Pathogenesis Of Epilepsy Research Articles

Molecular docking-guided in-depth investigation of the biological activities and phytochemical and mineral profiles of endemic Phlomis capitata.

Phlomis capitata is an endemic species of flowering aromatic and medicinal plant in the family Lamiaceae, native to regions of the Mediterranean and nearby areas. Understanding the chemical compounds present in P. capitata can reveal potential medicinal properties. The present study examines the quantification of bioactive phytochemicals, antioxidant capacity and enzyme inhibitory evaluation of P. capitata extract against key enzymes involved in the pathogenesis of Alzheimer's, diabetes mellitus, epilepsy and glaucoma for the first time. The mechanisms of enzyme inhibition activity of the predominant compounds in extract were also interpreted by molecular docking studies. Chemical characterization of the extract was performed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) (phytochemical profile) and inductively coupled plasma-mass spectrometry (mineral composition) analysis. Furthermore, the binding interactions of major phytochemicals with all enzymes were investigated by molecular docking studies. LC-MS/MS analysis of the P. capitata revealed the identification of 19 compounds predominated by quinic acid (4.883 mg g-1), followed by chlorogenic acid (4.36 mg g-1), vanilic acid (3.405 mg g-1), naringenin (2.571 mg g-1) and cyranoside (1.101 mg g-1). It was determined that the mineral element was rich (K, Ca, Al and Mg) and did not exceed the toxicity limits. The P. capitata extract demonstrated remarkable antioxidant activities in the order: 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (IC50: 20.533 μg mL-1) < 2,2-diphenyl-1-picrylhydrazyl (IC50: 23.151 μg mL-1) < N,N-dimethyl-p-phenylenediamine (IC50: 45.221 μg mL-1) and cupric reducing antioxidant capacity (0.889 μg mL-1) < Fe3+ reducing (0.969 μg mL-1) < ferric reducing antioxidant potency (0.974 μg mL-1). Moreover, of all the enzyme inhibitory assays (acetylcholinesterase, butyrylcholinesterase, α-amylase, α-glucosidase, and human carbonic anhydrases I and II), the extract showed outstanding inhibitory activities (IC50 values of 3.26, 7.15, 6.15, 6.81, 15.21 and 11.93 μg mL-1, respectively). In summary, the findings show that P. capitata is a versatile raw material that can be used in the pharmaceutical, cosmetic and food industries to develop products that promote health. © 2025 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Phagocytic Function Analyses of GABBR-Related Microglia in Immature Developing Epileptic Brain Based on 10× Single-Nucleus RNA Sequencing Technology

Background: Epilepsy is a neurological disorder defined by the occurrence of epileptic seizures, which can significantly affect children, often leading to learning and cognitive impairments. Microglia, the resident immune cells of the central nervous system, are essential in clearing damaged neurons through phagocytosis. Notably, GABBR-associated microglia have been implicated in regulating phagocytic activity. Since the phagocytic function of microglia is critical in the pathogenesis of epilepsy, this study aims to investigate the role of GABBR-associated microglia in the development of the immature brain following epileptic seizures. Methods: Epilepsy was induced in a mouse model by the intraperitoneal injection of KA. Changes in the expression of the GABBR-related gene, GABBR2, in hippocampal microglia were analyzed using single-nucleus RNA sequencing (snRNA-seq). Cognitive and emotional changes in the mice were assessed through behavioral analyses. The expression of GABBR2 was semi-quantitatively measured using Western blotting, quantitative reverse transcription PCR, and immunofluorescence. Additionally, the spatial relationship between GABBR2 and hippocampal neurons was evaluated using Imaris software. Results: The snRNA-seq analysis revealed that GABBR2 expression was elevated in activated microglia in the hippocampus during chronic epilepsy compared to the early phase of seizures. Behavioral assessments demonstrated heightened anxiety levels and learning and memory impairments in the chronic epilepsy group compared to the control group. GABBR2 expression was upregulated in chronic epilepsy. Three-dimensional reconstruction analyses revealed a significantly increased contact volume between GABBR-associated microglia and neurons in the chronic epilepsy group compared to the control group. Conclusions: GABBR-associated microglia significantly contribute to the progression of immature brain diseases by promoting neuronal phagocytic activity.

Identify and analyze ferroptosis-related molecular modules and immune signatures in epilepsy using microarray-based transcriptome profiling and single-cell sequencing.

Currently, the pathogenesis of epilepsy remains poorly understood. Although there is evidence indicating that iron death might play a significant role, its molecular immunological mechanisms are largely unknown. This study was designed to analyze and explore the molecular mechanisms and immunological characteristics of iron death-related genes in epilepsy. We obtained datasets of blood and brain tissues for epilepsy from the GEO database and the set of iron death-related genes from FerrDb. Through two machine learning algorithms, we identified three Hub genes, namely RELA, TFRC, and QSOX1. Unsupervised clustering revealed two distinct clusters. Immune infiltration analysis demonstrated that one cluster had significantly higher immune infiltration. We established an epilepsy diagnostic model and nomogram. The results were confirmed by RT-qPCR and Western Blot. Single-cell analysis showed that the SPP1 signalling pathway was overly activated in astrocytes and microglia. This study offers new perspectives and a theoretical foundation for the diagnosis of epilepsy.

The lactate metabolism and protein lactylation in epilepsy.

Protein lactylation is a new form of post-translational modification that has recently been proposed. Lactoyl groups, derived mainly from the glycolytic product lactate, have been linked to protein lactylation in brain tissue, which has been shown to correlate with increased neuronal excitability. Ischemic stroke may promote neuronal glycolysis, leading to lactate accumulation in brain tissue. This accumulation of lactate accumulation may heighten neuronal excitability by upregulating protein lactylation levels, potentially triggering post-stroke epilepsy. Although current clinical treatments for seizures have advanced significantly, approximately 30% of patients with epilepsy remain unresponsive to medication, and the prevalence of epilepsy continues to rise. This study explores the mechanisms of epilepsy-associated neuronal death mediated by lactate metabolism and protein lactylation. This study also examines the potential for histone deacetylase inhibitors to alleviate seizures by modifying lactylation levels, thereby offering fresh perspectives for future research into the pathogenesis and clinical treatment of epilepsy.

GABRA1 frameshift variants impair GABAA receptor proteostasis.

The gamma-aminobutyric acid type A receptor (GABAAR) is the most common inhibitory neurotransmitter-gated ion channel in the central nervous system. Pathogenic variants in genes encoding GABAAR subunits can cause receptor dysfunction and lead to genetic epilepsy. Frameshift variants in these genes can result in a premature termination codon, producing truncated receptor subunit variants. However, the pathogenic molecular mechanism as well as functional implications of these frameshift variants remains inadequately characterized. This study focused on four clinical frameshift variants of the α1 subunit of GABAAR (encoded by the GABRA1 gene): K401fs (c.1200del), S326fs (c.975del), V290fs (c.869_888del), and F272fs (c.813del). These variants result in the loss of one to three transmembrane helices, whereas wild type α1 has four transmembrane helices. Therefore, these variants serve as valuable models to evaluate membrane protein biogenesis and proteostasis deficiencies of GABAARs. In HEK293T cells, all four frameshift variants exhibit significantly reduced trafficking to the cell surface, resulting in essentially non-functional ion channels. However, the severity of proteostasis deficiency varied among these four frameshift variants, presumably due to their specific transmembrane domain deletions. The variant α1 subunits exhibited endoplasmic reticulum (ER) retention and activated the unfolded protein response (UPR) to varying extents. Our findings revealed that these frameshift variants of GABRA1 utilize overlapping yet distinct molecular mechanisms to impair proteostasis, providing insights into the pathogenesis of GABAAR-associated epilepsy.

Glycyrrhizin as a potential disease-modifying therapy for epilepsy: insights into targeting pyroptosis to exert neuroprotective and anticonvulsant effects.

For patients with epilepsy, antiseizure medication remains the primary treatment; however, it is ineffective in approximately 30% of cases. These patients experience progressive neuronal damage and poor outcomes. Therefore, there is an urgent need for disease-modifying therapy (DMT) that targets the pathogenesis of epilepsy. Glycyrrhizin has shown potential as a DMT in epilepsy due to its multiple targets and diverse mechanisms. Previous studies suggest that glycyrrhizin may regulate key processes involved in epilepsy pathogenesis, such as neuroinflammation and cell death, but its effects on pyroptosis have not been reported. This study employed bioinformatics techniques to identify potential molecular targets for glycyrrhizin in epilepsy treatment and then validated using a kainic acid-induced status epilepticus mouse model. Glycyrrhizin treatment significantly prolonged seizure latency, reduced seizure duration, and alleviated neuronal damage in the status epilepticus mouse model. Molecular experiments indicated that glycyrrhizin may regulate pyroptosis through mediation of the high mobility group box 1 (HMGB1)/Toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) signaling pathway. Glycyrrhizin exerts neuroprotective and anticonvulsant effects in epilepsy by regulating pyroptosis via the HMGB1/TLR4/NF-κB signaling pathway, offering novel insights into its potential as a DMT for epilepsy.

Identifying disulfidptosis-related biomarkers in epilepsy based on integrated bioinformatics and experimental analyses.

One of the underlying mechanisms of epilepsy (EP), a brain disease characterized by recurrent seizures, is considered to be cell death. Disulfidptosis, a proposed novel cell death mechanism, is thought to play a part in the pathogenesis of epilepsy, but the exact role is unclear. The gene expression omnibus series (GSE) 33,000 and GSE63808 datasets were used to search for differentially expressed disulfidptosis-related molecules (DE-DRMs). A correlation between the DE-DRMs was discovered. Individuals with epilepsy were then used to investigate molecular clusters based on the expression of DE-DRMs. Following that, the best machine learning model which is validated by GSE143272 dataset and predictor molecules were identified. The correlation between predictive molecules and clinical traits was determined. Based on the in vitro and in vivo seizures models, experimental analyses were applied to verify the DE-DRMs expressions and the correlation between them. Nine molecules were identified as DE-DRMs: glycogen synthase 1 (GYS1), solute carrier family 3 member 2 (SLC3A2), solute carrier family 7 member 11 (SLC7A11), NADH:ubiquinone oxidoreductase core subunit S1 (NDUFS1), 3-oxoacyl-ACP synthase, mitochondrial (OXSM), leucine rich pentatricopeptide repeat containing (LRPPRC), NADH:ubiquinone oxidoreductase subunit A11 (NDUFA11), NUBP iron‑sulfur cluster assembly factor, mitochondrial (NUBPL), and NCK associated protein 1 (NCKAP1). NDUFS1 interacted with NDUFA11, NUBPL, and LRPPRC, while SLC3A2 interacted with SLC7A11. The optimal machine learning model was revealed to be the random forest (RF) model. G protein guanine nucleotide-binding protein alpha subunit q (GNAQ) was linked to sodium valproate resistance. The experimental analyses suggested an upregulated SLC7A11 expression, an increased number of formed SLC3A2 and SLC7A11 complexes, and a decreased number of formed NDUFS1 and NDUFA11 complexes. This study provides previously undocumented evidence of the relationship between disulfidptosis and EP. In addition to suggesting that SLC7A11 may be a specific DRM for EP, this research demonstrates the alterations in two disulfidptosis-related protein complexes: SLC7A11-SLC3A2 and NDUFS1-NDUFA11.

D2HGDH Deficiency Regulates Seizures through GSH/Prdx6/ROS-Mediated Excitatory Synaptic Activity.

Current antiepileptic drugs are ineffective in one-third of patients with epilepsy; however, identification of genes involved in epilepsy can enable a precision medicine approach. Here, it is demonstrated that downregulating D-2-hydroxyglutarate dehydrogenase (D2HGDH) enhances susceptibility to epilepsy. Furthermore, its potential involvement in the seizure network through synaptic function modulation is investigated. D2HGDH knockdown reduces the glutathione reduced (GSH)/glutathione oxidized (GSSG) ratio and elevates reactive oxygen species (ROS) levels within neurons. Oxidative stress may play a crucial role in the pathogenesis of epilepsy. The specific contribution of each pathway varies among patients, highlighting the complexity of this disease. In this study, downregulation of D2HGDH affects modulation of ROS levels, synaptic transmission, and seizure susceptibility. Furthermore, the acid calcium-independent phospholipase A2 (aiPLA2) inhibitor, MJ33, restores the GSH/GSSG balance and reverses the increase in ROS levels caused by D2HGDH knockdown, resulting in remission of epilepsy-related behaviors. The results demonstrate that downregulation of D2HGDH affects synaptic function by regulating ROS production. These findings support the use of targeted gene therapy as a potential alternative to antioxidant-based treatments for refractory epilepsy.

The sphingosine-1-phosphate signaling pathway (sphingosine-1-phosphate and its receptor, sphingosine kinase) and epilepsy.

Epilepsy is one of the common chronic neurological diseases, affecting more than 70 million people worldwide. The brains of people with epilepsy exhibit a pathological and persistent propensity for recurrent seizures. Epilepsy often coexists with cardiovascular disease, cognitive dysfunction, depression, etc., which seriously affects the patient's quality of life. Although our understanding of epilepsy has advanced, the pathophysiological mechanisms leading to epileptogenesis, drug resistance, and associated comorbidities remain largely unknown. The use of newer antiepileptic drugs has increased, but this has not improved overall outcomes. We need to deeply study the pathogenesis of epilepsy and find drugs that can not only prevent the epileptogenesis and interfere with the process of epileptogenesis but also treat epilepsy comorbidities. Sphingosine-1-phosphate (S1P) is an important lipid molecule. It not only forms the basis of cell membranes but is also an important bioactive mediator. It can not only act as a second messenger in cells to activate downstream signaling pathways but can also exert biological effects by being secreted outside cells and binding to S1P receptors on the cell membrane. Fingolimod (FTY720) is the first S1P receptor modulator developed and approved for the treatment of multiple sclerosis. More and more studies have proven that the S1P signaling pathway is closely related to epilepsy, drug-resistant epilepsy, epilepsy comorbidities, or other epilepsy-causing diseases. However, there is much controversy over the role of certain natural molecules in the pathway and receptor modulators (such as FTY720) in epilepsy. Here, we summarize and analyze the role of the S1P signaling pathway in epilepsy, provide a basis for finding potential therapeutic targets and/or epileptogenic biomarkers, analyze the reasons for these controversies, and put forward our opinions. PLAIN LANGUAGE SUMMARY: This article combines the latest research literature at home and abroad to review the sphingosine 1-phosphate signaling pathway and epileptogenesis, drug-resistant epilepsy, epilepsy comorbidities, other diseases that can cause epilepsy, as well as the sphingosine-1-phosphate signaling pathway regulators and epilepsy, with the expectation of providing a certain theoretical basis for finding potential epilepsy treatment targets and/or epileptogenic biomarkers in the sphingosine-1-phosphate signaling pathway.

ALG13-Related Epilepsy: Current Insights and Future Research Directions.

The ALG13 gene encodes a subunit of the uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) transferase enzyme, which plays a key role in the N-linked glycosylation pathway. This pathway involves the attachment of carbohydrate structures to asparagine (Asn) residues in proteins within the endoplasmic reticulum, by which N-glycosylated proteins produced participate a wide range of processes such as electrical gradients formation and neurotransmission. Mutations in the ALG13 gene have been identified as a causative factor for congenital disorders of glycosylation (CDG) and have been frequently associated with epilepsy in affected individuals. Several studies have demonstrated a strong correlation between abnormal N-glycosylation due to ALG13 deficiency and the onset of epilepsy. Despite these findings, the precise role of ALG13 in the pathogenesis of epilepsy remains unclear. This review provides a comprehensive overview of the current literature on ALG13-related disorders, with a focus on recent evidence regarding its role in epilepsy development and progression. Future research directions are also proposed to further elucidate the molecular mechanisms underlying this association.

The role of the endocannabinoid system in the pathogenesis and treatment of epilepsy.

Epilepsy is a group of chronic neurological brain disorders characterized by recurrent spontaneous unprovoked seizures, which are accompanied by significant neurobiological, cognitive, and psychosocial impairments. With a global prevalence of approximately 0.5-1 % of thepopulation, epilepsy remains a serious public health concern. Despite the development and widespread use of over 20 anticonvulsant drugs, around 30 % of patients continue to experience drug-resistant seizures, leading to asubstantial reduction in quality of life and increased mortality risk. Given the limited efficacy of current treatments, exploring new therapeutic approaches is critically important. In recent years, Gi-protein-coupled receptors, particularly cannabinoid receptors CB1 and CB2, have garnered increasing attention as promising targets for the treatment seizures and prevention of epilepsy. Emerging evidence suggests a significant role of the cannabinoid system in modulating neuronal activity and protecting against hyperexcitability, underscoring the importance of further research inthis area. This review provides up-to-date insights into the pathogenesis and treatment of epilepsy, with a special focus on the role of the cannabinoid system, highlighting the need for continued investigation to develop more effective therapeutic strategies.

Metabolite Associations with Childhood and Juvenile Absence Epilepsy: A Bidirectional Mendelian Randomization Study.

The precise involvement of metabolites in the pathogenesis of Childhood absence epilepsy (CAE) and juvenile absence epilepsy (JAE) remains elusive. Consequently, this investigation introduces bidirectional Mendelian randomization (MR) as a tool to explore causality and underlying mechanisms. Bidirectional MR analysis was conducted employing a comprehensive set comprising 1091 human blood metabolites and 309 metabolite ratios, systematically probing potential causal associations with JAE and CAE. Genome-wide association study (GWAS) data pertaining to these epileptic conditions were meticulously obtained from the International League Against Epilepsy (ILAE) consortium. Sensitivity analyses were rigorously performed to evaluate for heterogeneity and pleiotropy. Reverse MR analysis was also conducted to verify the direction of causality, and no significant reverse causal relationships were identified. Following rigorous genetic variant selection, significant associations were identified based on PIVW < .05, PWM < .05, and PMR-Egger < .05 criteria in MR analysis. Only 1 metabolite, (2 or 3)-decaonate levels, exhibited an association with JAE (P = .005, OR=0.987, 95% CI=0.978-0.996). Childhood absence epilepsy was associated with 5 metabolites: X-23648 (P = .012, OR=0.982, 95% CI=0.968-0.996), X-21845 levels (P = .045, OR=1.018, 95% CI=1.001-1.035), 2'-o-methylcytidine (P = .008, OR=0.995, 95% CI=0.991-1.001), 2'-o-methyluridine (P = .007, OR=0.995, 95% CI=0.99-0.999), and spermidine-topyruvate ratio (P = .014, OR=0.973, 95% CI=0.954-0.992). No evidence of reverse causality was found between JAE and CAE and the aforementioned metabolites. The study establishes causal relationships between the aforementioned 6 metabolites and CAE and JAE. This integration of genomics with metabolism offers novel insights into epilepsy mechanisms and has important implications for screening and prevention.

ВЛИЯНИЕ ЭПИЛЕПСИИ НА ТЕЧЕНИЕ И ИСХОДЫ БЕРЕМЕННОСТИ

A retrospective analysis was conducted in 82 women with epilepsy. The course of pregnancy was analyzed in 58 women with epilepsy who took antiepileptic drugs during pregnancy - the main group, the comparison group - 24 pregnant women with drug-free remission of epilepsy. The etiology, pathogenesis, type and form of epilepsy were examined in the study groups. In the presence of epilepsy, other concomitant somatic pathology was present in 54 (93,1 %) pregnant women of the main and 21 (87,5 %) comparison groups, and the analyzed groups did not differ in terms of the two factors (p=0,409). There were no statistically significant differences between the groups in the incidence of anemia in pregnant women (59,6 % and 33,3 % (p=0,053), threatened miscarriage 39,7 % and 33,3 % (p=0,592), fetal growth restriction 12,1 % and 4,2 % (p=0,273). Chronic placental insufficiency in the main group was 11 (18,9 %) and 7 (29,2 %) in the comparison group (p=0,473), which indicated timely prevention in women of the main group

Mechanisms of Epilepsy and Efficacy of Neuroplasticity-Based Treatment

Epilepsy is a neurological disorder characterized by the development of trauma to the nervous system and recurrent seizures. Neuroplasticity, the ability of the nervous system to reorganize its structure and function in response to trauma, plays a crucial role in the development and treatment of epilepsy. Several recent studies have mentioned the potential of treating epilepsy based on neuroplasticity, such as deep brain stimulation (DBS), neurofeedback and non-invasive brain stimulation techniques. While conventional treatments focus primarily on seizure control, neuroplasticity interventions aim to alter neural circuits, reduce seizure frequency and severity, and may ameliorate the effects caused by the sequelae of epilepsy. There are already a number of therapies for epilepsy that incorporate neuroplasticity, which provides a basis for subsequent research. This paper explores the pathogenesis of epilepsy with a focus on the role of neuroplasticity in the onset and progression of epilepsy. However, further research is needed to optimize these approaches and fully understand their therapeutic potential.

Integrated computational approaches for identification of potent pyrazole-based glycogen synthase kinase-3β (GSK-3β) inhibitors: 3D-QSAR, virtual screening, docking, MM/GBSA, EC, MD simulation studies.

Glycogen synthase kinase-3β (GSK-3β) has emerged as a crucial target due to its substantial contribution in various cellular processes. Dysfunctional GSK-3β activity can lead to ion channel disturbances, sustain abnormal excitability, and contribute to the pathogenesis of epilepsy and other GSK-3β-related disorders. A set of 82 pyrazole analogs was utilized to study its structural features using a three-dimensional quantitative structure-activity relationship (3D-QSAR), virtual screening, molecular docking, and molecular dynamics. The QSAR model, validated using internal and external methods, demonstrated robustness with a high correlation coefficient r2training = 0.99, cross-validation coefficient q2 = 0.79, r2test = 0.69, and r2external = 0.74. The "Average of Actives" in the Activity Atlas model identified 17 molecules as active. Subsequent pharmacophore-based virtual screening of 17 actives yielded 70 compounds, which were selected as the prediction set to determine the potential GSK-3β inhibitors. Docking studies pinpointed compound P66 as the promising lead compound, with a docking score of - 10.555kcal/mol. These findings were further supported by electrostatic potential (ESP), electrostatic complementarity (EC), and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) analyses. Furthermore, a 500ns molecular dynamics (MD) simulation confirmed the structural and conformational stability of the lead complex throughout the simulation period. As a result, this study suggests that compound P66 holds the potential to be a potent lead candidate for the inhibition of GSK-3β, offering a novel therapeutic approach for GSK-3β related disorders, including epilepsy.

Long-Term High-Fat Diet Aggravates Absence Seizures and Neurobehavioral Disorders Without Inducing Metabolic Disorders in WAG/Rij Rats: Involvement of Systemic and Central Inflammation.

The consumption of a high-fat diet (HFD) represents a risk factor for diseases such as obesity, diabetes, insulin resistance (IR), and different brain disorders. HFD-induced obesity is linked with systemic and neuroinflammation implicated in the pathogenesis of metabolic impairment and epilepsy. In this study, we studied the negative effects of HFD consumption (16weeks) on absence epilepsy and behavior comorbidities in WAG/Rij rats, a well-validated idiopathic model of absence epilepsy and comorbidities. Moreover, we investigated how, by restoring a normocaloric diet (NCD; 12weeks), epileptic seizures and neuropsychiatric comorbidities could improve. We found that the HFD group showed a worsening of absence seizures, aggravation of depressive-like behavior, and performance in learning and memory than the NCD group even in the absence of hyperglycemia and/or obesity. In addition, intestinal villus rupture, inflammatory infiltrate, and intestinal permeability alteration increased after prolonged HFD intake, which could prevent weight gain. Inflammatory protein levels were found higher in the colon of the HFD group than in the NCD group, and also in the cortex and hippocampus, regions involved in absence seizures and behavioral alterations. After replacing HFD with NCD, a reduction in absence seizures and behavioral alterations was observed, and this decrease was well correlated with an improvement in inflammatory pathways. In conclusion, HFD consumption is sufficient to disrupt gut integrity resulting in systemic and brain inflammation contributing to the worsening of absence epilepsy and its comorbidities also without obesity development. These alterations can be improved by switching back the diet to NCD.

Exploring the Frontier: The Human Microbiome's Role in Rare Childhood Neurological Diseases and Epilepsy.

Emerging research into the human microbiome, an intricate ecosystem of microorganisms residing in and on our bodies, reveals that it plays a pivotal role in maintaining our health, highlighting the potential for microbiome-based interventions to prevent, diagnose, treat, and manage a myriad of diseases. The objective of this review is to highlight the importance of microbiome studies in enhancing our understanding of rare genetic epilepsy and related neurological disorders. Studies suggest that the gut microbiome, acting through the gut-brain axis, impacts the development and severity of epileptic conditions in children. Disruptions in microbial composition can affect neurotransmitter systems, inflammatory responses, and immune regulation, which are all critical factors in the pathogenesis of epilepsy. This growing body of evidence points to the potential of microbiome-targeted therapies, such as probiotics or dietary modifications, as innovative approaches to managing epilepsy. By harnessing the power of the microbiome, we stand to develop more effective and personalized treatment strategies for children affected by this disease and other rare neurological diseases.

Reduced serum neurotrophic factors and monoamine neurotransmitters in epilepsy patients with comorbid depression.

This study aimed to investigate the roles of neurotrophic factors (NTFs), monoamine neurotransmitters, and inflammatory processes in the pathophysiology of the comorbidity of epilepsy and depression. A retrospective analysis was conducted with 57 epilepsy patients (PWE), 50 patients with epilepsy and comorbid depression (PWECD), and 47 healthy controls (HC) admitted between June 2020 and June 2024. Serum levels of brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), 5-hydroxytryptamine (5-HT), norepinephrine (NE), dopamine (DA), interleukin-1β (IL-1β), and interleukin-6 (IL-6) were measured using enzyme-linked immunosorbent assay (ELISA). Additionally, BDNF and GDNF levels in cerebrospinal fluid (CSF) samples were analyzed from selected patients in the PWE and PWECD groups. Serum BDNF levels were significantly lower in both PWE and PWECD groups compared to HC, while no differences between the former two groups. GDNF levels were lower in PWECD compared to HC, but not between PWE and HC. Serum 5-HT was significantly reduced in PWECD compared to both HC and PWE groups. No significant differences were observed in serum DA, NE, and IL-6 levels across the groups. Serum IL-1β levels were elevated in the PWECD group compared to the HC group. The Self-Rating Depression Scale (SDS) score negatively correlated with serum 5-HT and GDNF levels. In terms of predictive ability, serum BDNF demonstrated higher accuracy for the diagnosis of epilepsy [area under the curve, AUC = 0.701, 95% confidence intervals (95% CI) 0.601 ~ 0.801], while serum 5-HT was the best marker for predicting the development of depression in epilepsy patients (AUC = 0.727, 95% CI 0.632 ~ 0.821). No significant correlation was found between serum and CSF BDNF levels within the same subject (r = 0.155; p = 0.221; Spearman correlation), and CSF GDNF levels were too low to be clinically informative. The findings suggest the involvement of NTFs, monoamine neurotransmitters, and inflammatory processes in the pathogenesis of epilepsy and depression. Decreased serum BDNF levels correlate with epilepsy but not necessarily with comorbid depression, while serum GDNF and 5-HT show potential clinical value in diagnosing this comorbidity. However, the deficient levels of NTFs in CSF suggest a need for more sensitive detection methods.

Establishment of a transgene-free iPS cell line (SDCHi002-A) from a young patient bearing a NPRL3 mutation and suffering from Epilepsy

Epilepsy affects ∼ 65 million people worldwide. In this study, peripheral blood mononuclear cells were isolated from a young patient patient bearing a Nitrogen Perntease Regulator Like 3 Protein (NPRL3) mutation and suffering from Epilepsy verified by clinical and genetic diagnosis. Induced pluripotent stem cells (iPSCs) were established by a non-integrative method, using plasmids carrying OCT4, SOX2, KLF4, BCL-XL and C-MYC. The established iPSCs presented typical pluripotent cells morphology, normal karyotype, and potential to differentiate into three germ layers. Our approach offers a useful model to explore pathogenesis and therapy of Epilepsy.

Causal relationship between oral microbiota and epilepsy risk: Evidence from Mendelian randomization analysis in East Asians.

Gut microbiota can traverse into the brain, activate the vagus nerve, and modulate immune responses and inflammatory processes, thereby influencing the onset of epileptic seizures. However, research on oral microbiota and epilepsy remains limited, and observational studies have been inconsistent. We aim to estimate the potential links between oral microbiota and epilepsy and elucidate which specific oral microbes may directly influence the pathogenesis of epilepsy. A two-sample MR analysis was conducted using genome-wide association study (GWAS) data specific to OM and epilepsy in East Asian individuals. Single nucleotide polymorphisms (SNPs) independent of confounders served as instrumental variables (IVs) to deduce causality. MR methodologies, including inverse variance weighted (IVW), MR-Egger, weighted median, and weighed mode methods, were utilized. Sensitivity analysis, including Cochrane's Q test, MR-Egger intercept test, and leave-one-out analysis, was applied to confirm the robustness of results. Among the 3117 bacterial taxa examined, we observed that 14 OM, like s_Streptococcus_mitis, s_Streptococcus_pneumoniae, and s_Haemophilus, were positively associated with epilepsy, while 7 OM, like g_Fusobacterium and g_Aggregatibacter, were negatively related to epilepsy. The MR-Egger intercept suggested that no evidence of horizontal pleiotropy was observed (p > 0.05). The leave-one-out analysis validated the robustness of the results. This study underscores the effect of OM on epilepsy, suggesting potential mechanisms between the OM and epilepsy. Further investigation into the potential role of the OM is needed to enhance our in-depth understanding of the pathogenesis of epilepsy. Previous research has demonstrated that the microbiota may influence the onset of epileptic seizures. We applied 3117 oral microbiota from the newest publicly available database of East Asian populations. Mendelian randomization analysis was utilized to estimate the causal relationship between oral microbiota and epilepsy. Our results showed that a causal effect exists between 21 oral microbiota and epilepsy. We provided genetic evidence for risk assessment and early intervention in epilepsy.