Ferrostatin-1 and Z-VAD-FMK potentially attenuated Iron-mediated neurotoxicity and rescued cognitive function in Iron-overloaded rats.

Aims: The present study was aimed to investigate the effects of cell death inhibitors including ferroptosis inhibitor, ferrostatin-1 (FER-1) and a pan-caspase inhibitor, z-VAD-FMK on brain parameters and cognitive function in iron-overloaded rats.

Main Methods: Male Wistar rats (n = 30) were divided into 2 groups to receive an intraperitoneal injection with either 10 % dextrose in normal saline solution (NSS) (control group, n = 6) or 100 mg/kg iron dextran (Fe group, n = 24) for 6 weeks. After 4 weeks of injection, Fe-injected rats were subdivided into 4 subgroups (n = 6/subgroup) to subcutaneously receive with 1) vehicle (10 % DMSO in NSS), 2) deferoxamine (25 mg/kg), 3) FER-1 (2 mg/kg), or 4) z-VAD-FMK (1 mg/kg). Control group was received vehicle. All subgroups were received each treatment for 2 weeks. Behavioral tests including the Morris water maze test and novel object recognition test, were performed at the end of treatment. Then, circulating iron levels and brain parameters including blood-brain barrier proteins, iron level, synaptic proteins, and ferroptosis/apoptosis were determined.

Key Findings: All treatment attenuated iron-overloaded condition, brain pathologies, and the cognitive impairment. FER-1 and z-VAD-FMK provided superior effects than deferoxamine by attenuating loss of synaptic proteins and restoring cognitive function in both hippocampal-dependent and hippocampal-independent manners.

Significance: These findings suggest that cell death inhibitors act as the novel therapeutic targets for neuroprotection in iron-overloaded condition.