Temporal dynamics of ferroptosis markers and neuroprotective intervention in cerebral ischemia-reperfusion injury: Insights for therapeutic strategy development

Objective(s): This study examines the temporal dynamics of ferroptosis following cerebral ischemia-reperfusion injury (CIRI) to establish a theoretical framework for innovative therapies that enhance neuronal survival by mitigating ferroptosis.Materials and Methods: An experimental CIRI model was established in mice via middle cerebral artery occlusion and reperfusion (MCAO/R). Behavioral assessments were conducted, and blood-brain barrier (BBB) integrity was evaluated using transmission electron microscopy. Immunoblotting and ELISA were performed to determine ferroptosis dynamics post-MCAO/R. Additionally, CIRI mice received intraperitoneal injections of Ferrostain-۱ (۱۰ mg/kg/d) and Erastin (۳۰ mg/kg/d). The effects of ferroptosis on CIRI were further verified through ۲,۳,۵-Triphenyltetrazolium chloride and hematoxylin-eosin staining.Results: MCAO/R induced BBB disruption, and was associated with a reduction in GSH activity (at ۱, ۳, and ۵ days), elevated Fe(۲+) levels (at ۱ day), as well as decreased MDA levels (at ۳ days). Concurrently, ferroptosis markers, including NRF۲, xCT, and GPX۴, were significantly down-regulated on day ۱, reaching their nadir by day ۳, whereas HO-۱ exhibited an inverse trend. Notably, Ferrostatin-۱ pretreatment conferred a protective effect against CIRI, in contrast to the MCAO and Erastin groups.Conclusion: This study elucidates the temporal dynamics of ferroptosis markers in the early stages of stroke, highlighting a therapeutic window for ferroptosis-related CIRI. These findings underscore the importance of targeting ferroptosis to improve neuronal survival and inform future CIRI therapies.

کلیدواژه ها:

Blood-brain barrier ، Ferroptosis ، Ischemic stroke ، Lipid Peroxidation ، Oxidative stress