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