Hou_2025_J.Integr.Neurosci_24_39469

BACKGROUND: Epilepsy, a significant neurological condition marked by the occurrence of repeated seizures, continues to pose a substantial health challenge. Previous studies have indicated that Dipeptidyl Peptidase-4 (DPP4) inhibitors may possess antiepileptic properties. Ferroptosis, a newly discovered type of programmed cell death, has recently surfaced as a promising therapeutic target in the management of epilepsy. Nevertheless, the exact mechanisms responsible for the effects of DPP4 inhibitors have not yet been fully elucidated. METHODS: The anti-epileptic effect was evaluated through electroencephalogram (EEG) recordings, behavioral assessments, and immunohistochemical analysis in a mouse model of epilepsy induced by LiCl/Pilocarpine. Public RNA-sequencing data was used to search the key targets of epilepsy. Neuronal ferroptosis was assessed through western blotting and immunofluorescence in an epilepsy rat model and a glutamate-induced neuronal cell model. RESULTS: Administration of the DPP4 inhibitor sitagliptin was observed to markedly reduce seizure severity in an animal model of epilepsy. Furthermore, sitagliptin effectively diminished epileptiform activity, as assessed by EEG. Additionally, pretreatment with sitagliptin led to a notable decrease in the expression of heme oxygenase-1 (HO-1), reactive oxygen species (ROS) production, and mitochondrial damage, while increasing glutathione peroxidase 4 (GPX4) expression in the epilepsy rat model. Similar effects were observed in cell-based experiments, where sitagliptin pretreatment enhanced GPX4 expression in glutamate-induced neuronal models. CONCLUSIONS: The DPP4 inhibitor sitagliptin mitigates ferroptosis in epilepsy models. These findings highlight new potential targets and treatment modalities for epilepsy.