Precision Therapeutics in Lennox–Gastaut Syndrome: Targeting Molecular Pathophysiology in a Developmental and Epileptic Encephalopathy

Children, Год журнала: 2025, Номер 12(4), С. 481 - 481

Опубликована: Апрель 8, 2025

Lennox-Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, distinctive electroencephalographic patterns. Current treatments primarily focus on symptom management through antiseizure medications (ASMs), dietary therapy, epilepsy surgery, neuromodulation, but often fail to address the underlying pathophysiology or improve outcomes. As genetic causes are identified in 30-40% of LGS cases, precision therapeutics targeting specific molecular mechanisms emerging as promising disease-modifying approaches. This narrative review explores therapeutic strategies for based pathophysiology, including channelopathies (SCN2A, SCN8A, KCNQ2, KCNA2, KCNT1, CACNA1A), receptor ligand dysfunction (GABA/glutamate systems), cell signaling abnormalities (mTOR pathway), synaptopathies (STXBP1, IQSEC2, DNM1), epigenetic dysregulation (CHD2), CDKL5 deficiency disorder. Treatment modalities discussed include traditional ASMs, targeted pharmacotherapy, antisense oligonucleotides, gene repurposing existing with mechanism-specific effects. Early intervention may not only control could also potentially prevent progression susceptible populations. Future directions developing computable phenotypes accurate diagnosis, refining subgrouping, enhancing drug development, advancing gene-based therapies, personalizing implementing adaptive clinical trial designs, ensuring equitable access While significant challenges remain, integrating biological insights innovative offers new hope transforming treatment from symptomatic disease modification.

Язык: Английский

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Dynamic functional connectivity and gene expression correlates in temporal lobe epilepsy: insights from hidden markov models

Journal of Translational Medicine, Год журнала: 2024, Номер 22(1)

Опубликована: Авг. 14, 2024

Temporal lobe epilepsy (TLE) is associated with abnormal dynamic functional connectivity patterns, but the changes in brain activity at each time point remain unclear, as does potential molecular mechanisms temporal characteristics of TLE. Resting-state magnetic resonance imaging (rs-fMRI) was acquired for 84 TLE patients and 35 healthy controls (HCs). The data then used to conduct HMM analysis on rs-fMRI from an HC group order explore intricate dynamics cognitive impairment (TLE-CI). Additionally, we aim examine gene expression profiles modular using Allen Human Brain Atlas (AHBA) database. Five states were identified this study. Compared HCs, TLE-CI exhibited distinct dynamics, including fractional occupancy, lifetimes, mean dwell switch rate. Furthermore, transition probability across significantly different between (p < 0.05). reconfiguration several networks (including high-order default mode network (DMN), subcortical (SCN), cerebellum (CN). a total 1580 genes revealed be TLE, mainly enriched neuronal signaling synaptic function. This study provides new insights into characterizing neural defined by may deepen our understanding neurobiological underpinnings TLE-CI, indicating linkage configuration

Язык: Английский

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Hypotheses of pathophysiological mechanisms in epileptic encephalopathies: A review

Brain and Development, Год журнала: 2025, Номер 47(1), С. 104318 - 104318

Опубликована: Янв. 8, 2025

Язык: Английский

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Lethal Interactions of neuronal networks in epilepsy mediated by both synaptic and volume transmission indicate approaches to prevention

Progress in Neurobiology, Год журнала: 2025, Номер 249, С. 102770 - 102770

Опубликована: Апрель 19, 2025

Язык: Английский

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Regulatory Mechanism of CRTC1 on Autophagy and GluA2 Expression in Epilepsy

Molecular Neurobiology, Год журнала: 2025, Номер unknown

Опубликована: Май 10, 2025

The objective of this study was to elucidate the molecular mechanisms by which cAMP-regulated transcription coactivator1 (CRTC1) regulates autophagy and GluA2 expression in patients with epilepsy. We initially established a magnesium-free epilepsy cell model recorded cellular discharges using whole-cell patch clamp technique. Next, we experimentally activated identified effective methods for silencing CRTC1 gene RNA interference technology. Furthermore, developed an animal models status epilepticus employed immunofluorescence Western Blot CRTC1's role regulating autophagy-related genes observed mouse hippocampal neurons under extracellular conditions. Treatment activator decreased expression; however, not dephosphorylated. siRNA suppressed LC3 PSD95 expression, whereas intervention restored expression. indirectly influences synaptic-related proteins directly modulating during pathological process findings reveal novel targets treatment

Язык: Английский

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Brain basis for physical activity levels mediate beta Inhibition to improve cognitive function in elderly based on multimodality monitoring

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Май 23, 2025

Abstract The ameliorative effect of regular physical activity (PA) on cognitive function (CF) in older adults has been demonstrated. However, there are differences the effects different levels PA CF over time. To provide a more efficient exercise prescription for adults, we compared with neural mechanisms individuals weekly levels. In this study, 68 ( n = 68, M 47, F 21, Age 62.43 ± 4.36) were categorized according to International Physical Activity Questionnaire (IPAQ) into high volume group (HG) (MET-min/week 1516.64 138.68), moderate (MG) 1248.02 119.86), and control 119.86). 846.78 97.53). Differences Stop Signal, Stroop, 2-Back among three groups. Electroencephalogram (EEG), event-related potential (ERP), magnetic resonance imaging (MRI) features also observed. results showed that CF, Stroop was significantly higher MG versus HG than CG (F 121.45, P < 0.01; 88.74, 0.01), opposite true response 236.83, 187.64, 0.01). 38.78, 0.037) Signal 52.03, terms EEG, alpha band share at rest 41.34, 0.040) work 25.67, 0.046). Although remaining not statistically significant, inversely proportional resting midrange-band β (CG 8.98 1.02, 8.07 0.76, 8.13 0.88), positively midrange high-band WORK (midrange β: 12.41 2.29, 12.98 3.04, 13.21 2.85; 6.76 2.23, 7.35 1.96, 7.91 2.3). ERP, latencies N200, P300, N450 shorter those 44.63, 0.041; 29.69, 0.045; 76.48, only 59.62, On MRI, had Middle Frontal Gyrus (MFG) (HG > CG, voxel 188, t 3.72), Right Superior (RSFG) 238, 4.07), Left Cingulate 343, 4.36), Supplementary Motor Area (LSMA) activated CG. MFG (MG 172, 3.56), LSMA 331, 4.28), PHG 204, 3.35) It concluded enhanced effective volume. Specifically, VPA found be MPA LPA enhancing individuals’ inhibition function, flexibility, working memory, reaction speed. This may attributed increase ERP amplitude latency greater gray matter density frontal temporal lobe regions.

Язык: Английский

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Developmental mechanisms underlying pediatric epilepsy

Frontiers in Neurology, Год журнала: 2025, Номер 16

Опубликована: Июнь 3, 2025

Pediatric epilepsy affects a large proportion of children, with huge variability in seizure onset. Due to complicated etiology, wide range associated comorbidities, and difficulty obtaining clear physiological data from management pediatric patients often poses critical challenge. Importantly, around 30% these remain non-responsive current anti-seizure drugs develop higher risk developmental cognitive delay and, worse situations, premature death. One the key treatment methods currently used for drug-resistant epilepsies is surgical resection epileptic foci. However, such new foci post-surgery. This, turn, enhances need recurrent invasive brain surgeries, impairing overall quality life children. Thus, mechanistic understanding different types discovering more targeted molecular approach(es). For long time, occurrence was considered solely due abnormal functioning single ion channels. recent years, number genetic non-genetic (environmental) factors have been epilepsy. Clinical diagnoses, coupled basic cellular mechanisms using model systems, instrumental unraveling avenues modern non-invasive pharmacological therapies. Yet, field has just started evolve, many challenges contradictory hypotheses still exist. This comprehensive review discusses underlying Specifically, we highlight how PI3K-AKT–MTOR pathway acts as node interconnecting diverse strategies, that may eventually help overcome burden future.

Язык: Английский

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Molecular Mechanisms Underlying the Generation of Absence Seizures: Identification of Potential Targets for Therapeutic Intervention

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(18), С. 9821 - 9821

Опубликована: Сен. 11, 2024

Understanding the molecular mechanisms underlying generation of absence seizures is crucial for developing effective, patient-specific treatments childhood epilepsy (CAE). Currently, one-third patients remain refractive to antiseizure medications (ASMs), previously called antiepileptic drugs (AEDs), available treat CAE. Additionally, these ASMs often produce serious side effects and can even exacerbate symptoms in some patients. Determining precise cellular directly responsible causing this type has proven challenging as they appear be complex multifactorial with different genetic backgrounds. Aberrant neuronal activity CAE may caused by several that are not fully understood. Thus, dissecting causal factors could targeted development precision medicines without remains a high priority ultimate goal field research. The aim review highlight our current understanding potential causative seizure generation, based on latest research using cutting-edge technologies. This information will important identifying targets future therapeutic intervention.

Язык: Английский

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Voltage-gated ion channels in epilepsies: circuit dysfunctions and treatments

Trends in Pharmacological Sciences, Год журнала: 2024, Номер 45(11), С. 1018 - 1032

Опубликована: Окт. 14, 2024

Язык: Английский

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Dynamic functional connectivity and gene expression correlates in temporal lobe epilepsy: insights from hidden markov models

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Авг. 5, 2024

Backgroud Temporal lobe epilepsy (TLE) is associated with abnormal dynamic functional connectivity patterns, but the changes in brain activity at each time point remain unclear, as does potential molecular mechanisms temporal characteristics of TLE. Methods Resting-state magnetic resonance imaging (rs-fMRI) was acquired for 84 TLE patients and 35 healthy controls (HCs). The data then used to conduct HMM analysis on rs-fMRI from an HC group order explore intricate dynamics cognitive impairment (TLE-CI). Additionally, we aim examine gene expression profiles modular using Allen Human Brain Atlas (AHBA) database. Results Five states were identified this study. Compared HCs, TLE-CI exhibited distinct dynamics, including fractional occupancy, lifetimes, mean dwell switch rate. Furthermore, transition probability across significantly different between (p < 0.05). reconfiguration several networks (including high-order default mode network (DMN), subcortical (SCN), cerebellum (CN). a total 1580 genes revealed be TLE, mainly enriched neuronal signaling synaptic function. Conclusions This study provides new insights into characterizing neural defined by may deepen our understanding neurobiological underpinnings TLE-CI, indicating linkage configuration

Язык: Английский

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