Rezweratrol zmniejsza uszkodzenia mózgu spowodowane epilepsją poprzez aktywację szlaku P62-Keap1-Nrf2: badanie wielopoziomowe z udziałem kohorty pilotażowej, analiz komputerowych i walidacji doświadczalnej
Resveratrol Alleviates Epilepsy-Induced Brain Damage via the P62-Keap1-Nrf2 Pathway: A Multi-Omics Study Integrating the Pilot Cohort, In Silico Analyses, and Experimental Validation
W skrócie
Badacze zbadali, jak rezweratrol (substancja naturalna ze śliwek i rodzynek) chroni mózg dzieci chorych na epilepsję. Odkryli, że epilepsja powoduje w mózgu nagromadzenie żelaza i stres oksydacyjny, które uszkadzają neurony. Rezweratrol działa poprzez aktywację specjalnego mechanizmu ochronnego w komórkach i zmniejsza napady, co sugeruje, że może być nowym sposobem leczenia pediatrycznej epilepsji.
Oryginalny abstract (angielski)
BACKGROUND: Pediatric epilepsy is frequently associated with long-term cognitive, behavioral, and neurodevelopmental impairments. Although oxidative stress and metabolic dysfunction contribute to seizure-induced brain injury, how ferroptosis operates and is regulated within the context of pediatric epilepsy has yet to be fully elucidated. METHODS: A pediatric pilot cohort of 15 pediatric patients at first seizure onset alongside age-matched neurotypical peers was established. Untargeted metabolomics, neuroimaging, biochemical assays, and gene expression analyses were performed to evaluate metabolic dysregulation, iron accumulation, oxidative stress, and ferroptosis-related alterations. Integrated bioinformatics, Mendelian randomization, external transcriptomic validation, single-cell RNA sequencing, virtual perturbation analysis, and in silico drug screening were used to identify key regulatory pathways and candidate therapeutic compounds. The effects of resveratrol were further validated in a kainic acid-based murine epilepsy model and glutamate-challenged HT22 neuronal cells. RESULTS: Pediatric epilepsy was characterized by metabolic reprogramming, iron accumulation, lipid peroxidation, inflammation, and impaired antioxidant defense. Integrated bioinformatics identified SQSTM1/P62 and NFE2L2/NRF2 as key regulators linking autophagy and ferroptosis. External validation and single-cell transcriptomic analyses further confirmed ferroptosis- and autophagy-related dysregulation, particularly in neuronal populations. In silico screening identified resveratrol as a candidate therapeutic compound. In epileptic mice, resveratrol reduced seizure severity, epileptiform discharges, neurobehavioral deficits, iron accumulation, lipid peroxidation, inflammation, and hippocampal neuronal injury. CONCLUSION: Pediatric epilepsy is associated with metabolic dysregulation, oxidative stress, iron accumulation, and ferroptosis-related neuronal injury. Resveratrol protects against seizure-associated brain damage by activating P62-Keap1-Nrf2 signaling and suppressing ferroptosis, suggesting a potential therapeutic strategy for pediatric epilepsy.