AbstractBackgroundOur study indicated that iron‐overloaded condition induced neurotoxicity in rats and cognitive impairment (1). Furthermore, neuronal deaths caused by apoptosis and ferroptosis, have been identified as one of the underlying mechanisms of neurotoxicity in iron‐overloaded condition (1, 2). Recently, a ferroptosis inhibitor; ferrostatin‐1 and a pan‐caspase inhibitor; z‐VAD‐FMK exerted neuroprotection in traumatic brain injury and intracerebral hemorrhagic brain. Nonetheless, the comparative efficacy of these cell death inhibitors on brain parameters and cognitive function in iron‐overloaded rats has not yet been investigated.MethodThirty male Wistar rats were divided into 2 groups to receive an intraperitoneal injection with 10% dextrose in normal saline solution (NSS) as a control group (n = 6) or 100 mg/kg iron dextran as an iron‐overloaded group (n = 24). After 4 weeks of injection, iron‐overloaded group was subdivided into 4 groups (n = 6/ group) to subcutaneously receive with the pharmacological interventions including 1) vehicle (10% DMSO in NSS), 2) deferoxamine (25 mg/kg), 3) ferrostatin‐1 (2 mg/kg), and 4) z‐VAD‐FMK (1 mg/kg). In contrast, rats in the control group were received vehicle. Those mice were received the assigned treatment for further 2 weeks. Behavioral tests including the Morris water maze test (hippocampal‐dependent memory) and novel object recognition test (hippocampal‐independent memory), were performed. At the end of experiments, systemic iron overload and brain parameters including blood‐brain tight junction proteins, brain iron, synaptic markers, and brain ferroptosis/apoptosis were determined.ResultNot only systemic iron overload, but iron‐overloaded rats exhibited blood‐brain barrier breakdown, brain iron overload, iron‐mediated brain toxicity including brain oxidative stress, loss of synaptic proteins, and brain ferroptosis/apoptosis, leading to cognitive impairment. Treatment with deferoxamine attenuated rats from systemic iron overload, brain pathologies, and hippocampal‐independent memory (Figure 1A), but failed to rescue hippocampal‐dependent memory in iron‐overloaded rats (Figure 1B). Interestingly, cell death inhibitors including ferrostatin‐1 and z‐VAD‐FMK provided superior neuroprotection than deferoxamine by attenuating loss of synaptic proteins and restoring cognitive function in hippocampal‐dependent and hippocampal‐independent manners (Figure 1A‐1C).ConclusionFerrostatin‐1 and z‐VAD‐FMK exerted neuroprotective effects and cognitive restoration in rats under iron‐overloaded condition, suggesting the novel therapeutic strategy using cell death inhibitors in brain following iron‐overloaded condition.