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Object: In the authors' previous studies they found that brain iron accumulation and oxidative stress contribute to secondary brain damage after intracerebral hemorrhage (ICH). In the present study they investigated whether deferoxamine, an iron chelator, can reduce ICH-induced brain injury.
Methods: Male Sprague-Dawley rats received an infusion of 100 µl of autologous whole blood into the right basal ganglia and were killed 1, 3, or 7 days thereafter. Iron distribution was examined histochemically (enhanced Perl reaction). The effects of deferoxamine on ICH-induced brain injury were examined by measuring brain edema and neurological deficits. Apurinic/apyrimidinic endonuclease/redox effector factor-1 (APE/Ref-1), a repair mechanism for DNA oxidative damage, was quantitated by Western blot analysis.
Iron accumulation was observed in the perihematoma zone beginning 1 day after ICH. Deferoxamine attenuated brain edema, neurological deficits, and ICH-induced changes in APE/Ref-1.
Conclusions: Deferoxamine and other iron chelators may be potential therapeutic agents for treating ICH. They may act by reducing the oxidative stress caused by the release of iron from the hematoma.
Spontaneous ICH is a frequent fatal subtype of stroke. Many patients harboring an intracerebral hematoma deteriorate progressively because of secondary brain edema formation. In our previous studies we demonstrated that toxic factors, including thrombin and hemoglobin, released from a blood clot may account for perihematoma edema formation.
Iron, a hemoglobin degradation product, is associated with lipid peroxidation and free radical formation in the brain after ICH. Oxidative DNA damage has been found in the brain after ICH. Iron overload plays an important role in many kinds of brain injury such as Alzheimer disease and Parkinson disease. Considering the potential for massive iron overload in ICH, it is surprising that it has not been extensively studied as a therapeutic target.
Deferoxamine, an iron chelator, is used to treat hemochromatosis caused by iron toxicity. Favorable effects of iron chelator therapy have been reported in various models of cerebral ischemia. In our previous study we found that deferoxamine reduces hemoglobin-induced brain edema.
Given the hypothesis that iron released from the clot contributes to brain injury following ICH, we have chosen to examine the effect of systemic deferoxamine treatment on brain edema and neurological deficits. We also studied the effects of deferoxamine on ICH-induced changes in APE/Ref-1, a multifunctional protein in the DNA base excision repair pathway responsible for repairing apurinic/ apyrimidinic sites in DNA after oxidative DNA damage. Reductions in this protein have been found in forms of brain injury associated with oxidative stress, and we hypothesized that such changes in ICH might be prevented by treatment with deferoxamine.
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