Deferasirox, a trivalent iron chelator, ameliorates neuronal damage in hemorrhagic stroke models

Purpose Intracranial hemorrhage (ICH) is a devastating disease with high mortality and morbidity. After ICH, iron released from the hematoma plays a crucial role in secondary brain injury. Deferasirox (DFR) is a trivalent iron chelator, which was approved to treat iron overload syndrome after transfusion. The aim of the present study was to investigate the protective effects of DFR in both in vitro and in vivo ICH models. Methods Using a hemin-induced SH-SY5Y cell damage model, we performed an intracellular bivalent iron (Fe2+) accumulation assay, cell death assay, oxidative stress assessments, and Western blotting analysis. Moreover, the effects of DFR intraventricular administration on hematoma, neurological deficits, and histological alteration were evaluated in an in vivo ICH mouse model by collagenase. Results DFR significantly suppressed the intracellular Fe(2+)accumulation and cell death caused by hemin exposure. These effects were related to the suppression of both reactive oxygen species and lipid peroxidation over-production. In Western blotting analysis, hemin increased the expression of ferritin (an iron storage protein), LC3 and p62 (autophagy-related markers), phosphorylated p38 (a stress response protein), and cleaved-caspase3 and cleaved-poly (adenosine diphosphate ribose) polymerase (PARP) (apoptosis-related makers). However, DFR suppressed the increase of these proteins. In addition, DFR attenuated the neurological deficits until 7 days after ICH without affecting hematoma and injury area. Furthermore, DFR also suppressed microglia/macrophage activation in peri-hematoma area at 3 days after ICH. Conclusion These findings indicate that DFR might be a useful therapeutic agent for the therapy of ICH.

Automated summary

The study found that DFR can significantly suppress intracellular Fe(2+) accumulation and cell death caused by hemin exposure, which is related to the suppression of oxidative stress. DFR can also attenuate neurological deficits after ICH and suppress microglia/macrophage activation in the peri-hematoma area.