Neuroprotective Effect And Mechanism Of Deferoxamine Inhibits Ferroptosis On Early Brain Injury In Rats After Subarachnoid Hemorrhage

Background Subarachnoid hemorrhage(SAH)is a serious cerebrovascular disease that manifests a high mortality rate and an early age of onset than other types of stroke.Deferoxamine(DFO)has been applied clinically as a chelator of ferric ion to prevent iron overload,and is found to be an inhibitor of ferroptosis that manifests therapeutic efficacy in numerous diseases,nevertheless,its role in SAH has not been elucidated.Therefore,the aim of this study is to explore the implication of ferroptosis in EBI and to clarify the neuroprotective mechanism of DFO.Methods The rat model of SAH was established by applying injection of blood into cisterna magna.Subsequently,we observed the mortality rate,the severity grade of SAH,brain water content,blood-brain barrier permeability and neurological function of the rats.Malondialdehyde(MDA)was measured to evaluate the level of lipid peroxidation.TUNEL staining was employed to assess cell death,whereas iron staining was used to evaluate iron content.The protein expressions of GPX4,xCT,TfR1 and Fpn were measured by conducting Western blot,whereas the mRNA expression of GPX4,xCT and IREB2 were analyzed by performing q PCR.Results After the induction of SAH,the neurological function scores were reduced,blood-brain barrier permeability was elevated,and brain edema increased.The content of iron in the rat brain tissue,TfR1 expression level and MDA content were markedly increased after SAH.In contrast,Fpn,GPX4,xCT expression levels were notably decreased.Intraperitoneal injection of DFO elevated the expression of GPX4,xCT and Fpn,lowered the levels of TfR1 and IREB2,led to reduced iron deposition,lowered lipid peroxidation and diminished EBI.Conclusions Taken together,our data indicate that ferroptosis is implicated in EBI following SAH and that DFO therapy functions to ameliorate EBI by inhibiting ferroptosis.Such a molecular mechanism may be related to reduced intracellular iron deposition and the upregulation of xCT/GPX4 axis that promote the repairing of lipid peroxidation.