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

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.