Perinatal Brain Iron Deficiency Predisposes the Rat Hippocampus to Long-term Damage following Hypoxic-ischemic Insult • 1566

Abstract

The offspring of pregnancies complicated by diabetes mellitus or intrauterine growth retardation are at increased risk for perinatal asphyxia and for long-term neurocognitive sequelae. Both gestational conditions are characterized by an increased prevalence of brain iron deficiency. The hippocampus is important for a variety of cognitive functions (e.g., recognition memory) and is susceptible to hypoxicischemic (HI) injury. To evaluate the hypothesis that brain iron deficiency increases the vulnerability of the hippocampus to HI injury and to assess whether iron induced reperfusion injury has any role in such injuries, we ligated the right common carotid artery in 15 perinatally iron-deficient and 15 iron-sufficient 7-day-old rat pups,and exposed them to 2.5 hours of 8% FIO2(Levine model). The non-ligated left side served as the undamaged internal control. On day 14, neuronal injury was quantified histochemically by assessing intensity of staining for Nissl substance in 4 hippocampal subareas in both hemispheres using optical densitometry in gray scale units (range: 1/white-254/black). To assess iron induced reperfusion injury, sections were stained for iron by modified Perl's reaction. The brain iron concentration of the iron-deficient group was 55% of control (p<0.001). In the iron-deficient group,there was significant loss of Nissl substance on the ligated right side in subareas CA1 (124 ± 14 v. 112 ± 15, p=0.002), CA3ab (144 ± 10 v. 129 ± 15, p=0.001) and the dentate gyrus (136 ± 14 v. 128 ± 13, p=0.012), when compared with the unligated left side.The iron-sufficient group had significant right sided Nissl loss only in CA1 (111 ± 14 v. 106± 15, p = 0.05). The mean number of subareas with detectable right sided Nissl loss per animal was greater in the iron-deficient group than the iron-sufficient group (2.9 ± 1.0 v. 2.0 ± 1.2, p<0.05). The degree of right-sided Nissl substance loss per animal in the iron-deficient group was also greater in CA1(p=0.042), CA3ab(p=0.003) and the dentate gyrus(p=0.037)when compared with the iron-sufficient group. There were no side-to-side differences in the number of iron stained cells in either group. Perinatal iron deficiency increases the vulnerability of hippocampal subareas of CA1, CA3ab and dentate to HI injury. Iron deposition is not involved in the pathophysiology of this injury. These findings may explain the increased risk of perinatal asphyxia and its neurocognitive sequelae in infants born of pregnancies complicated by perinatal iron deficiency.