Iron and Iron-Handling Proteins in the Brain After Intracerebral Hemorrhage

Abstract

Background and Purpose-Evidence indicates that brain injury after intracerebral hemorrhage (ICH) is due in part to the release of iron from hemoglobin. Therefore, we examined whether such iron is cleared from the brain and the effects of ICH on proteins that may alter iron release or handling: brain heme oxygenase-1, transferrin, transferrin receptor, and ferritin. Methods-Male Sprague-Dawley rats received an infusion of 100 L autologous whole blood into the right basal ganglia and were killed 1, 3, 7, 14, or 28 days later. Enhanced Perl's reaction was used for iron staining, and brain nonheme iron content was determined. Brain heme oxygenase-1, transferrin, transferrin receptor, and ferritin were examined by Western blot analysis and immunohistochemistry. Immunofluorescent double labeling was performed to identify which cell types express ferritin. Results-ICH upregulated heme oxygenase-1 levels and resulted in iron overload in the brain. A marked increase in brain nonheme iron was not cleared within 4 weeks. Brain transferrin and transferrin receptor levels were also increased. In addition, an upregulation of ICH on ferritin was of very long duration. Conclusions-The iron overload and upregulation of iron-handling proteins, including transferrin, transferrin receptor, and ferritin, in the brain after ICH suggest that iron could be a target for ICH therapy.

Inflammation after Intracerebral Hemorrhage

“…One is an autologous whole-blood model, and the other uses collagenase to induce intracerebral bleeding; both require stereotactic injections. The autologous whole-blood model is one of the earliest models used for the study of ICH in rats (Bullock et al, 1984;Nath et al, 1986;Wu et al, 2003), rabbits (Kaufman et al, 1985;Koeppen et al, 2004), dogs (Qureshi et al, 2001a;Steiner et al, 1975), and pigs (Thiex et al, 2003;Wagner et al, 1996), and has recently been adapted for use in mice (Lee et al, 2006;Nakamura et al, 2004b). It consists of whole blood drawn from the animal being injected directly into the cerebrum.…”

Heme Regulation in Traumatic Brain Injury: Relevance to the Adult and Developing Brain

“…Red blood cell lysis has been shown to contribute to edema formation after intracerebral hemorrhage at the same time that HO-1 expression and iron accumulation are enhanced, suggesting that heme and its degradation products are associated with breakdown of the blood-brain barrier (Bhasin et al, 2002;Hoff and Xi, 2003;Wu et al, 2003Wu et al, , 2002Xi et al, 2001). Damage to the vascular endothelium may be because of oxidative stress perpetuated by iron (Ogihara et al, 1999;Wu et al, 2003Wu et al, , 2002 and furthermore the administration of iron chelators attenuates edema after intracerebral hemorrhage (Huang et al, 2002).…”

“…Damage to the vascular endothelium may be because of oxidative stress perpetuated by iron (Ogihara et al, 1999;Wu et al, 2003Wu et al, , 2002 and furthermore the administration of iron chelators attenuates edema after intracerebral hemorrhage (Huang et al, 2002).…”

CD163, a Hemoglobin/Haptoglobin Scavenger Receptor, After Intracerebral Hemorrhage: Functions in Microglia/Macrophages Versus Neurons

“…1) [21]. Both HO-1 and ferritin are markedly upregulated in microglia/macrophages after ICH [22,23].…”