Perampanel attenuates ferroptosis-related hippocampal injury after status epilepticus in association with reduced ERK/MAPK signaling

This study investigated whether perampanel (PER), a selective α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, mitigates ferroptosis-related hippocampal injury after status epilepticus (SE) and whether these changes are associated with the extracellular regulated protein kinase/mitogen-activated protein kinase (ERK/MAPK) pathway. Male C57BL/6 N mice were subjected to pilocarpine-induced SE. Ninety minutes post-onset, seizures were terminated with diazepam (4 mg/kg). Mice then received vehicle, PER (1 or 2 mg/kg), or PER combined with either the ERK activator phorbol-12-myristate-13-acetate (PMA) 100 µg/kg or the mitogen-activated protein kinase kinase (MEK) inhibitor PD98059 10 mg/kg. Seizure severity, hippocampal morphological alterations, mitochondrial damage, iron metabolism, and MAPK activation were assessed using electroencephalography (EEG), histology, transmission electron microscopy (TEM), Western blotting, and biochemical assays. Pilocarpine induced persistent Racine IV-V seizures, high-amplitude EEG discharges, and progressive CA3 neurodegeneration. Ferroptosis-related alterations, including iron overload, glutathione (GSH) depletion, malondialdehyde (MDA) accumulation, decreased GPX4 and ferroportin (FPN1), and increased transferrin (TF) and transferrin receptor (TFR), emerged at 8–12 h and peaked at 24 h. PER, at both 1 and 2 mg/kg, attenuated seizures, preserved mitochondrial ultrastructure, restored GSH, lowered MDA, normalized GPX4/FPN1 and TF/TFR levels, and reduced iron deposition. PER selectively suppressed ERK phosphorylation, while JNK and P38 levels remained unchanged. PMA attenuated the PER-associated reduction in ERK phosphorylation and ferroptosis-related injury, whereas PD98059 further enhanced these effects. These findings suggest that PER treatment is associated with reduced hippocampal ferroptosis-related changes after SE, accompanied by seizure suppression and decreased ERK/MAPK activation. However, whether PER directly inhibits ferroptosis independently of its anti-seizure effect, and whether ERK/MAPK signaling is a primary causal mediator, requires further investigation.