ferrostatin-1 and Cognitive-Dysfunction

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. The preparation of PTE was performed by stereotaxical injection in the somatosensory cortex region of 50 mM FeCl

Topics: Animals; Chlorides; Cognition; Cognitive Dysfunction; Cyclohexylamines; Ferric Compounds; Ferroptosis; Humans; Mice; Phenylenediamines; Seizures

Evidence indicates that ferrostain-1 (Fer-1), a specific inhibitor of ferroptosis, could ameliorate cognitive dysfunction of rats with kainic acid (KA)-induced temporal lobe epilepsy (TLE) by suppressing ferroptosis processes. Recent studies suggest that P38 mitogen-activated protein kinase (MAPK) pathway could be mediated by ferroptosis processes. The activation of P38 MAPK results in cognitive impairment by suppressing the expression of synaptic plasticity-related proteins. However, it is unclear whether Fer-1 can mitigate cognitive impairment of rats with KA-induced TLE by inhibiting P38 MAPK activation. In the present study, treatment with Fer-1 blocked the activation of P38 MAPK, which resulted in an increased expression of synaptophysin (SYP) and postsynaptic density protein 95 (PSD-95) in the hippocampus of rats with KA-induced TLE, hence, ameliorating their cognitive impairment. Also, P38 MAPK activation in the hippocampus of the rats reduced the expression of both PSD-95 and SYP proteins. Treatment of the rats with SB203580, a P38 MAPK-specific inhibitor, prevented the activation of P38 MAPK, which resulted in an increase in SYP and PSD95 protein levels in the hippocampus. These results suggest that Fer-1 could mitigate the cognitive impairment by suppressing P38 MAPK activation thus restoring the expression of synaptic proteins. Ferroptosis processes might be involved in suppressing synaptic protein expression.

Topics: Animals; Biomarkers; Cognitive Dysfunction; Cyclohexylamines; Epilepsy, Temporal Lobe; Ferroptosis; Hippocampus; Male; Neuronal Plasticity; Neuroprotective Agents; p38 Mitogen-Activated Protein Kinases; Phenylenediamines; Random Allocation; Rats; Rats, Sprague-Dawley; Treatment Outcome