Effect Comparison of Both Iron Chelators on Outcomes, Iron Deposit, and Iron Transporters After Intracerebral Hemorrhage in Rats

Abstract

Iron overload plays a key role in brain injury after intracerebral hemorrhage (ICH). We explored the roles of ferric iron chelator-deferiprone (DFP)-and ferrous iron chelator-clioquinol (CQ)-in ICH rats through the outcomes, iron deposits, reactive oxygen species (ROS), brain water content, and related iron transporters. One hundred eight Sprague-Dawley rats received intra-striatal infusions of 0.5 U of type IV collagenase to establish ICH models. The rats were randomly assigned to the sham, vehicle, DFP, and CQ groups. We evaluated the outcomes, iron levels, brain water content, and ROS; meanwhile, immunohistochemistry and real-time quantitative polymerase chain reaction (RT-qPCR) were utilized to determine ferritin, transferrin, transferrin receptor, divalent metal transport 1 (DMT1), and ferroportin at 48 and 72 h, 7 and 14 days after surgery. Our results showed ICH induced iron overload, brain edema, ROS formation, and neurological deficits. Both iron chelators decreased iron levels; CQ improved the neurological outcome, attenuated brain edema, and ROS production. DFP reduced iron contents but not brain water content and ROS generation. DFP failed to improve the outcome. ICH initiated endogenous iron chelators and transporters, both exogenous iron chelators enhanced expression of transferrin and transferrin receptor. CQ enhanced expression of ferroportin but not DMT1, while DFP enhanced expression of DMT1 but not ferroportin. Ferrous iron contributed to brain injury, and binding ferrous iron can modestly improve outcome after ICH in rats. The exogenous ferrous iron chelator possibly functioned via endogenous ferrous iron transporters on ICH. Therefore, ferrous iron may be a promising target for ICH in future.

Brain iron overload following intracranial haemorrhage

“…In a rat model of ICH, CQ administration ameliorated motor dysfunction due to its ability to reduce ROS production in oligodendrocytes 214. In addition, CQ improved neurological outcome, reduced brain oedema and improved mortality rates in a different rat model while enhancing expression of the iron exporting protein FP1 96. These findings suggest CQ as a promising upcoming treatment option for ICH.…”

“…There has been no research to assess whether it could play an equivalent role in the brain. Nevertheless, iron overload has been shown to increase brain water content following ICH 96. Important to the formation of cerebral oedema is aquaporin 4 (AQP4), one of the most abundant water channel proteins in the brain 97–99.…”

“…The few studies that have performed so have had mixed results; DFP administration at 8 hours post-SAH resulted in significantly decreased cerebral vasospasm in a rabbit model 210. However, in a rat ICH model, DFP failed to decrease ROS generation, oedema formation and morbidity, despite successfully reducing iron content 96. This latter study used a high dosage of DFP (125 mg/kg, which is above the 75–100 mg/kg typical dosage usually used to treat thalassaemia), and found that a dosage of 200 mg/kg was highly toxic to the rats in the study.…”

Microglial Polarization and Inflammatory Mediators After Intracerebral Hemorrhage

“…However, others claim that although deferoxamine can reduce iron content in the brain, it cannot attenuate injury or improve neurologic function [144–146]. In one recent study, ferrous iron chelator (clioquinol), but not ferric iron chelator (deferiprone), improved brain outcomes after ICH [147]. Ferric iron chelator is more likely to facilitate the Fenton reaction process and increase free radical production.…”

Intracerebral Hemorrhage: Perihemorrhagic Edema and Secondary Hematoma Expansion: From Bench Work to Ongoing Controversies

“…In animal models, heme diffused rapidly through perivascular spaces and induced heme oxygenase-1 enzyme that led to accumulation of ferritin and hemosiderin; generation of free radicals; neuronal injury; and BBB disruption (61). In a rat study, ferrous iron was found to cause brain injury, making this a potential target for chelation therapy (62). Lipocalin-2, a siderophore-binding protein, present in astrocytes, microglia, neurons, and endothelial cells, is involved in cellular iron transport and neuroinflammation.…”