Ferrostatin-1 obviates seizures and associated cognitive deficits in ferric chloride-induced posttraumatic epilepsy via suppressing ferroptosis

Background: and Purpose: Posttraumatic epilepsy (PTE) is a prevalent complication of brain trauma. Current anti-epileptic drugs available do not have satisfactory response to PTE. It is of desperate need to explore novel therapeutic approaches for curing PTE. Our prior work revealed that ferroptosis, a recently discovered mode of cell death, occurs in rodent model of PTE. In the present study, we aimed to further investigate the effect of ferrostatin-1 (Fer-1), a specific ferroptosis inhibitor, on seizure behavior and cognitive deficit in a mouse model of PTE. Experimental approach: The preparation of PTE was performed by stereotaxical injection in the somatosensory cortex region of 50 mM FeCl3. Seizure activity was assessed via Racine scoring and electroencephalogram analysis. PTE-related cognitive function was evaluated by novel object recognition and Morris water maze tests. Ferroptosis-related indices including glutathione peroxidase (GPx) activity and protein expressions of 4-hydroxynonenal (4-HNE) were detected using a commercial kit and immunofluorescence, respectively. Key Results: It was found that treatment with Fer-1 significantly exerted protective effects against acute seizure and memory decline, although no evident effect on epileptic progression. Fer-1 also exhibited good tolerability and safety as we observed that it hardly influenced the body weight. Furthermore, it was noted that administration of Fer-1 suppressed ferroptosis-related indices including GPx activity and protein expressions of 4-HNE in hippocampus. Conclusion and Implications: These data altogether indicate that Fer-1 has potent therapeutic effects against seizures and cognitive impairment following PTE-induced brain insult. Fer-1 may act as a promising drug for curing PTE patients.