Epilepsy is a debilitating neurological disorder that impacts approximately 50 million people worldwide. The treatment of epilepsy with antiepileptic drugs has not achieved effective seizure managemen Show more
Epilepsy is a debilitating neurological disorder that impacts approximately 50 million people worldwide. The treatment of epilepsy with antiepileptic drugs has not achieved effective seizure management and thus requires new therapeutic options. This study investigated the catechins' affect on epilepsy-related molecular targets using a computational method that combined network pharmacology, molecular docking, and molecular dynamics (MDs) simulation. We fetched 84 catechins-related and 5356 disease-associated targets from various databases, yielding 31 common targets. The protein-protein interaction (PPI) network of 31 common targets identified 10 hub genes, including ALB, INS, brain-derived neurotrophic factor (BDNF), PTGS2, tumor necrosis factor (TNF), IL1B, FOS, IL6, LEP, and FGF2. Further, the functional enrichment analysis revealed that these common targets have a high prevalence in multiple pathways and gene ontology functions. Furthermore, "compound-target" and "compound-gene-pathway" networks were constructed and analyzed. Network pharmacology data show TNF, IL1B, and IL6 could influence epilepsy treatment by regulating several pathways. The Cresset Flare Pro+ docking study unveiled that the lead catechin, epigallocatechin gallate (EGCG), exhibited the highest Lead Finder (LF) dG scores of -10.2, -9.40, and -8.15 kcal/mol against TNF, IL6, and IL1B, respectively. The electrostatic complementarity and Molecular Mechanics with Generalized Born and surface area (MMGBSA) results supported the docking results. Further, the stability of EGCG-bound complexes was analyzed using a 300 ns MD simulation. The principal component analysis yielded promising results for the EGCG-2AZ5 and EGCG-1ALU complexes collective motion. These findings provide computational evidence suggesting that EGCG has a promising scaffold for designing multi-target molecules that could modulate epilepsy, meriting further experimental validation. Show less
Epilepsy is increasingly linked to neurodegeneration, yet the cellular drivers of the neuron-microglia interplay remain unclear. Herein, we present "EpiNeuroid", a 3D-bioprinted human neural organoid Show more
Epilepsy is increasingly linked to neurodegeneration, yet the cellular drivers of the neuron-microglia interplay remain unclear. Herein, we present "EpiNeuroid", a 3D-bioprinted human neural organoid that incorporates barium titanate piezoelectric nanoparticles to generate an on-demand, ultrasound-triggered electrostimulatory microenvironment that induces a hyperexcitable state, recapitulating key electrophysiological signatures indicative of a trend toward epileptiform discharges. EpiNeuroid recapitulates neuronal DAMPs release (HMGB1, TLR4, NF-κB), microglial activation (Iba1, TNF-α, IL-1β, IL-6, iNOS), heightened neuronal Ca Show less
Epilepsy is generally described as a pathology resulting from an imbalance between excitatory and inhibitory activities. In recent years, neurotrophins have been recognized as key players in the patho Show more
Epilepsy is generally described as a pathology resulting from an imbalance between excitatory and inhibitory activities. In recent years, neurotrophins have been recognized as key players in the pathophysiology of nervous system diseases. One such neurotrophin, BDNF, and its receptor, TrkB, play critical roles as epileptogenic factors that regulate neuronal hyperexcitability and synaptic plasticity. In this study, we sought to elucidate the exact mechanisms underlying the neuroprotective and antiepileptic effects of pantoprazole. The molecular docking study indicated key interactions of pantoprazole with the TrkB receptor (PDB ID: 4AT3). Furthermore, pantoprazole exhibited notable in vitro TrkB kinase inhibitory activity (IC Show less
To date, the burden of alcohol-related seizures is increasing, with an unexplored etiological complex, and the psychopharmacological interplay remains significantly scarce. In this study, we developed Show more
To date, the burden of alcohol-related seizures is increasing, with an unexplored etiological complex, and the psychopharmacological interplay remains significantly scarce. In this study, we developed an experimental approach to investigate the contrasting impact of alcohol on pentylenetetrazol-induced seizures and the effects of diosgenin, a phytosteroid agent with neuroprotective effects. After 7 days of binge alcoholism with ethanol (2 g/kg, oral gavage) in male mice, they were subjected to maximum and sub-convulsive pentylenetetrazol-induced seizures concomitantly with diosgenin (25 and 50 mg/kg, p.o.) or diazepam (3 mg/kg, p.o) treatments from days 8-14. The interaction between ethanol and pentylenetetrazol-induced seizures was investigated, along with behavioral comorbidities, hypothalamic-adrenal-pituitary-axis (HPA-axis), neurochemical and neurotrophic dysfunctions, oxidative stress, and neuroinflammation in the hippocampus, prefrontal cortex, and striatum. Ethanol-exacerbated pentylenetetrazol-induced seizure and frequency, characterized by rearing with myoclonic jerks, and clonic-tonic convulsions. It increased anxiety, depressive behavior and impaired spatial working memory, influenced by heightened alcohol preference and corticosterone levels, which were normalized by diosgenin. Concomitant ethanol administration exacerbated reductions in GABAergic-dependent glutamic acid decarboxylase and increased glutamate levels associated with pentylenetetrazol-induced seizures, alongside depletions of serotonin and brain-derived neurotrophic factor in the hippocampus, prefrontal cortex, and striatum. Among others, diosgenin, compared to ethanol-pentylenetetrazol exacerbation, reduced levels of myeloperoxidase, TNF-α, and IL-6, nitrite and malondialdehyde in the hippocampus, prefrontal cortex, and striatum while increasing IL-10 cytokine and antioxidant system (superoxide-dismutase, glutathione, and glutathione-transferase). These findings suggest that alcoholism exacerbates seizures across brain regions, involving neurochemical imbalance, HPA-axis dysfunction, oxidative stress, and neuroinflammation, which are reversible by diosgenin. Show less
Stress exposure, whether acute or chronic, is now recognized to be a determinant of epileptogenic vulnerability. Psychological stress or trauma may not only precipitate seizures but also actively cont Show more
Stress exposure, whether acute or chronic, is now recognized to be a determinant of epileptogenic vulnerability. Psychological stress or trauma may not only precipitate seizures but also actively contribute to the development of epilepsy, a concept that in the clinical setting could be termed "psychoepileptogenesis". Recent evidence from both animal models and clinical studies supports the role of emotional stress in facilitating epileptogenesis, particularly within limbic structures such as the amygdala and hippocampus. In rodent models, chronic stress has been shown to lower seizure thresholds and promote epileptogenesis through mechanisms involving brain-derived neurotrophic factor (BDNF) and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Human studies reinforce these findings: individuals exposed to trauma or suffering from post-traumatic stress disorder (PTSD) exhibit an elevated risk of developing epilepsy, especially temporal lobe epilepsy (TLE), with structural and functional neuroimaging revealing changes in limbic and paralimbic circuits. These converging lines of evidence suggest that psychoepileptogenesis is a plausible, albeit complex, phenomenon. Further research is needed to identify biomarkers of vulnerability and evaluate whether early interventions targeting stress pathways might alter the course of epileptogenesis. Show less