Changes in iron histochemistry after hypoxic-ischemic brain injury in the neonatal rat

Abstract

Iron can contribute to hypoxic-ischemic brain damage by catalyzing the formation of free radicals. The immature brain has high iron levels and limited antioxidant defenses. The objective of this study was to describe the early alterations in nonheme iron histochemistry following a hypoxic-ischemic (HI) insult to the brain of neonatal rats. We induced a HI insult to the right cerebral hemisphere in groups of 7-day-old rats. Rats were anesthetized, then their brains were perfused and fixed at 0, 1, 4, 8, 24 hr, and 1, 2, and 3 weeks of recovery. Forty-micron-thick frozen sections were stained for iron using the intensified Perls stain. Increased iron staining was first detected within the cytoplasm of cells with pyknotic nuclei at 4 hr of recovery. Staining increased rapidly over the first 24 hr in regions of ischemic injury. By 7 days recovery, reactive glia and cortical blood vessels also stained. Increased staining in gray matter persisted at 3 weeks of recovery, whereas white matter tracts had fewer iron-positive cells compared to normal. The early increase in iron staining could be caused by an accumulation of iron posthypoxicischemic injury or a change in iron from nonstainable heme iron to stainable nonheme iron. Regardless of the source, our results indicate that there is an increase in iron available to promote oxidant stress in the neonatal rat brain following hypoxia-ischemia.

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

“…Similar findings of excess iron deposition have been observed in brain regions that are immediately adjacent to the site of maximal tissue injury after experimental hypoxia/ischemia at postnatal day 7 (Cheepsunthorn et al, 2001;Palmer et al, 1999). Moreover, there is a rapid appearance of iron staining (as early as 1 h recovery) in the developing brain, exposed to hypoxia/ischemia compared with a more delayed onset in the adult (Kondo et al, 1995;Palmer et al, 1999). Although the biologic basis for this difference is unclear, it is nevertheless intriguing as it may offer an explanation for the heightened vulnerability of the immature brain to injury.…”

“…There is increased iron deposition in the basal ganglia, thalami, and white matter in children with severe ischemia/ anoxia (Dietrich and Bradley, 1988). Similar findings of excess iron deposition have been observed in brain regions that are immediately adjacent to the site of maximal tissue injury after experimental hypoxia/ischemia at postnatal day 7 (Cheepsunthorn et al, 2001;Palmer et al, 1999). Moreover, there is a rapid appearance of iron staining (as early as 1 h recovery) in the developing brain, exposed to hypoxia/ischemia compared with a more delayed onset in the adult (Kondo et al, 1995;Palmer et al, 1999).…”

Neurodevelopmental outcome of preterm infants with ventricular dilatation with and without associated haemorrhage

“…However, acidosis and hypoxia may also lead to the release of free iron from ferritin within brain cells by acidosis and hypoxia (Palmer et al 1999). …”

Perinatal Iron Deficiency Predisposes the Developing Rat Hippocampus to Greater Injury from Mild to Moderate Hypoxia—Ischemia

“…Nevertheless, the study shows the importance of optimal iron homeostasis during brain development. Through its role in the production of free radicals, iron is thought to play a significant role in perinatal HI injury (Palmer et al, 1999;Vexler and Ferriero, 2001). High iron content, combined with immature antioxidant mechanisms, is postulated to predispose the developing brain to HI injury (Vexler and Ferriero, 2001).…”