dalfampridine / Generic mfg. - LARVOL DELTA

Illuminating Multiple Sclerosis: Next-Generation PET Tracers for Molecular Insights. (PubMed, J Nucl Med) - "Among them, [18F]3F4AP-a fluorinated analog of 4-aminopyridine-targets voltage-gated potassium channels that become exposed after demyelination, offering a promising tool to detect myelin loss...These agents have demonstrated utility in both animal studies and early clinical investigations, supporting their translational relevance. This review focuses on the pharmacologic properties, imaging protocols, and developmental progress of PET tracers that directly or indirectly reflect demyelination, advancing personalized approaches to diagnosis, monitoring, and therapeutic evaluation in multiple sclerosis."

Journal • CNS Disorders • Multiple Sclerosis

TREAT-FGF14: A Randomized, Parallel-arm, Double Blind, Placebo-controlled Study to Assess the Efficacy of Fampridine for Patients With Spinocerebellar Ataxia SCA27B Caused by a GAA Expansion in the FGF14 Gene (clinicaltrials.gov) - P3 | N=70 | Recruiting | Sponsor: Assistance Publique - Hôpitaux de Paris | Not yet recruiting ➔ Recruiting

Enrollment open • Ataxia • Movement Disorders

Effect of Aminopyridines on Oculomotor Dysfunction in Anti-GAD Ataxia: A Brief Report. (PubMed, Cerebellum) - "A 69-year-old woman with confirmed anti-GAD cerebellar ataxia underwent clinical and videonystagmography (VNG) assessments at baseline, Day 7, and Day 30 after start of fampridine 20 mg/day...APs may offer adjunctive symptomatic benefit in selected individuals with visually disabling downbeat nystagmus. Controlled studies are needed to confirm these observations."

Journal • Ataxia • Movement Disorders • Ophthalmology

"Effectiveness and associated factors of response to Fampridine in multiple sclerosis: A prospective observational study from an expert center". (PubMed, Mult Scler Relat Disord) - "Fampridine significantly improves gait performance in MS patients in real-world settings. Simple clinical variables such as age, sex, EDSS, and subjective walking impairment (MSWS-12) may help identify individuals most likely to benefit from treatment."

Journal • Observational data • CNS Disorders • Multiple Sclerosis

Distal HCN channels mediate, while potassium channels modulate, ectopic action potential generation in neocortical parvalbumin positive interneurons. (AES 2025) - "Tetraethylammonium (TEA) abolished ectopic action potentials in 6/13 PV+ cells, and 4-aminopyridine (4AP) decreased ectopic action potential initiation threshold and increased robustness in all 13 neurons, suggesting a heterogeneous contribution of voltage-gated potassium subtypes to ectopic action potential generation. The hyperpolarization activated cation channel (HCNC) antagonist Ivabradine (30 μM) abolished ectopic action potential generation in 7/10 cells and diminished robustness in all 10 cells. Given prior associations between HCNC deficiencies and some epilepsies, as well as potassium channel abnormalities and epilepsies, our data suggest that ectopic action potential generation in PV+ cells should be investigated as a potential contributor to seizure genesis and propagation."

Late-breaking abstract • CNS Disorders • Epilepsy

Single White Matter Electrode for Bilateral Epileptic Activity Detection and Monitoring (AES 2025) - "This study investigates the feasibility of using a single electrode placed in the CC or fimbria to detect and monitor epileptic activity across both hemispheres and evaluates its potential for closed-loop epilepsy management. We employed both in vitro (4-aminopyridine bath and focal epilepsy models) and in vivo (4-AP focal epilepsy) models to induce epileptic activity... White matter recordings via a single electrode provide a novel, efficient method for detecting and monitoring epileptic activity across large cortical and hippocampal territories. This approach reduces the need for multiple electrodes and precise localization of seizure foci. The correlation between RMS values and seizure severity further supports the utility of this method for real-time monitoring and closed-loop therapeutic interventions, particularly in conjunction with low-frequency white matter stimulation strategies."

Cardiovascular • CNS Disorders • Epilepsy

Seizure network characterization and manipulation in vivo (AES 2025) - "To better understand this process, we have developed methods to study excitatory and inhibitory activity across a bilateral brain network in mice that is also amenable to neurostimulation testing. We performed widefield calcium imaging of Thy1+ excitatory and PV+ inhibitory neurons in focal onset seizures induced by the chemoconvulsant 4-Aminopyridine (4-AP) in awake mice... Our findings suggest that focal onset seizures propagate to distant brain sites based on excitatory and inhibitory balance. Our stimulation findings suggest that low frequency stimulation, similar to the dominant frequency of seizures, induces facilitating activity of both excitatory and inhibitory cell types. Meanwhile, high frequency stimulation induces slow adaptation of excitatory cell responses, re-affirming the therapeutic potential of high frequency neurostimulation for epilepsy."

Preclinical • CNS Disorders • Epilepsy

Suppression of Electric Field Coupled Epileptic Activity Using a Perforated Carbon NanoTube Film (AES 2025) - "To counteract these fields, the lab made an extracellular clamp that successfully eliminated epileptiform activity in a 4-Aminopyridine (4-AP) hippocampal in-vitro mouse model by maintaining the focus at zero volts... By short-circuiting the electric field responsible for seizure propagation, perforated CNTFs halt nearly all epileptiform propagation, offering a non-invasive, reliable, and biocompatible alternative to more complex interventions. Their flexibility, permeability, and lack of active electronics make them especially suitable for clinical translation, potentially reducing the need for tissue resection and minimizing the risk of reintervention."

CNS Disorders • Epilepsy • CA3

First Human In Vitro Model of Circadian Rhythms in Epilepsy Reveals Clock Gene Disruption in Genetic and Acute Seizure Condition (AES 2025) - "Gene expression and neuronal network activity were evaluated at baseline and following seizure induction using 4-aminopyridine (4-AP; 5 mM, 10 min) in DS, isogenic, and healthy control cultures. Neuron-astrocyte co-cultures showed robust circadian oscillations, with activator genes peaking at CT12 and repressors at CT4—rhythms absent in iPSCs and phase-delayed in neuron-only cultures... This is the first demonstration of a human iPSC-derived culture system that models molecular and electrophysiological circadian rhythms in epilepsy. Our findings reveal conserved disruptions in core clock gene dynamics across both genetic and acute seizure models, supporting the hypothesis that epilepsy perturbs fundamental circadian machinery. This platform opens new avenues to dissect circadian pathophysiology in epilepsy and guide future development of time-targeted (chronotherapeutic) interventions."

Late-breaking abstract • Preclinical • CNS Disorders • Epilepsy • Sleep Disorder • ARNTL • BMAL1 • CLOCK • CRY1 • NPAS2 • PER1

Aminopyridine Treatment for An Adult Case of Developmental And Epileptic Encephalopathy with A Gain-of-function Mutation in KCNA2 (AES 2025) - "Encouragingly, 4-aminopyridine (4-AP), a inhibitor of voltage-gated potassium channels, was reported to be effective in treating KCNA2-DEE... We report the 4-AP treatment for an adult case with KCNA2-DEE. Despite the long duration of DEE, the patient's symptoms improved following a short course of low-dose, targeted treatment with 4-AP. Further follow-up is required to evaluate long-term treatment outcomes of 4-AP for KCNA2-DEE."

Clinical • Absence Seizure Disorder • Alzheimer's Disease • Ataxia • CNS Disorders • Cognitive Disorders • Developmental Disorders • Epilepsy • Mental Retardation • Movement Disorders

Spatial Dynamics Of Seizure-Like Events In The Neonatal And Adolescent Mouse Brain (AES 2025) - "Seizure-like activity was induced with 4-aminopyridine (4-AP) in both coronal and horizontal acute brain slices from transgenic mice expressing a genetically encoded calcium indicator, GCaMP6s, under the Thy1 promoter... Our data reveal that neonates have a greater number of interictal foci. The number of foci decreased in neonates when inhibition was blocked. This data suggests that the neonatal brain is more prone to develop multifocal activity than the adolescent brain."

Preclinical • CNS Disorders • Epilepsy • THY1

A High-Resolution Approach for Cerebrospinal Fluid Cytokine Detection Using Push-Pull Sampling and Nano Dot Blot: Minute by Minute TNF-α Dynamics During Epileptiform Activity. (PubMed, J Neurosci Methods) - "Our findings demonstrate the utility of this minute-by-minute approach in capturing transient neuroinflammatory events and suggest that TNF-α may play a role in the initiation or modulation of acute epileptiform activity."

Journal • CNS Disorders • Epilepsy • Inflammation • TNFA

Triple Amperometric Microsensor for Simultaneous Real-Time In Vivo Monitoring of NO, CO, and H2S During Epileptic Seizures. (PubMed, ACS Sens) - "To demonstrate in vivo applicability, the sensor was positioned on the cortical surface of a living rat brain, where it successfully monitored real-time concentration changes of NO, CO, and H2S during seizure events induced by 4-aminopyridine: NO exhibited the earliest concentration increase, followed sequentially by CO and H2S, providing the first temporally resolved evidence of in vivo gasotransmitter crosstalk during neural hyperactivity. This work establishes a powerful electrochemical platform for probing multigasotransmitter dynamics in real time."

Journal • Preclinical • CNS Disorders • Epilepsy

Impairment of local metabolic coronary control involves perfusion-contraction matching not supply-demand imbalance. (PubMed, Basic Res Cardiol) - "To address this question we performed experiments in a cannulated coronary preparation in swine to precisely control flow as myocardial oxygen consumption (MVO2) and contractile function were modulated by dobutamine (1-10 μg/kg/min, iv), reductions in coronary perfusion pressure (CPP), and the inhibition of voltage-gated K+ channels with 4-aminopyridine (4-AP; 1 mM, ic). Wall thickening progressively decreased as coronary flow was reduced below ~ 5.0-7.5 μL/g/beat regardless of whether the decrease was due to diminished "supply" (CPP, 4-AP) or limitations during increased "demand" (flow clamp or restriction with dobutamine). These findings demonstrate that impairments in local metabolic control of coronary flow are reliably demonstrated by decreases in contractile function as a consequence of reductions in the volume of myocardial perfusion per beat."

Journal

Precision neural activity mapping in brain organoids through field potential imaging with ultra-high-density CMOS microelectrode array (Neuroscience 2025) - "In cortical organoids, the GABAA receptor antagonist picrotoxin increased propagation velocity, whereas the NMDA receptor antagonist MK-801 broadly reduced propagation area with regionally localized enhancements...Connectivity analysis further demonstrated that treatment with 4-aminopyridine significantly enhanced inter-organoid coupling. This single-cell-resolved, high-density FPI approach enables robust quantification of neuronal firing, connectivity, propagation dynamics, and frequency characteristics. Our platform offers a powerful tool for investigating functional neural circuits in brain organoids and assembloids, with significant potential for applications in drug screening and disease modeling."

CNS Disorders

Examining neural activation in bipolar I disorder during mania: A meta-analysis of functional magnetic resonance imaging studies [WITHDRAWN] (Neuroscience 2025) - "Examining neural activation in bipolar I disorder during mania: A meta-analysis of functional magnetic resonance imaging studies.Ariana Sanchez Virrueta1, Summer Herrera1, Fabiola Amaya Reyes1, Gabrielle Johnson-Venegas1, Caitlin Baten1, Gladys Zamora1, Matthew Sacchet, Ph.D.,2 Ian Gotlib, Ph.D.,3 Paul Hamilton, Ph.D.,4 Patrick Durkee, Ph.D.,1 Ellen Woo, Ph.D.,1 Dawson Hedges, M.D.,5 Chris Miller, Ph.D.11California State University, Fresno, 2Massachusetts General Hospital, Harvard Medical School, 3Stanford University, 4University of Bergen, 5Brigham Young UniversityIntroduction: Bipolar I disorder (BD-I) is an affective disorder characterized by cycles of recurrent manic and major depressive episodes... These findings suggest that the current literature on fMRI studies investigating mania are too sparse to warrant any robust conclusions. Additional studies are needed to better characterize the neural correlates of mania in BD-I."

MRI • Retrospective data • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry • GAS1

Development of a High-Throughput Human iPSC-Based Pain Assay Platform: Functional Characterization of Nociceptors for Analgesic Screening (Neuroscience 2025) - "We also detected increased activity in the somas and neurites after addition of Nav1.7 agonist OD1 and K+ channel antagonist 4-aminopyridine (4-AP)...Pre-incubation with tetrodotoxin (TTX), an antagonist of voltage gated sodium channels, led to more modest effects, with inhibition of the VTD-induced response speed but not amplitude. This result suggests the presence of TTX-independent channels in the cells. Collectively this data suggests that targeting DRG ion channels is an attractive avenue for discovering new therapeutics for modulating DRG function and ultimately the mitigation of pain."

Addiction (Opioid and Alcohol) • CNS Disorders • Pain • NAV1

Combinatorial approaches increasing neuronal activity accelerate recovery after spinal cord injury (Neuroscience 2025) - "We hypothesized that enhancing neuronal activity—by strengthening corticospinal synapses through Hebbian stimulation and increasing neuronal transmission with 4-aminopyridine (4-AP), a potassium blocker—could accelerate locomotor recovery in individuals with chronic SCI...Improvement in the 4-AP group was still present approximately 12 months later. These findings suggest that 4-AP represents a strategy to potentiate and accelerate Hebbian stimulation effects on motor recovery in individuals with chronic SCI."

CNS Disorders

Development of new aminopyridines for the safe and effective treatment of peripheral neurological disorders (Neuroscience 2025) - "Grant Support NIH Grant AI093504; Grant Support NIH Grant AI173059; Grant Support NIH Grant AI180532; Grant Support DTRA BAA CB11178; Grant Support DOD OTA MCDC2212-003 Aminopyridine-based voltage-gated potassium channel (VGKC) blockers, such as 3,4-diaminopyridine (3,4-DAP) and 4-aminopyridine, enhance neurotransmitter release by prolonging presynaptic action potentials...Lead compounds are advancing into translational development as fast-acting NAT2-resistant therapeutics for BoNT intoxication and other peripheral neuromuscular pathologies. These findings validate an aminopyridine drug discovery platform with the potential to identify VGKC modulators targeting new indications, such as pain, muscular dystrophy, and seizures."

CNS Disorders • Epilepsy • Myasthenia Gravis • NAT2

Tdp43's role in synaptic metabolism in the adult mouse brain (Neuroscience 2025) - "To test this hypothesis, we present preliminary evidence using orthogonal validation approaches such as proximity ligation within brain tissue, as well as within primary neuronal cultures before and after 4-aminopyridine and bicuculline treatment supporting these findings. Collectively, these findings point to a novel mechanism by which TDP-43 dysfunction may impair synaptic metabolism, driving synaptic loss and accelerating cognitive decline in neurodegenerative disease."

Preclinical • CNS Disorders • Tauopathies And Synucleinopathies • TARDBP

Neurophysiological and proteomic alterations in heterozygous AppNL-G-F mouse model of Alzheimer's disease: an ex vivo study (Neuroscience 2025) - "Next we tested seizure succeptibility in brain slices, using K+ channel blocker, 4-aminopyridine...This study provides the first integrated physiological and proteomic characterization of the heterozygous AppNL-G-F model. Our findings identify specific neurophysiological alterations that may serve as early indicators of disease progression, and potential targets for intervention prior to overt amyloid pathology."

Preclinical • Alzheimer's Disease • CNS Disorders • Epilepsy • SYT11

Evaluation of Bee Venom's Effects on Convulsive Seizures Induced by 4-Aminopyridine in Rats (Neuroscience 2025) - "Although bee venom has not yet been widely explored as a treatment for epilepsy, its effects on seizure modulation requires further investigation, particularly regarding its mechanisms of action within the nervous system. Supported by University of Guadalajara (PROSNI 2024, CVM/LMC, Fortalecimiento 2024, LMC)."

Preclinical • CNS Disorders • Epilepsy

A high-throughput in vitro functional platform for anti-epileptic drug screening in genetic and chemically induced seizure models (Neuroscience 2025) - "We established a chemically induced seizurogenic model by applying traditional pro-seizurogenic compounds with different mechanisms of action - picrotoxin (PTX), 4-aminopyridine, and pentylenetetrazol - as well as elevated extracellular K⁺ concentrations, to rat hippocampal neurons cultured on mwMEA plates. Then, we evaluated the anti-seizurogenic effects of valproate (VPA) and retigabine (RTG), which act on different molecular targets...Furthermore, VPA exhibited a more pronounced concentration-dependent inhibition in the DS group. Based on our study, the in vitro, cell-based mwMEA assay provides a novel approach for high-throughput screening and evaluation of antiepileptic drug candidates in both chemically induced and genetic defect models, potentially accelerating the discovery of new therapies for neurological disorders."

Preclinical • CNS Disorders • Epilepsy • NAV1

Neuron-targeted Nrf2 gene therapy confers long-term antioxidant and neuroprotective effects in refractory epilepsy (Neuroscience 2025) - "Under seizure-like conditions induced by picrotoxin and 4-aminopyridine, Nrf2 overexpression reduced calcium hyperexcitability, suppressed ROS accumulation, and decreased neuronal death...In conclusion, neuron-targeted Nrf2 gene therapy provides durable antioxidant and neuroprotective effects across multiple stages of epilepsy. By enhancing endogenous defense pathways in excitatory neurons, this strategy holds promise as a preventive and disease-modifying treatment for drug-resistant epilepsy."

Gene therapy • CNS Disorders • Epilepsy • NFE2L2 • NQO1

Evaluation of anti-epileptic mechanisms in the entorhinal cortex (EC) ex vivo using different convulsant models and analysis methods (Neuroscience 2025) - "We compared effects of several compounds (with known mechanisms of action) on different measures of epileptiform activity induced by either the GABAA antagonist gabazine, or the potassium channel blocker 4-aminopyridine (4-AP).Epileptiform activity was recorded from adult mouse EC brain slices using extracellular electrodes. Slices were maintained in an interface chamber at 32C and were preincubated for 75 minutes in test compounds including a WNK-kinase inhibitor (WNK463, 1 µM), a KV7 channel enhancer (retigabine, 20 µM), a GABAA receptor positive allosteric modulator (diazepam, 50 µM), a mGlu2/3 receptor agonist (LY354740, 3µM), or vehicle...Retigabine appeared to enhance delta band power (124±7% increase) but reduced other frequency bands' power (73±21% decrease).Taken together, these results show that different analysis methods can reveal distinct facets of epileptiform activity and their modulation by anti-convulsant mechanisms. In..."

Preclinical • CNS Disorders • Epilepsy