Search Results (209)

Background: This study aimed to compare serum levels of nitric oxide (NO) related metabolites, glial fibrillary acidic protein (GFAP), and ubiquitin (UBI) between children with controlled epilepsy (CE) and drug-resistant epilepsy (DRE) of unknown etiology, and to investigate the associations between these biomarkers and electroclinical features. Methods: Eighty-five children aged 2–18 years with epilepsy of unknown etiology who had been receiving antiseizure treatment for at least six months were enrolled; 58 were classified as CE and 27 as DRE. Serum GFAP and UBI concentrations were measured using enzyme-linked immunosorbent assay, and serum NO-related metabolites were assessed using a Griess-based colorimetric assay. Between-group comparisons were performed using the Mann–Whitney U test, and associations between biomarkers and clinical variables were evaluated using Spearman rank correlation analysis. Bonferroni correction was applied for multiple comparisons. Results: Historical seizure frequency, comorbidity rate, and seizure detection on initial video-EEG differed significantly between the CE and DRE groups. However, serum NO-related metabolite, GFAP, and UBI levels did not differ significantly between the CE and DRE groups. Correlation analyses revealed a significant positive correlation between serum NO-related metabolite levels and age exclusively in the DRE group (ρ = 0.594, p = 0.001), which remained significant after Bonferroni correction. No such association was observed in the CE group. Conclusion: No statistically significant differences in the measured peripheral serum biomarkers were detected between the CE and DRE groups in this sample. The age-related increase in NO-related metabolites observed in the DRE group should be interpreted cautiously and does not establish progressive NO upregulation or cumulative neuroinflammatory burden. Studies incorporating a healthy control group, standardized sampling intervals, and longitudinal designs are needed to clarify the clinical utility of these biomarkers in childhood epilepsy. Full article

Background: Drug-resistant epilepsy (DRE) affects approximately one-third of individuals with epilepsy, where seizures remain uncontrolled despite appropriate trials of at least two antiseizure medications (ASMs). Neuroinflammation, specifically chronic microglial activation, plays an important role in epileptogenesis, seizure perpetuation, and pharmacoresistance. Traditionally, antiseizure medications (ASMs) target neuronal excitability through modulation of ion channels and neurotransmitter systems; however, several ASMs, including sodium valproate and lamotrigine, have demonstrated anti-inflammatory and microglia-modulating properties beyond their conventional antiseizure mechanisms. Rational polytherapy involving combinations of ASMs with complementary mechanisms and anti-neuroinflammatory effects may provide enhanced seizure control while minimizing adverse effects. Among available combinations, sodium valproate and lamotrigine have consistently been regarded as one of the few combinations demonstrating potential pharmacodynamic synergism. Although several clinical studies have evaluated this combination in pediatric DRE, the overall evidence has not been quantitatively synthesized. Objectives: To systematically evaluate the efficacy and safety of rational polytherapy with sodium valproate plus lamotrigine in children with drug-resistant epilepsy. Methods: Electronic databases, including PubMed, Medline, Scopus, Embase, Web of Science, Google Scholar, PubMed Central, ScienceDirect, Cochrane Library, and clinicaltrials.gov, were systematically searched. Studies involving pediatric patients aged 18 years or less with DRE receiving polytherapy regimens containing sodium valproate plus lamotrigine were included. Primary outcomes were total treatment effect defined as ≥50% seizure reduction and seizure freedom. Secondary outcomes included changes in seizure frequency, adverse events, treatment discontinuation, and serious adverse events. Risk of bias was assessed using the Cochrane Risk of Bias tool and Newcastle–Ottawa Scale. Meta-analyses were performed using random-effects models. Results: A total of 7 studies met the eligibility criteria. The pooled proportion of patients achieving an overall treatment response was 65.3% (95% CI 51.8–78.8%), with high heterogeneity (I² = 63.4%, p = 0.027). Rational polytherapy with sodium valproate plus lamotrigine combination provided preliminary comparative evidence of higher responder rates in a single comparative trial, requiring confirmation in larger randomized trials. Overall, sodium valproate plus lamotrigine was well tolerated, and most reported adverse events were mild to moderate in severity. The pooled adverse event rate was 18.1% (95% CI 8.3–28.0%), with high heterogeneity (I² = 64.3%, p = 0.024). Conclusions: Rational polytherapy with sodium valproate plus lamotrigine that have both complementary antiseizure and immunomodulatory mechanisms appears to represent an effective and generally well-tolerated therapeutic strategy for pediatric drug-resistant epilepsy. However, the basis of this conclusion is derived mainly from observational studies, requiring confirmation in larger randomized trials. This systematic review provides quantitative evidence supporting its clinical use while highlighting the need for larger prospective comparative studies to strengthen the evidence base. Full article

Background/Objectives: Antiseizure drugs (ASDs) are the primary therapeutic approach for epilepsy in small animals. Although ASDs are primarily used to modulate central neuronal excitability, they are commonly administered systemically, most often by the oral route, and may therefore influence neuronal populations outside the central nervous system. Nevertheless, their functional effects on peripheral neuronal populations, including enteric and dorsal root ganglion (DRG) neurons, remain incompletely characterized at a comparative pharmacological level. This study aimed to perform a comparative functional neuropharmacological profiling of commonly used ASDs in primary cultured myenteric and DRG neurons. Methods: Changes in neuronal activity were assessed in primary cultured guinea pig myenteric and DRG neurons using voltage-sensitive dye imaging with Di-8-ANEPPS following direct ASD application under standardized in vitro conditions. Results: ASDs exerted distinct drug- and neuron-type-specific effects on peripheral neuronal excitability. Topiramate induced the most pronounced reduction in neuronal excitability in myenteric neurons, whereas phenobarbital and levetiracetam produced only minor changes compared with buffer control. Potassium bromide induced mainly excitatory effects in both enteric and DRG neurons. Overall, most ASDs predominantly increased neuronal excitability in DRG neurons. Conclusions: These findings demonstrate distinct functional response profiles of ASDs in enteric and sensory neuronal populations. This comparative in vitro approach may provide a basis for future studies investigating peripheral neuronal drug effects and may help relate experimental pharmacological profiling to clinically relevant challenges associated with ASD treatment across different disorders. Full article

Epilptogenesis is a long-term process that involves the transformation of a healthy brain into a seizure-producing brain. Since approximately 30% of epilepsy patients suffer from drug-resistant seizures, the concept of inhibiting the epileptogenesis process and thus preventing seizures has emerged. The search for effective methods of inhibiting epileptogenesis is possible thanks to animal models, which include kindled seizures; models based on the induction of status epilepticus resulting in subsequent spontaneous recurrent seizures, or brain trauma; and genetic models. Blood–brain barrier dysfunction, inflammatory processes in the brain, and oxidative stress appear to play a major role in epileptogenesis. This prompted testing of a number of anti-inflammatory agents and antioxidants in the epileptogenic process. One noteworthy finding was that losartan (an antihypertensive drug), as a TGF-β antagonist, proved effective in inhibiting epileptogenesis due to blood–brain barrier damage. Due to the many mechanisms involved in the process of epileptogenesis, it seems that the use of a combination of drugs will be an effective method of inhibiting it. The most promising combination includes levetiracetam (a second-generation antiseizure drug), atorvastatin, and ceftriaxone (a beta-lactam antibiotic), which effectively inhibits spontaneous seizures in animals experiencing status epilepticus. Any clinical trials on the inhibition of epileptogenesis must take into account the fact that a small percentage of patients develop epileptic seizures after stroke or brain injury. Recently suggested markers predicting a high probability of epileptic seizures after brain damage may facilitate appropriate patient selection for studies on inhibition of epileptogenesis. Full article

Background: Microbiome-based mechanisms have emerged as a key area of investigation in epilepsy, given the growing recognition that gut microbial communities can modulate central nervous system (CNS) function through the gut–brain axis. Epilepsy is a common chronic neurological disorder affecting more than 65 million people worldwide, and despite the availability of anti-seizure medications (ASMs), approximately 30% of patients develop drug-resistant epilepsy. Current ASMs primarily suppress seizures rather than prevent disease progression, highlighting the need for alternative therapeutic strategies. In this context, increasing evidence supports a role for microbiota-dependent pathways in modulating seizure activity and treatment responsiveness. However, the mechanistic basis of these interactions remains incompletely understood. Methods: This narrative review synthesizes findings from the existing literature to examine the role of microbiota-derived metabolites, including neurotransmitters, vitamins, and the polyphenol metabolite S-equol, in gut–brain communication relevant to epilepsy. Evidence was drawn from both preclinical animal models and clinical studies to provide an integrated, mechanistic perspective on how these pathways may influence central nervous system function and seizure susceptibility. Emphasis was placed on studies describing molecular, metabolic, and signaling mechanisms linking the gut microbiome to epileptogenesis and treatment response. Results: Current evidence indicates that communication between the gut and CNS occurs through neural pathways, such as the vagus nerve, as well as through circulating microbial metabolites. These metabolites can cross the intestinal barrier and, in some cases, the blood–brain barrier (BBB), serving as key mediators of host–microbiota signaling. Emerging studies suggest that while some microbial metabolites may directly influence neuronal hyperexcitability and seizure susceptibility, others likely exert secondary or modulatory effects through broader metabolic and immune pathways. However, the precise mechanisms underlying these interactions remain incompletely understood. Conclusions: Some microbial-derived metabolites may serve as promising biomarkers and mechanistic mediators of epilepsy; however, further investigation is needed to define the molecular and cellular pathways through which these metabolites influence seizure susceptibility and epileptogenesis. Full article

Background: Despite more than 30 licenced antiseizure medications (ASMs), approximately one third of people with epilepsy remain drug-resistant, and developmental and epileptic encephalopathies represent one of the greatest unmet needs in epilepsy therapeutics. The past decade has produced a substantial reorientation of ASM discovery, driven by epilepsy genetics, new disease models, advances in drug screening, and innovative therapeutic modalities. Objective: The objective of this study was to review the contemporary clinical-stage pipeline of ASMs with novel or differentiated mechanisms of action, organized by molecular target, while placing recent regulatory successes and instructive failures within the broader transition toward mechanism-based, precision, and potentially disease-modifying therapies. Findings: A 2024 pipeline analysis identified more than 200 epilepsy therapies in preclinical or clinical development; at the cutoff of the present literature search (30 June 2026), over 40 compounds had reached phase II or III, with the majority directed at DEEs. Functional-state-selective sodium channel modulation has emerged as a leading conceptual advance supported by converging mechanistic and early clinical evidence, exemplified by relutrigine (PRAX-562), a preferential persistent-current inhibitor for which a regulatory decision is pending in SCN2A/SCN8A-DEEs, and vormatrigine (PRAX-628), whose large open-label effect was not reproduced in a controlled (blinded) trial. Several of the efficacy figures summarized here derive from congress presentations, interim analyses, or open-label extensions and await full peer-reviewed publication. Parallel advances include the selective Kv7 opener azetukalner; the dual-mechanism benchmark cenobamate; cholesterol-24-hydroxylase inhibition (soticlestat); selective serotonergic agonism (bexicaserin); glutamatergic precision agents (radiprodil); subtype-selective GABA_A modulators (darigabat, ganaxolone); and gene-directed therapies (zorevunersen, elsunersen). Pre-symptomatic intervention in tuberous sclerosis complex provides an early, single-trial clinical proof of principle for delaying and reducing the incidence of epilepsy in a genetically defined population; this should not yet be equated with established disease prevention. Conclusions: The pipeline reflects an ongoing shift from broad symptomatic agents toward mechanism-led, genotype-matched, and potentially disease-modifying treatments. This shift is tempered by a persistent translational gap between early signals and randomized-trial confirmation, and by the preliminary status of much of the supporting evidence. Full article

Introduction. In recent years, cannabidiol (CBD) has been used as an adjunct therapy to anti-seizure medications for the control of seizures in patients with drug-resistant epilepsy. In addition to its anticonvulsant effect, CBD also has well-defined anti-inflammatory properties. Since neuroinflammation can trigger various pro-epileptogenic mechanisms, CBD could play an inhibitory role in this process. Epileptogenesis is the process by which epilepsy becomes a chronic disease following a brain injury, and one of its main characteristics is an increased susceptibility to seizures due to a reduced seizure threshold. However, the role of CBD in modulating this susceptibility remains poorly understood. Methodology. We developed an experimental protocol to discretely measure the seizure threshold (DMST) 7 or 14 days after lithium-pilocarpine-induced status epilepticus (SE) through the administration of small intraperitoneal (i.p.) doses of pentylenetetrazol (15 mg/kg/every 10 min). Results. Using the DMST, we observed a significant decrease in the seizure threshold after SE associated with a hypersensitivity state characterized by irritability and marked weight loss. A separate cohort of rats was treated with CBD (20 mg/kg) for 14 days following SE. Conclusions. Treatment with CBD did not improve the seizure threshold; moreover, it worsened the hypersensitivity state and delayed recovery following SE. Our results suggest that orally administered CBD, at a human-equivalent therapeutic and safe dose, does not improve susceptibility to seizure development after SE. Full article

Neuroprotection in childhood developmental and epileptic encephalopathies may require approaches, distinct from adult brain injury models of neuroprotection, with a primary focus on preservation of synaptic density rather than prevention of cellular necrosis. There is growing evidence to indicate early-life seizures activate complement cascade proteins C1q and C3. Subsequently, localized microglia may excessively phagocytose structurally intact synaptic neurons disrupting normal brain maturation. This review incorporates kinetic models of neuro-immune interactions based on human histopathology from epileptogenic tissues and quantitative neuro-immune biomarkers to provide suggestions that complement-mediated synaptic pruning may contribute to structural network disruption and cognitive decline in pediatric epilepsy. While standard anti-seizure medications effectively stabilize electrical activity, they do not mitigate underlying neuro-inflammatory responses. Consequently, targeted pharmacological inhibition of the complement microglia axis may provide a potential disease modifying strategy to protect developing neural circuits. The translational feasibility of using targeted complement inhibitors should be evaluated addressing critical challenges such as central nervous system drug delivery across the blood–brain barrier, immunosuppression management and the application of non-invasive biomarkers to define the precise therapeutic window for intervention. Full article

Background/Objectives: Epilepsy remains a major neurological disorder, with approximately one-third of patients continuing to experience pharmacoresistant seizures despite the availability of numerous antiseizure medications (ASMs). While current therapies primarily target neuronal hyperexcitability through modulation of ion channels and neurotransmitter systems, increasing evidence suggests that epileptogenesis arises from multiscale interactions involving molecular, cellular, circuit, network, neuroinflammatory, and neurovascular mechanisms. Although therapeutic strategies have diversified, this expanded mechanistic understanding has not yet been fully incorporated into therapeutic development and evaluation. This review integrates current knowledge of multiscale epilepsy pathophysiology with recent therapeutic advances and emerging experimental platforms. Methods: This narrative review synthesized literature identified primarily through PubMed and Google Scholar searches through January 2026, supplemented by targeted updates of therapeutic development and regulatory status through July 2026. Particular emphasis was placed on ion channel modulators, synaptic and neuromodulatory therapies, neuroinflammatory interventions, precision genetic approaches, and human-relevant experimental platforms, including induced pluripotent stem cell (iPSC)-derived models, brain organoids, multi-electrode arrays (MEAs), organ-on-a-chip systems, multi-omics technologies, and artificial intelligence (AI)-based analytical frameworks. Results: Current and emerging therapies target increasingly diverse molecular, circuit, neuromodulatory, and neuroinflammatory mechanisms. However, drug resistance remains multifactorial, and the long-term effects of therapeutic interventions on network remodeling, neuro-glial interactions, and sustained clinical response remain incompletely understood. NAMs provide complementary capabilities for patient-specific disease modeling, functional network phenotyping, neurovascular modeling, and the integration of molecular, electrophysiological, and computational data across biological scales. Conclusions: Epilepsy is increasingly recognized as a multiscale network disorder rather than solely a condition of neuronal hyperexcitability. The coordinated use of complementary human-relevant platforms may help incorporate multiscale mechanistic insights into therapeutic development and evaluation, narrow persistent translational gaps, and support more predictive and mechanism-informed treatment strategies. Full article

Background/Objective: Status epilepticus (SE) is a life-threatening condition that requires immediate response to effectively control. Although benzodiazepines are the first-line treatment against SE, when treatment is delayed, benzodiazepine pharmacoresistance develops. In preclinical models of benzodiazepine refractory SE, the addition of antiseizure medications (ASMs) as adjunct to midazolam to reduce neuronal excitability and enhance inhibitory function is essential to protect against the neurodegeneration and epileptogenesis that follows prolonged seizure. Brivaracetam is a recently FDA-approved ASM to treat partial onset seizures in pediatric and adult patients as a monotherapy or adjunct therapy. We evaluated the potential of brivaracetam as monotherapy or in combination with midazolam and ketamine for efficacy against organophosphorus nerve agent (OPNA)-induced refractory SE in rats. Methods: Adult male rats were exposed to a seizure-inducing dose of soman and treated with atropine sulfate and the oxime asoxime chloride one minute after soman exposure and with brivaracetam alone or in combination with midazolam and ketamine 40 min after seizure onset. Multiple metrics of protection such as seizure severity, spontaneous recurrent seizure (SRS), neuronal loss, and neuroinflammation were evaluated. Results: Although brivaracetam monotherapy resulted in 100% survival, protection from the development of SRS and neurodegeneration only occurred when brivaracetam was administered as an adjunct to ketamine and midazolam. Initial seizure severity was also reduced by the combination of brivaracetam–midazolam–ketamine over monotherapy. Conclusions: Although further research is needed to determine optimal drug combinations, these preclinical findings provided further evidence that simultaneous polytherapy with ASMs improves OPNA-induced seizure outcomes. Full article

Objective: Voltage-gated potassium channel genes are among the most frequently implicated in epilepsy and antiseizure medication (ASM) response. In this pilot study, we aimed to identify rare and common variants by sequencing voltage-gated potassium channel (Kv) genes in epilepsy patients using ASM, and to reveal the potential drug responses of these variants. Methods: To investigate the role of genetic variants in Kv genes (KCNQ1, KCNQ2, KCNQ3, KCNA1, KCNA2, and KCNV2) in response to ASMs among 31 epilepsy patients, we used targeted next-generation sequencing (tNGS). Patients were classified as responders or persistent based on seizure control status. Selected variants in the genes were annotated, filtered, and analyzed for association with ASM response. Results: We identified 181 variants in the 6 channel genes, including missense, synonymous, intronic, UTR, and stop-gained variants. Six variants of uncertain significance (VUSs) were observed, including KCNA2c.*1314C>T, KCNQ1c.*976G>A, KCNQ2 (c.2613G>T p.Arg871Ser and c.1148+62T>G), and KCNQ3 (c.*6282A>G and c.*2860T>C). Two novel variants were identified in our study group, KCNA2:c.*1314C>T and KCNQ3:c.*2860T>C. Both were located in the 3′ UTR region and classified as VUSs according to ACMG guidelines. In the KCNV2 gene, the CG haplotype comprising rs7029012 and rs10967705 was observed more frequently in patients with drug-persistent epilepsy than in those with drug-responsive epilepsy (18.5% vs. 0.8%; χ² = 6.756, p = 0.009, BH-FDR q = 0.036), suggesting a potential association with pharmacoresistant epilepsy. Conclusions: Our haplotype analysis suggests the potential pharmacogenetic contribution of the KCNV2 gene to ASM response; however, these exploratory findings require validation in larger independent cohorts and functional studies. Full article

Background: Volumetric absorptive microsampling (VAMS) is an emerging tool for therapeutic drug monitoring (TDM) of several drugs including antiseizure medications (ASMs). Here, we compared the concentrations of carbamazepine (CBZ), levetiracetam (LEV), lacosamide (LCS), topiramate (TPR) and the benzodiazepine (BZ) clobazam (CLB) in plasma and VAMS samples. Methods: VAMS samples were collected by fingerprick in pediatric patients followed at our center. Patients were also subjected to conventional venous blood sampling. Plasma and VAMS samples were analyzed by using a UHPLC-MS/MS validated kit for AEs and BZs (ClinMass LC-MS/MS Complete Kit^®). A cross-validation analysis was performed by using Spearman correlation (rho), Deming regression and Bland–Altman plots. Results: Two analytical methods for measuring selected AEs and BZs in VAMS samples were developed and validated in accordance with the ICH M10 guidelines. Based on Bland–Altman results, a satisfactory agreement was observed between VAMS and plasma for CBZ, LCS, TPR, LEV and N-CLB. Considering the absence of interchangeability between capillary blood and plasma levels for CBZ-Diol, -Epoxi and CLB, a blood to plasma ratio was used to convert VAMS values into estimated plasma concentrations. Comparison of estimated vs. observed plasma results showed a successful predictive performance for this conversion approach. Conclusions: A positive agreement between plasma and VAMS was found for CBZ, LCS, TPR, LEV and N-CLB. Conversely, a conversion factor based on blood to plasma ratio should be adopted to convert CBZ-Diol, -Epoxi and CLB VAMS results into estimated plasma concentrations. This study confirmed the utility of VAMS for TDM of selected ASMs in pediatric patients during routine clinical practice. Full article

Background/Objectives: Voltage-gated sodium channels (VGSCs) are among the most important molecular targets in epilepsy therapy. Unlike classical antiseizure medications (ASMs), newer sodium channel modulators selectively affect slow inactivation or persistent sodium currents, potentially improving seizure control while preserving physiological neuronal activity. This review summarizes the pharmacology, mechanisms of action, clinical efficacy, and therapeutic potential of eslicarbazepine acetate, lacosamide, and cenobamate. Methods: A narrative review of published clinical trials, meta-analyses, and real-world evidence was conducted. The analysis focused on sodium channel modulation, pharmacokinetic properties, efficacy in monotherapy and adjunctive therapy, and safety profiles in focal epilepsy. Main findings of the review: Eslicarbazepine acetate and lacosamide primarily enhance slow inactivation of VGSCs, suppressing pathological repetitive neuronal firing with limited effects on normal neuronal signaling. Both agents demonstrated efficacy in monotherapy and add-on therapy, with favorable pharmacokinetic properties and a relatively low potential for drug–drug interactions. Cenobamate represents a novel therapeutic approach through preferential inhibition of persistent sodium currents combined with positive allosteric modulation of GABA_A receptors. Clinical trials and real-world studies demonstrated high responder and seizure freedom rates, particularly in patients with drug-resistant focal epilepsy. The most common adverse effects across these agents included dizziness, somnolence, fatigue, and gastrointestinal symptoms, while notable safety concerns included hyponatremia with eslicarbazepine acetate and drug interactions or dose-dependent adverse effects with cenobamate. Conclusions: Recent advances in sodium channel modulation have expanded therapeutic options for focal epilepsy and support the development of more selective, mechanism-based ASM therapies. Eslicarbazepine acetate, lacosamide, and cenobamate demonstrate favorable efficacy and tolerability profiles and may improve seizure control in patients with drug-resistant epilepsy. Full article

Epilepsy is a multifactorial disorder, yet routine management still focuses on neuronal excitation and insufficient inhibition, with antiseizure medications (ASMs) as the primary therapeutic strategy. This approach fails in roughly one-third of patients who develop drug-resistant epilepsy (DRE). Converging evidence links DRE with neuroinflammation, oxidative stress (OS), and mitochondrial dysfunction—an interconnected distal pathophysiological triad that progressively lowers seizure thresholds yet remains peripheral to clinical epilepsy management. We map this triad mechanistically and show that ASMs modulate it beyond their anticonvulsant activity, while triad-targeting pharmacological, dietary, and botanical interventions independently reduce seizure susceptibility. Common precipitants are reinterpreted as acute activators of the distal triad, linking precipitant identification and patient agency to threshold elevation. Integrating these elements, we propose a threshold management framework for DRE, built on a revised reservoir model, and translate it into three structural priorities: mechanistic phenotyping to stratify patients by pathophysiological domain, dual-mechanism drug development, and trial designs suited to multicomponent, context-dependent interventions. Together, these proposals reframe epilepsy management from sequential pharmacological trials toward coordinated optimization of the full seizure threshold landscape. Full article

Disease variants in GABR genes encoding γ-aminobutyric acid type A receptor (GABA_AR) subunits are major causes of developmental and epileptic encephalopathies (DEEs). There is no effective treatment for these DEEs, although the GABA_AR is a major target for antiseizure drugs. We previously identified the therapeutic effect of 4-phenylbutyrate (PBA) in Gabrg2^+/Q390X knockin DEE mice and in this study tested the effect of the drug in GABRA1 variants that encode the α1 subunit of GABA_AR. We used a multidisciplinary approach including in silico structural modeling, flow cytometry, patch-clamp recordings and biochemistry in conjunction with differential tagging of the wildtype (WT) and the mutant alleles to evaluate the effect of PBA on rescue of GABA_AR subunit expression, surface trafficking, and function in vitro in a heterologous HEK293T cell model and in vivo in Gabra1^+/A322D mice. We found that the α1 subunit expression at both the total level and the cell surface was reduced when the variant α1 protein was present, suggesting reduced functional receptor availability on the cell membrane and synapse. Patch-clamp recordings identified that α1 variants reduced GABA-evoked current amplitude. In silico prediction indicated reduced protein stability for GABRA1 variants by negative ∆∆G values. PBA increased both total and surface expression of WT α1 and α1 variants and improved expression of both WT and variant α1 alleles when these were co-expressed. Importantly, PBA also increased the GABA_AR expression in the cortex and thalamus of the Gabra1^+/A322D mice. This study indicates that PBA is a promising treatment option for DEEs associated with GABRA1 mutations. Our previous work has demonstrated that PBA improves proteostasis by enhancing expression of the WT allele, repairing the mutant allele, and reducing endoplasmic reticulum stress in other DEEs associated with GABRG2 and SLC6A1 mutations. Importantly, it can mitigate seizures and improve neurobehavioral phenotypes at behavioral levels. Based on this and our previous work on GABRG2 and SLC6A1 mutations, we propose that PBA holds promise as a common medicine for multiple genetic neurologic disorders that share the proteostasis pathology with a broad clinical application in DEEs. Full article