title: Suppression of post-hypoxic-ischemic EEG transients with dizocilpine is associated with partial striatal protection in the preterm fetal sheep.
abstract: 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.
authors.affiliation: Department of Physiology, University of Auckland, New Zealand.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Dean
authors.forename: Sherly A
authors.initials: SA
authors.lastname: George
authors.forename: Guido
authors.initials: G
authors.lastname: Wassink
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Gunn
authors.forename: Laura
authors.initials: L
authors.lastname: Bennet
mesh_terms: 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
chemical_list: D018696:Neuroprotective Agents; D016291:Dizocilpine Maleate