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Patients with mutations that alter the function of the sodium channel SCN8A present with a range of clinical features, including mild to severe seizures, developmental delay, intellectual disability, autism, feeding dysfunction, motor impairment, and hypotonia. In an effort to identify compounds that could be potentially beneficial in SCN8A- associated epilepsy, Atkin et al. conducted an in vitro screen which resulted in the identification of 90 compounds that effectively reduced sodium influx into the cells expressing the human SCN8A R1872Q mutation. The top compounds that emerged from this screen included amitriptyline, carvedilol, and nilvadipine. In the current study, we evaluated the ability of these three compounds to increase resistance to 6 Hz or pentylenetetrazole (PTZ)-induced seizures in wild-type CF1 mice and in a mouse line expressing the human SCN8A R1620L mutation. We also evaluated the effects of fenfluramine administration, which was recently associated with a 60%–90% decrease in seizure frequency in three patients with SCN8A -associated epilepsy. While amitriptyline, carvedilol, and fenfluramine provided robust protection against induced seizures in CF1 mice, only carvedilol was able to significantly increase resistance to 6 Hz- and PTZ-induced seizures in RL/+ mutants. These results provide support for further evaluation of carvedilol as a potential treatment for patients with SCN8A mutations.

Voltage-gated sodium channel genes are an important family of human epilepsy genes. De novo missense mutations in SCN8A (encoding Na v 1.6) are associated with a spectrum of clinical presentation, including multiple seizure types, movement disorders, intellectual disability, and behavioral abnormalities such as autism. Patients with SCN8A mutations are often treated with multiple antiepileptic drugs, the most common being sodium channel blockers. Cannabidiol (CBD) has been included as a component of treatment regimens for some SCN8A patients; however, to date, there are no clinical trials that have evaluated the therapeutic potential of CBD in patients with SCN8A mutations. In the current manuscript, we demonstrated a dose-dependent increase in seizure resistance following CBD treatment in mice expressing the human SCN8A mutation R1620L (RL/+). We also found that CBD treatment improved social behavior and reduced hyperactivity in the RL/+ mutants. Our findings suggest that CBD may be beneficial in patients with SCN8A- associated disease.

Background: The neuropeptide oxytocin has been identified as a potential therapeutic molecule. However, the therapeutic potential of this molecule is limited due to the challenges faced in oxytocin delivery to the brain. Scientific innovation has led to the breakthrough discovery of many modalities to encapsulate molecules for targeted drug delivery, which can enhance oxytocin delivery to the brain. This research aimed to explore a microfluidics-based system that optimizes the formulation of cross-linked bovine serum albumin (BSA) nanoparticles encapsulating oxytocin. Methods: First, the formulation parameters were optimized using a design of experiments (DOE) by evaluating the effect of flow rate, polymer concentration, and the binary solvent mixture polarity on the nanoparticle size. Drug encapsulation efficiency, release, and kinetics profile were characterized. These oxytocin nanoparticles were conjugated to rabies virus glycoprotein (RVG), a brain-targeting ligand, and the conjugation efficiency was determined. Results: The sizes of the nanoparticles were between 50 nm and 75 nm with a <0.4 polydispersity index. The encapsulation efficiency was >80%. Approximately 58% of oxytocin was released from the nanoparticles within the first six hours, showing an initial burst that is ideal for seizure control and thereafter exhibiting the Korsmeyer–Peppas release kinetics. Conclusions: For the first time, we demonstrated the microfluidics method of formulating nanoparticles with particle size of less than 100 nm, with improved encapsulation efficiency and optimal release profile for oxytocin brain delivery.

loss-of-function mutations in the voltage-gated sodium channel (VGSC) (encoding Na 1.1) are the main cause of Dravet syndrome (DS), a catastrophic early-life encephalopathy associated with prolonged and recurrent early-life febrile seizures (FSs), refractory afebrile epilepsy, cognitive and behavioral deficits, and a 15-20% mortality rate. mutations also lead to genetic epilepsy with febrile seizures plus (GEFS+), which is an inherited disorder characterized by early-life FSs and the development of a range of adult epilepsy subtypes. Current antiepileptic drugs often fail to protect against the severe seizures and behavioral and cognitive deficits found in patients with mutations. To address the need for more efficacious treatments for -derived epilepsies, we evaluated the therapeutic potential of Huperzine A, a naturally occurring reversible acetylcholinesterase inhibitor. In CF1 mice, Hup A (0.56 or 1 mg/kg) was found to confer protection against 6 Hz-, pentylenetetrazole (PTZ)-, and maximal electroshock (MES)-induced seizures. Robust protection against 6 Hz-, MES-, and hyperthermia-induced seizures was also achieved following Hup A administration in mouse models of DS ( ) and GEFS+ ( ). Furthermore, Hup A-mediated seizure protection was sustained during 3 weeks of daily injections in mutants. Finally, we determined that muscarinic and GABA receptors play a role in Hup A-mediated seizure protection. These findings indicate that Hup A might provide a novel therapeutic strategy for increasing seizure resistance in DS and GEFS+, and more broadly, in other forms of refractory epilepsy.

De novo loss‐of‐function mutations in SCN1A are the main cause of Dravet syndrome, a catastrophic encephalopathy characterized by recurrent early‐life febrile seizures, a number of other afebrile seizure types that are often refractory to treatment, and behavioral abnormalities including social deficits, motor dysfunction, and cognitive impairment. We previously demonstrated that the reversible acetylcholinesterase inhibitor, Huperzine A, increases seizure resistance in Scn1a mutants. In the present study, we evaluated the therapeutic potential of donepezil, a reversible acetylcholinesterase inhibitor approved by the Food and Drug Administration, in a mouse model of Dravet syndrome (Scn1a+/−). We found that donepezil conferred robust protection against induced seizures in Scn1a+/− mutants.

Numerous SCN8A mutations have been identified, of which, the majority are de novo missense variants. Most mutations result in epileptic encephalopathy; however, some are associated with less severe phenotypes. Mouse models generated by knock-in of human missense SCN8A mutations exhibit seizures and a range of behavioral abnormalities. To date, there are only a few Scn8a mouse models with in-frame deletions or insertions, and notably, none of these mouse lines exhibit increased seizure susceptibility. In the current study, we report the generation and characterization of two Scn8a mouse models (ΔIRL/+ and ΔVIR/+) carrying overlapping in-frame deletions within the voltage sensor of domain 4 (DIVS4). Both mouse lines show increased seizure susceptibility and infrequent spontaneous seizures. We also describe two unrelated patients with the same in-frame SCN8A deletion in the DIV S5-S6 pore region, highlighting the clinical relevance of this class of mutations.

Rationale High doses of cocaine can elicit seizures in humans and in laboratory animals. Several mechanisms have been proposed for the induction of seizures by cocaine, including enhanced monoaminergic signaling, blockade of ion channels, and alterations in GABA and glutamate transmission. Mutations in the SCN1A gene, which encodes the central nervous system (CNS) voltage-gated sodium channel (VGSC) Na v 1.1, are responsible for several human epilepsy disorders including Dravet syndrome and genetic (generalized) epilepsy with febrile seizures plus (GEFS+). Mice heterozygous for the R1648H GEFS+ mutation (RH mice) exhibit reduced interneuron excitability, spontaneous seizures, and lower thresholds to flurothyl- and hyperthermia-induced seizures. However, it is unknown whether impaired CNS VGSC function or a genetic predisposition to epilepsy increases susceptibility to cocaine-induced seizures. Objectives Our primary goal was to determine whether Scn1a dysfunction caused by the RH mutation alters sensitivity to cocaine-induced behavioral and electrographic (EEG) seizures. We also tested novelty- and cocaine-induced locomotor activity and assessed the expression of Na v 1.1 in midbrain dopaminergic neurons. Results We found that RH mice had a profound increase in cocaine-induced behavioral seizure susceptibility compared to wild-type (WT) controls, which was confirmed with cortical EEG recordings. By contrast, although the RH mice were hyperactive in novel environments, cocaine-induced locomotor activity was comparable between the mutants and WT littermates. Finally, immunofluorescence experiments revealed a lack of Na v 1.1 immunoreactivity in dopaminergic neurons. Conclusion These data indicate that a disease-causing CNS VGSC mutation confers susceptibility to the proconvulsant, but not motoric, effects of cocaine.

▪ Abstract  The development of molecular markers and genomic resources has facilitated the isolation of genes responsible for rare monogenic epilepsies in human and mouse. Many of the identified genes encode ion channels or other components of neuronal signaling. The electrophysiological properties of mutant alleles indicate that neuronal hyperexcitability is one cellular mechanism underlying seizures. Genetic heterogeneity and allelic variability are hallmarks of human epilepsy. For example, mutations in three different sodium channel genes can produce the same syndrome, GEFS+, while individuals with the same allele can experience different types of seizures. Haploinsufficiency for the sodium channel SCN1A has been demonstrated by the severe infantile epilepsy and cognitive deficits in heterozygotes for de novo null mutations. Large-scale patient screening is in progress to determine whether less severe alleles of the genes responsible for monogenic epilepsy may contribute to the common types of epilepsy in the human population. The development of pharmaceuticals directed towards specific epilepsy genotypes can be anticipated, and the introduction of patient mutations into the mouse genome will provide models for testing these targeted therapies.

Patients with SCN8A epileptic encephalopathy exhibit a range of clinical features, including multiple seizure types, movement disorders, and behavioral abnormalities, such as developmental delay, mild-to-severe intellectual disability, and autism. Recently, the de novo heterozygous SCN8A R1620L mutation was identified in an individual with autism, intellectual disability, and behavioral seizures without accompanying electrographic seizure activity. To date, the effects of SCN8A mutations that are primarily associated with behavioral abnormalities have not been studied in a mouse model. To better understand the phenotypic and functional consequences of the R1620L mutation, we used CRISPR/Cas9 technology to generate mice expressing the corresponding SCN8A amino acid substitution. Homozygous mutants exhibit tremors and a maximum lifespan of 22 days, while heterozygous mutants (RL/+) exhibit autistic-like behaviors, such as hyperactivity and learning and social deficits, increased seizure susceptibility, and spontaneous seizures. Current clamp analyses revealed a reduced threshold for firing action potentials in heterozygous CA3 pyramidal neurons and reduced firing frequency, suggesting that the R1620L mutation has both gain- and loss-of-function effects. In vivo calcium imaging using miniscopes in freely moving RL/+ mutants showed hyperexcitability of cortical excitatory neurons that is likely to increase seizure susceptibility. Finally, we found that oxcarbazepine and Huperzine A, a sodium channel blocker and reversible acetylcholinesterase inhibitor, respectively, were capable of conferring robust protection against induced seizures in RL/+ mutants. This mouse line will provide the opportunity to better understand the range of clinical phenotypes associated with SCN8A mutations and to develop new therapeutic approaches.

Background Despite significant scientific progress since the 2012 discovery that variants in the SCN8A gene can cause human epilepsy, disease mechanisms and best practices for management of SCN8A-related disorders (SCN8A-RD) remain incompletely understood. To accelerate the rate of progress, the International SCN8A Alliance sponsored a conference in Boston, Massachusetts, on August 16–18, 2024. The goals were to identify core knowledge gaps and research priorities, and to establish a collaborative research strategy to improve quality of life. In addition to a number of family leaders representing caregiver priorities, the meeting included laboratory scientists, clinicians, and representatives from the biopharmaceutical industry. Main body The scientific literature and requests for proposals from epilepsy funding agencies were reviewed prior to the meeting. Stakeholder-specific surveys were conducted focusing on knowledge gaps, research priorities, and scientific roadblocks. Interviews with biotechnology leaders were conducted to identify their priorities. These data were analyzed to assess responsiveness to caregiver concerns and to identify top research priorities for advancing the field. The Caregiver survey (n = 175) revealed top challenges and identified novel therapeutics and management of non-seizure phenotypes/comorbidities as top priorities. Clinician (n = 46) and scientist (n = 23) surveys identified a number of common research priorities, partially overlapping with caregiver concerns. Five core areas emerged from integrated analysis of all four stakeholder surveys and became the focus areas of five Working Groups : (1) Transformative Therapeutics, (2) Non-Seizure Outcomes, (3) Current Therapeutics, (4) Biomarkers, and (5) Whole Brain/Whole Body. Conclusions Taking account of the concerns and priorities of the caregiver community, the five working groups identified research directions to address knowledge gaps that include both short- and long-term priorities to improve understanding of disease mechanisms and management for the spectrum of SCN8A-RD phenotypes. Challenges included identification of suitable funding mechanisms and the lack of expertise in certain methodologies and research areas. This Research Roadmap is expected to accelerate progress toward the goals of improved quality of life and transformative care for all those with SCN8A-RD.