Perinatal Brain Iron Deficiency Increases the Vulnerability of Rat Hippocampus to Hypoxic Ischemic Insult

Manuscript received 15 May 1998. Initial reviews completed 9 June 1998. Revision accepted 26 October 1998.

Raghavendra Rao^*, Marissa de Ungria^*, Daniel Sullivan^*, Peggy Wu^*, Jane D. Wobken^*, Charles A. Nelson^*, , and Michael K. Georgieff^{*, ,}

^* Division of Neonatology, Department of Pediatrics, School of Medicine, and the  Institute of Child Development, University of Minnesota, Minneapolis, MN 55455

Fetal brain iron deficiency occurs in human pregnancies complicated by diabetes mellitus or intrauterine growth retardation. Because neurocognitive deficits are more common in the offspring of these pregnancies, we tested the hypothesis that perinatal brain iron deficiency predisposes the neonatal hippocampus, a structure important for memory processing, to injury. Brain iron concentration was reduced by 45% in 45 neonatal rats by maternal dietary iron restriction during gestation. Right-sided neuronal injury in four hippocampal subareas was induced by hypoxic-ischemic insult (ipsilateral carotid artery ligation and subsequent hypoxia on postnatal d 7) and was quantified histochemically on d 8 by cytochrome c oxidase activity (n = 30), and on d 14 by Nissl staining (n = 15). Acute right-sided cytochrome c oxidase activity loss occurred in CA1 (P = 0.02), CA3c (P < 0.001) and dentate gyrus (P < 0.001) in the iron-deficient group, whereas only CA1 (P = 0.003) was affected in the iron-sufficient group. Long-term right-sided Nissl substance loss occurred in CA1 (P = 0.001), CA3a,b (P < 0.001) and dentate gyrus (P = 0.008) in the iron-deficient group, but only in CA1 (P = 0.004) in the iron-sufficient group. No increase in right-sided free-iron staining was present in either group. Perinatal iron deficiency predisposes the neonatal hippocampus to a greater acute loss of neuronal metabolic activity after an hypoxic-ischemic event, suggesting compromised cellular energetics. The subsequently greater loss of hippocampal neuronal integrity suggests poorer recoverability after injury in the perinatal iron-deficient brain.

The Journal of Nutrition Vol. 129 No. 1 January 1999, pp. 199-206
Copyright ©1999 by the American Society for Nutritional Sciences

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