Failure of deferoxamine, an iron chelator, to improve outcome after collagenase-induced intracerebral hemorrhage in rats

Warkentin, Lindsey M.; Auriat, Angela M.; Wowk, Shannon; Colbourne, Frederick

doi:10.1016/j.brainres.2009.10.058

Cited by 50 publications

(48 citation statements)

References 44 publications

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“…These effects can be reduced with deferoxamine, an iron chelator [38][39][40][41][42][43][44][45] . However, two studies [46,47] have reported that deferoxamine reduces the level of iron, but does not improve outcomes, in a collagenase-induced ICH model. In our experimental design, Fe 2+ was added to cultured astrocytes and AQP4 and AQP9 protein expression were strongly induced, suggesting that iron was related to cytotoxic edema.…”

Section: Discussionmentioning

confidence: 99%

Curcumin attenuates brain edema in mice with intracerebral hemorrhage through inhibition of AQP4 and AQP9 expression

et al. 2015

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Aim: Aquaporins (AQPs) are the water-channels that play important roles in brain water homeostasis and in cerebral edema induced by brain injury. In this study we investigated the relationship between AQPs and a neuroprotective agent curcumin that was effective in the treatment of brain edema in mice with intracerebral hemorrhage (ICH). Methods: ICH was induced in mice by autologous blood infusion. The mice immediately received curcumin (75, 150, and 300 mg/kg, ip). The Rotarod test scores, brain water content and brain expression of AQPs were measured post ICH. Cultured primary mouse astrocytes were used for in vitro experiments. The expression of AQP1, AQP4 and AQP9 and NF-κB p65 were detected using Western blotting or immunochemistry staining. Results: Curcumin administration dose-dependently reduced the cerebral edema at d 3 post ICH, and significantly attenuated the neurological deficits at d 5 post ICH. Furthermore, curcumin dose-dependently decreased the gene and protein expression of AQP4 and AQP9, but not AQP1 post ICH. Treatment of the cultured astrocytes with Fe 2+ (10-100 µmol/L) dose-dependently increased the expression and nuclear translocation of NF-κB p65 and the expression of AQP4 and AQP9, which were partly blocked by co-treatment with curcumin (20 µmol/L) or the NF-κB inhibitor PDTC (10 µmol/L). Conclusion: Curcumin effectively attenuates brain edema in mice with ICH through inhibition of the NF-κB pathway and subsequently the expression of AQP4 and AQP9. Curcumin may serve as a potential therapeutic agent for ICH.

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Section: Discussionmentioning

confidence: 99%

Curcumin attenuates brain edema in mice with intracerebral hemorrhage through inhibition of AQP4 and AQP9 expression

et al. 2015

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“…However, the therapeutic efficacy of deferoxamine might depend on the type of ICH model. Reports mentioned above demonstrating beneficial effects of deferoxamine are based on the model made by autologous blood injection, whereas deferoxamine did not improve the outcome of the collagenase-induced ICH model in rats (37). On the other hand, a study on clioquinol, another kind of metal chelator, has demonstrated that oral administration of the drug, starting 6 h after induction of hemorrhage near the internal capsule by collagenase, alleviated motor dysfunction of rats (38).…”

Section: Heme and Ironmentioning

confidence: 99%

Exploring Neuroprotective Drug Therapies for Intracerebral Hemorrhage

Katsuki

2010

J Pharmacol Sci

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Abstract. Intracerebral hemorrhage (ICH) is a devastating neurological disorder with high mortality and poor prognosis, for which virtually no effective drug therapies are available at present. Experimental animal models, based on intrastriatal injection of collagenase or autologous blood, have enabled great advances in elucidation of cellular/molecular events contributing to brain pathogenesis associated with ICH. Many lines of evidence indicate that blood constituents, including hemoglobin-derived products as well as proteases such as thrombin, play important roles in the pathogenic events. Inflammatory reactions involving neutrophils, activated microglia, and production of proinflammatory cytokines also constitute a critical aspect of pathology leading to neurodegeneration and tissue damage. Efforts are continuing to find drugs that potentially alleviate pathologi cal and neurological outcomes of ICH. Various drugs that possess antioxidative, antiinflammatory or neurotrophic/neuroprotective properties have been demonstrated to produce therapeutic effects on ICH animal models. Drugs already in clinical use such as minocycline, statins, and several nuclear receptor ligands are among the list of effective drugs, but whether they also show therapeutic efficacy in human ICH patients remains unproven. Here, current knowledge of ICH pathogenesis and problems arising with respect to exploration of new drug candidates are discussed.

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“…Deferoxamine, a ferric iron chelator, which is the most popular treatment in experimental intervention strategy in ICH, has been shown to mitigate iron-mediated damage [3,4]. Unfortunately, recent data showed that deferoxamine can reduce the iron contents in the brain, but could not attenuate injury and improve neurological outcome [10,11]. Deferiprone, another ferric iron chelator, because of its easy taking, stability, lipophilicity, high tissue penetration, and clearance of the iron complex, can be used as a potent pharmaceutical alternative therapy, especially in conditions when other treatments failed [12,13].…”

Section: Introductionmentioning

confidence: 97%

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

Wang

Tang

et al. 2015

Mol Neurobiol

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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.

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Failure of deferoxamine, an iron chelator, to improve outcome after collagenase-induced intracerebral hemorrhage in rats

Cited by 50 publications

References 44 publications

Curcumin attenuates brain edema in mice with intracerebral hemorrhage through inhibition of AQP4 and AQP9 expression

Curcumin attenuates brain edema in mice with intracerebral hemorrhage through inhibition of AQP4 and AQP9 expression

Exploring Neuroprotective Drug Therapies for Intracerebral Hemorrhage

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

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