Ferric iron chelation lowers brain iron levels after intracerebral hemorrhage in rats but does not improve outcome

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Abstract

Iron-mediated free radical damage contributes to secondary damage after intracerebral hemorrhage (ICH). Iron is released from heme after hemoglobin breakdown and accumulates in the parenchyma over days and then persists in the brain for months (e.g., hemosiderin). This non-heme iron has been linked to cerebral edema and cell death. Deferoxamine, a ferric iron chelator, has been shown to mitigate iron-mediated damage, but results vary with less protection in the collagenase model of ICH. This study used rapid-scanning X-ray fluorescence (RS-XRF), a synchrotron-based imaging technique, to spatially map total iron and other elements (zinc, calcium and sulfur) at three survival times after collagenase-induced ICH in rats. Total iron was compared to levels of non-heme iron determined by a Ferrozine-based spectrophotometry assay in separate animals. Finally, using RS-XRF we measured iron levels in ICH rats treated with deferoxamine versus saline. The non-heme iron assay showed elevations in injured striatum at 3 days and 4 weeks post-ICH, but not at 1 day. RS-XRF also detected significantly increased iron levels at comparable times, especially notable in the peri-hematoma zone. Changes in other elements were observed in some animals, but these were inconsistent among animals. Deferoxamine diminished total parenchymal iron levels but did not attenuate neurological deficits or lesion volume at 7 days. In summary, ICH significantly increased non-heme and total iron levels. We evaluated the latter and found it to be significantly lowered by deferoxamine, but its failure to attenuate injury or functional impairment in this model raises concern about successful translation to patients.

Highlights

▸ Brain iron levels are persistently high after collagenase-induced ICH in rats. ▸ X-ray florescence (XRF) measured several elements, including iron, after ICH. ▸ Deferoxamine (DFX) lowered total brain iron levels measured with XRF after ICH. ▸ DFX did not reduce injury or behavioral deficits in the collagenase model of ICH.

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