Ascorbic acid mitigates the impact of oxidative stress in a human model of febrile seizure and mesial temporal lobe epilepsy

Prolonged febrile seizures (FS) in children are linked to the development of temporal lobe epilepsy (MTLE). The association between these two pathologies may be ascribed to the long-term effects that FS exert on neural stem cells, negatively affecting the generation of new neurons. Among the insults associated with FS, oxidative stress is noteworthy. Here, we investigated the consequences of exposure to hydrogen peroxide (H2O2) in an induced pluripotent stem cell-derived neural stem cells (iNSCs) model of a patient affected by FS and MTLE. In our study, we compare the findings from the MTLE patient with those derived from iNSCs of a sibling exhibiting a milder phenotype defined only by FS, as well as a healthy individual. In response to H2O2 treatment, iNSCs derived from MTLE patients demonstrated an elevated production of reactive oxygen species and increased apoptosis, despite the higher expression levels of antioxidant genes and proteins compared to other cell lines analysed. Among the potential causative mechanisms of enhanced vulnerability of MTLE patient iNSCs to oxidative stress, we found that these cells express low levels of the heat shock protein HSPB1 and of the autophagy adaptor SQSTM1/p62. Pre-treatment of diseased iNSCs with the antioxidant molecule ascorbic acid restored HSBP1 and p62 expression and simultaneously reduced the levels of ROS and apoptosis. Our findings suggest the potential for rescuing the impaired oxidative stress response in diseased iNSCs through antioxidant treatment, offering a promising mechanism to prevent FS degeneration in MTLE.