Suppression of post-hypoxic-ischemic EEG transients with dizocilpine is associated with partial striatal protection in the preterm fetal sheep.
In vitro studies suggest that glutamate receptor activation is important in the genesis of post-hypoxic preterm brain injury, but there are limited data on post-hypoxic N-methyl-D-aspartate (NMDA) receptor activation. We therefore examined an infusion of the specific, non-competitive NMDA receptor antagonist dizocilpine (2 mg kg(-1) bolus plus 0.07 mg kg(-1) h(-1) i.v.) from 15 min to 4 h after severe hypoxia-ischemia induced by umbilical cord occlusion for 25 min in fetal sheep at 70% of gestation. Dizocilpine suppressed evolving epileptiform transient activity in the first 6 h after reperfusion (2.3 +/- 0.9 versus 9.3 +/- 2.3 maximal counts min(-1), P < 0.05) and mean EEG intensity up to 11 h after occlusion (P < 0.05). Fetal extradural temperature transiently increased during the dizocilpine infusion (40.1 +/- 0.2 versus 39.3 +/- 0.1 degrees C, P < 0.05). After 3 days recovery, treatment was associated with a significant reduction in neuronal loss in the striatum (31 +/- 7 versus 58 +/- 2%, P < 0.05), expression of cleaved caspase-3 (111+/-7 versus 159 +/- 10 counts area(-1), P < 0.05) and numbers of activated microglia (57 +/- 9 versus 92 +/- 16 counts area(-1), P < 0.05); there was no significant effect in other regions or on loss of immature O4-positive oligodendrocytes. In conclusion, abnormal NMDA receptor activation in the first few hours of recovery from hypoxia-ischemia seems to contribute to post-hypoxic striatal damage in the very immature brain.
Dean
Justin M
JM
Department of Physiology, University of Auckland, New Zealand.
George
Sherly A
SA
Wassink
Guido
G
Gunn
Alistair J
AJ
Bennet
Laura
L
D000818:Animals; D002545:Brain Ischemia / Q000196:embryology* / Q000517:prevention & control; D003342:Corpus Striatum / Q000196:embryology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000627:therapeutic use*; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D005865:Gestational Age; D000860:Hypoxia; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents; D011247:Pregnancy; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D012756:Sheep
D018696:Neuroprotective Agents; D016291:Dizocilpine Maleate