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

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Abstract
The hippocampus is injured in both hypoxia—ischemia (HI) and perinatal iron deficiency that are co-morbidities in infants of diabetic mothers and intrauterine growth restricted infants. We hypothesized that preexisting perinatal iron deficiency predisposes the hippocampus to greater injury when exposed to a relatively mild HI injury. Iron-sufficient and iron-deficient rats (hematocrit 40% lower and brain iron concentration 55% lower) were subjected to unilateral HI injury of 15, 30, or 45 mins ( n = 12 to 13/HI duration) on postnatal day 14. Sixteen metabolite concentrations were measured from an 11 //L volume on the ipsilateral (HI) and contralateral (control) hippocampi 1 week later using in vivo1H NMR spectroscopy. The concentrations of creatine, glutamate, myo-inositol, and N-acetylaspartate were lower on the control side in the iron-deficient group ( P < 0.02, each). Magnetic resonance imaging showed hippocampal injury in the majority of the iron-deficient rats (58% versus 11%, P < 0.0001) with worsening severity with increasing durations of HI ( P = 0.0001). Glucose, glutamate, N-acetylaspartate, and taurine concentrations were decreased and glutamine, lactate and myo-inositol concentrations, and glutamate/glutamine ratio were increased on the HI side in the iron-deficient group ( P < 0.01, each), mainly in the 30 and 45 mins HI subgroups ( P < 0.02, each). These neurochemical changes likely reflect the histochemically detected neuronal injury and reactive astrocytosis in the iron-deficient group and suggest that perinatal iron deficiency predisposes the hippocampus to greater injury from exposure to a relatively mild HI insult.