Iron and early brain injury after subarachnoid hemorrhage

Abstract

Aneurysmal subarachnoid hemorrhage (SAH) affects approximately 27,000 Americans per year. Although delayed cerebral vasospasm is of high clinical significance, mortality within the first 2 days may approach 30%. In this issue of the Journal of Cerebral Blood Flow and Metabolism, Lee et al have studied the role of iron in early brain injury after experimental SAH. They found that iron chelation with deferoxamine reduced mortality and oxidative DNA damage, and lessened the induction of iron-handling proteins. Taken together, these results highlight the deleterious potential of blood breakdown products and provide an insight into future intervention.

Aneurysmal subarachnoid hemorrhage (SAH) affects approximately 27,000 Americans per year (Pluta, 2005). Although delayed cerebral vasospasm is of high clinical significance, mortality within the first 2 days may approach 30% (Broderick et al, 1994). Early SAH injury has been classically thought to be a result of elevated intracranial pressure (ICP), global cerebral ischemia and brain edema (Cahill et al, 2006). Although these have an important role, it is likely that there are other mechanisms of early brain injury and mortality, including those mediated by iron (Ayer and Zhang, 2008).

A very interesting report (Lee et al, 2010) in the current issue of the Journal of Cerebral Blood Flow and Metabolism has studied the role of iron chelation therapy in early brain injury after experimental SAH. Lee and colleagues induced SAH in rats by endovascular perforation of the internal carotid artery. When first given 2 h after SAH, the iron chelator deferoxamine (DFX) reduced mortality, attenuated DNA damage and lessened induction of iron-handling proteins. DFX treatment showed benefit as early as day 1 by substantially reducing terminal deoxynucleotidyl transferase dUTP nick end labeling and 8-hydroxyl-2′-deoxyguanosine immunoreactivity compared with SAH without DFX. The latter is a marker of oxidative DNA damage, but is not specific for iron-catalyzed reactive oxygen species. At day 3, DFX-treated SAH rats had levels of non-heme iron, transferrin, transferrin receptor and ferritin that were not different from those of sham controls, suggesting that DFX successfully chelated free iron in these experiments.

The authors observed a significant increase in ICP after SAH; yet, the mortality rate in rats receiving DFX was approximately half that of the SAH plus vehicle group. Similarly, hemorrhage grading suggested that there was no difference in the amount of bleeding between the two groups. This is strong evidence for the contribution of toxic blood metabolites, in particular iron, in early brain injury. Indeed, other studies have shown benefit from iron or hemoglobin sequestration in intracerebral hemorrhage (Nakamura et al, 2004; Zhao et al, 2009), a stroke subtype that also leads to significant amounts of extravascular iron.

Both ferrous (Fe²⁺) and ferric (Fe³⁺) iron can generate the very destructive hydroxyl radical (OH^−*) through the Fenton reaction and Haber–Weiss cycle, respectively. DFX preferentially binds to ferric iron and prevents its entry into these catalytic pathways (Gutteridge et al, 1979). Although DFX chelates only ferric iron, this may still be protective by interrupting iron redox cycling.

Reactive oxygen species can activate the transcription factors nuclear factor-κB and activator protein-1, among others, through alteration of the cellular redox state (Arrigo, 1999; Chan, 2001). Oxygen radical production catalyzed by free iron may also disrupt the blood–brain barrier (Pun et al, 2009), leading to increased vasogenic edema and higher ICP. Therefore, prevention of direct damage to biomolecules by the hydroxyl radical may not account for the only mechanism by which DFX attenuated injury. Nonetheless, the findings of Lee et al are an important advancement and may serve to guide further studies on early SAH intervention.

The author declares no conflict of interest.