received IPC (2 × 5 min of occlusion), XE991, or a combination. After a 2 h reperfusion period, the hearts were excised, and the area at risk and infarct size were determined. In both anesthetized and conscious rats, XE991 increased blood pressure, and the highest dose (7.5 mg/kg) of XE991 also increased heart rate, and 44% of conscious rats died. XE991 induced marked changes in the electrocardiogram (e.g., increased PR interval and prolonged QT C interval) without changing cardiac action potentials. The infarct size to area at risk ratio was reduced from 53 ± 2% (n = 8) in the vehicle compared to 36 ± 3% in the IPC group (P < 0.05, n = 9). XE991 (0.75 mg/kg) treatment alone or on top of IPC failed to reduce myocardial infarct size. Similar to the effect in isolated hearts, locally applied IPC was cardioprotective in intact animals exposed to ischemia-reperfusion. Systemic administration of XE991 failed to protect the heart against ischemia-reperfusion injury suggesting effects on the autonomic nervous system counteracting the cardioprotection in intact animals., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Disruptions in the ubiquitin protein ligase E3A ( UBE3A ) gene cause Angelman syndrome (AS). Whereas AS model mice have associated synaptic dysfunction and altered plasticity with abnormal behavior, whether similar or other mechanisms contribute to network hyperactivity and epilepsy susceptibility in AS patients remains unclear. Using human neurons and brain organoids, we demonstrate that UBE3A suppresses neuronal hyperexcitability via ubiquitin-mediated degradation of calcium- and voltage-dependent big potassium (BK) channels. We provide evidence that augmented BK channel activity manifests as increased intrinsic excitability in individual neurons and subsequent network synchronization. BK antagonists normalized neuronal excitability in both human and mouse neurons and ameliorated seizure susceptibility in an AS mouse model. Our findings suggest that BK channelopathy underlies epilepsy in AS and support the use of human cells to model human developmental diseases., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Prolonged-release (PR) fampridine is a potassium channel blocker used as a symptomatic treatment for walking disability in patients with multiple sclerosis (MS). Its clinical effects in such patients have not been systematically reviewed, and may be more wide-ranging than expected., Objectives: To summarize the evidence on the effects of PR fampridine in patients with MS., Methods: A systematic search of Pubmed, Scopus (including EMBASE), and PsycINFO (completed in 01/2019) was carried out to identify randomized controlled trials (RCT) that compared PR fampridine to placebo. When appropriate, data were pooled using a random-effects model, and standardized mean differences (SMD) were computed. Study quality was assessed using the Downs and Black checklist. PRISMA guidelines were followed. All retrieved functional outcomes were categorized according to the International Classification of Functioning, Disability and Health (ICF)., Results: A total of 706 articles were screened for inclusion. Twenty RCTs involving 2616 patients met the eligibility criteria. Most studies were of good-to-excellent quality. PR fampridine administration resulted in significant benefits in relation to walking short distances (SMD: 1.23 (95% IC 0.65-1.81)) and perceived walking capacity (0.64 (0.27-1.02)). Its effects on muscle strength and middle-distance walking were not significant (0.53 (- 0.04 to 1.10) and 0.31 (- 0.18 to 0.80), respectively). No effect on higher-level cognitive functions (- 0.07 (- 0.58 to 0.45)) or hand and arm use (0.16 (- 0.33 to 0.64)) was observed. Individual studies reported effects on other outcomes across the ICF domains., Conclusions: There is strong evidence that PR fampridine exerts strong effects on the ability to walk short distances and on perceived walking capacity. Other effects of PR fampridine according to the ICF are possible but still unclear.

Introduction : The present status of amifampridine (AFP) for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) is reviewed. Areas covered : All relevant literature identified through a PubMed search under treatment of LEMS, aminopyridine, and amifampridine are reviewed. An expert opinion on AFP was formulated. Expert opinion : AFPs, 3,4-DAP and 3,4-DAPP, are the most studied drugs in neuromuscular diseases. Randomized and non-randomized studies showed the most effective drug as symptomatic medication for LEMS. AFPs are safe and tolerable. Thus, AFPs should be the drug of choice for the symptomatic treatment in LEMS. As long as the daily dose is less than 80 mg a day, there is no concern for the serious side-reaction, seizure. Because of short-acting drug effects, it should be given three or four times a day. Peri-oral and finger paresthesia, the most common side-reaction, is accepted as a sign of drug-intake by many patients. Gastro-intestinal side reactions, the next common side-reaction of AFPs, are tolerable. AFPs are also the drug of choice and life-saving for LEMS crisis. For the long-term usage, it is proven to be safe and AFPs can be supplemented with liberal amount of pyridostigmine to sustain a symptomatic improvement without any undue side-reaction.

Background: Macrophages are a primary type of innate immune cells activated in colitis. Kv1.3 channel is one of the major potassium channels in macrophages. NLRP3 inflammasome is a downstream molecule of Kv1.3 channel. PAP-1, a specific Kv1.3 channel blocker, has been shown to have immune-regulatory effects., Objective: To investigate the effect of PAP-1 on intestinal inflammation in DSS-induced colitis and explore its possible mechanism., Methods: C57BL/6 mice were divided into four groups: normal control group, normal+PAP-1 injection group, DSS model group, DSS model+PAP-1 injection group. Experimental colitis was induced by 5% DSS treatment; mice were injected intraperitoneally with PAP-1 from the first day for 7 consecutive days; then all mice were sacrificed, followed by isolation of colon tissue, peritoneal macrophages and spleen macrophages. The anti-inflammatory effects of PAP-1 and the expression levels of Kv1.3, iNOS, pro-IL-1β, IL-1β and NLRP3 inflammasome were measured., Results: PAP-1 reduced DSS-induced colonic pathological damage, DAI score, MPO activity and levels of IL-1, IL-6, TNF-a, IL-18. Compared with the DSS model group, the expression of Kv1.3, iNOS, NLRP3, ASC, caspase-1p20, pro-IL-1β and IL-1β in colon were decreased in the DSS-induced colitis mice with PAP-1 injection. PAP-1 also reduced the expression of Kv1.3, iNOS, NLRP3, caspase-1p20 and IL-1β on macrophages in colitis mice., Conclusion: PAP-1 had protective effects on DSS-induced colitis, which might be ascribed to the regulation of NLRP3 inflammasome pathway. Therefore, we found that PAP-1 was useful as a therapeutic agent in IBD and suggested a potential important role of PAP-1 in NLRP3 inflammasome-associated diseases., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: There are no validated, practical, and quantitative measures of disease severity in Lambert-Eaton myasthenia (LEM)., Methods: Data from the Effectiveness of 3,4-Diaminopyridine in Lambert-Eaton Myasthenic Syndrome (DAPPER) trial were analyzed to assess triple timed up-and-go (3TUG) reproducibility and relationships between 3TUG times and other measures of LEM severity., Results: The coverage probability technique showed ≥0.90 probability for an acceptable 3TUG difference of ≤0.2, indicating that it is reproducible in LEM patients. The correlation between 3TUG times and lower extremity function scores was significant in subjects who continued and in those who were withdrawn from 3,4-diaminopyridine free base. Worsening patient-reported Weakness Self-Assessment Scale and Investigator Assessment of Treatment Effect scores corresponded with prolongation of 3TUG times., Discussion: The 3TUG is reproducible, demonstrates construct validity for assessment of lower extremity function in LEM patients, and correlates with changes in patient and physician assessments. These findings, along with prior reliability studies, indicate 3TUG is a valid measure of disease severity in LEM., (© 2019 Wiley Periodicals, Inc.)

Objective: To test a possible benefit of dalfampridine on information processing speed (IPS), a key function for cognitive impairment (CogIm) in multiple sclerosis (MS)., Methods: In this randomized, double-blind, placebo-controlled trial, we included patients with a score on the Symbol Digit Modalities Test (SDMT) under the 10th percentile of the reference value. Patients were randomized in a 2:1 ratio to receive dalfampridine 10 mg or placebo twice daily for 12 weeks. They underwent a comprehensive neuropsychological evaluation at screening (T0), at the end of treatment (T1), and after a 4-week follow-up (T2). The primary endpoint was improvement in SDMT., Results: Out of 208 patients screened, 120 were randomized to receive either dalfampridine (n = 80) or placebo (n = 40). At T1, the dalfampridine group presented an increase of SDMT scores vs placebo group (mean change 9.9 [95% confidence interval (CI) 8.5-11.4] vs 5.2 [95% CI 2.8-7.6], p = 0.0018; d = 0.60 for raw score; and 0.8 [95% CI 0.6-1] vs 0.3 [95% CI 0.0-0.5], p = 0.0013; d = 0.61 for z scores; by linear mixed model with robust standard error). The improvement was not sustained at T2. A beneficial effect of dalfampridine was observed in the Paced Auditory Serial Addition Test and in cognitive fatigue., Conclusion: Dalfampridine could be considered as an effective treatment option for IPS impairment in MS., Trial Registration: 2013-002558-64 EU Clinical Trials Register., Classification of Evidence: This study provides Class I evidence that for patients with MS with low scores on the SDMT, dalfampridine improves IPS., (© 2019 American Academy of Neurology.)

Introduction : Multiple sclerosis (MS) is a demyelinating disease, causing axonal damage and disability. Dalfampridine (DAL) is an extended-release formulation of 4-aminopyridine (4AP) and broad-spectrum voltage-dependent potassium channel blocker that is reported to improve motor, visual and cognitive functions. Furthermore, it is presently the only approved drug for walking impairment in MS. Areas covered : Herein, the authors evaluate DAL as a relapsing-remitting MS treatment, reporting and commenting on all aspects of the drug including its chemistry, safety, pharmacokinetics, and cost-effectiveness. A bibliographic search was performed on PubMed using the terms 'dalfampridine OR fampridine OR 4-aminopyridine'. Expert opinion : Evidence from post-marketing studies suggests that DAL, consistent with the effects of 4AP, may not only improve walking speed, but also arm function, fatigue, mood and cognition through restored nerve conduction in central nervous system demyelinated areas. Long-term safety data confirm that the approved dose of 10 mg twice daily is generally well tolerated. However, despite the reported efficacy, the extent of the benefits is limited in real life activities, although significant improvements have been demonstrated in the clinical setting. Patients often complain of side effects (such as cramps and painful paraesthesia) or lack of efficacy. Also, its considerably higher pricing in comparison to 4AP represents an important limitation.