Global hypoxia-ischemia in the late-gestation ovine: Assessment of brain damage and the protective effects of glutamate receptor antagonists

Hypoxia-ischemia can cause permanent neurological morbidity and mortality in both adults and neonates. While much research is being focused on the treatment of adult forms of hypoxia-ischemia, these therapies may not be applicable to the neonate due to differences in the density, distribution and characteristics of excitatory amino acid receptors and transporters between neonates and adults. In this study, a fetal model of global hypoxia-ischemia was used.; Hypoxia-ischemia was induced for 20 minutes in a 134 day gestation sheep and two glutamate receptor antagonists (MK-801 and NBQX) were infused directly into fetal circulation immediately following reperfusion. Analysis of brains four days following hypoxia-ischemia included glutamate receptor and transporter density and distribution, white and grey matter loss and TUNEL-positive cells (a marker for apoptosis).; Following hypoxia-ischemia, there was a significant reduction in the volume of grey matter, however white matter was not significantly decreased. Grey regions damaged included the lateral and parasagittal cortex, with deeper grey matter structures not usually affected. N-methyl-D-aspartate (NMDA) receptors and glutamate transporters were significantly decreased when compared to non-ischemic controls. No change was found in the density of kainate receptors between any group. Glutamate receptor antagonism was unable to significantly affect the loss of NMDA receptor binding sites and glutamate transporters, as well as changes in grey matter volume.; A significant increase in TUNEL-positive cells was noted following hypoxia-ischemia in the cerebral cortex, hippocampal formation and cerebellum. NBQX was able to significantly reduce the number of TUNEL-positive cells in the cerebellum only.; Physiological recordings obtained pre-, during and post-occlusion were analyzed off-line and correlated with the histological data. There was positive correlation between the amount of histological damage observed at 4 days and the depression of electrocortical activity 4 hours following occlusion.; This study demonstrated that global hypoxia-ischemia in the late gestation sheep causes a loss of grey matter and induces apoptosis. Additionally, there was a loss of NMDA receptor binding sites and glutamate transporter density. MK-801 and NBQX do not significantly reduce the amount of damage seen following 20 minutes of global hypoxia-ischemia.