Accumulation of Cytotoxins During the Development of Seizures and Edema after Hypoxic-Ischemic Injury in Late Gestation Fetal Sheep

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Abstract
Several hours after an hypoxic-ischemic injury to the developing brain, hyperemia, then seizures, edema, and infarction can develop. The roles of nitric oxide (NO) synthesis and excitotoxin accumulation during these later phases of injury are not known. The time course of extracellular levels of amino acids within the parasagittal parietal cortex were measured with microdialysis during and for 3 d after 30 min of cerebral ischemia in nine chronically instrumented near-term fetal sheep (119-133 d). Cortical electroencephalographic (EEG) activity and extracellular space (ECS) were quantified simultaneously with real-time spectral analysis and cortical impedance measurements, respectively. Amino acid concentrations were measured using HPLC. During ischemia, citrulline (by-product of NO synthesis), glutamate, glycine, and γ-aminobutyric acid (GABA) concentrations rose to 147 ± 18%, 180 ± 20%, 290 ± 50% and 4800 ± 1300% of baseline respectively (p < 0.05). The excitotoxic index([glutamate] × [glycine]/[GABA]) decreased to 15 ± 8%. Upon reperfusion, the cytotoxic edema and amino acid accumulation largely resolved within 1 h, and the EEG was depressed. Citrulline began to rise again by 4 h(p < 0.05), reaching a maximum (273 ± 21%) at 32 ± 2 h. Seizure activity developed at 7 ± 2 h, and impedance plus the excitotoxic index then rose progressively and peaked at 32 ± 2 h (480± 170%). At 72 h, there was severe neuronal loss and laminar necrosis within the parasagittal cortex. These data suggest that, several hours after a severe hypoxic-ischemic injury, NO synthesis increased, then seizures arose, and edema developed concomitantly with the accumulation of excitotoxins.