Endogenous alpha2-adrenergic receptor-mediated neuroprotection after severe hypoxia in preterm fetal sheep.
Central alpha-adrenergic receptor activity is important for fetal adaptation to hypoxia before birth. It is unclear whether it is also important during recovery. We therefore tested the hypothesis that an infusion of the specific alpha(2)-adrenergic receptor antagonist idazoxan (1 mg/kg/h i.v.) from 15 min to 4 h after profound hypoxia induced by 25 min umbilical cord occlusion in fetal sheep at 70% of gestation (equivalent to the 28-32 weeks in humans) would increase neural injury. After 3 days' recovery, idazoxan infusion was associated with a significant increase in neuronal loss in the hippocampus (P<0.05), expression of cleaved caspase-3 (P<0.05), and numbers of activated microglia (P<0.05). There was no significant effect on other neuronal regions or on loss of O4-positive premyelinating oligodendrocytes in the subcortical white matter. Idazoxan was associated with an increase in evolving epileptiform electroencephalographic (EEG) transient activity after occlusion (difference at peak 2.5+/-1.0 vs. 11.7+/-4.7 counts/min, P<0.05) and significantly reduced average spectral edge frequency, but not EEG intensity, from 54 until 72 h after occlusion (P<0.05). Hippocampal neuronal loss was correlated with total numbers of epileptiform transients during idazoxan infusion (P<0.01; r(2)=0.7). In conclusion, endogenous inhibitory alpha(2)-adrenergic receptor activation after severe hypoxia appears to significantly limit evolving hippocampal damage in the immature brain.
Dean
J M
JM
Department of Physiology, Faculty of Medicine and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand.
Gunn
A J
AJ
Wassink
G
G
George
S
S
Bennet
L
L
D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage; D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002339:Carotid Arteries / Q000187:drug effects / Q000503:physiopathology; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D004569:Electroencephalography / Q000379:methods; D004622:Embryo, Mammalian; D005260:Female; D006340:Heart Rate, Fetal / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D000860:Hypoxia / Q000473:pathology* / Q000503:physiopathology; D019329:Idazoxan / Q000008:administration & dosage; D007150:Immunohistochemistry / Q000379:methods; D017628:Microglia / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D019081:O Antigens / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000473:pathology* / Q000503:physiopathology; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D012039:Regional Blood Flow / Q000187:drug effects; D012756:Sheep; D013997:Time Factors
D000317:Adrenergic alpha-Antagonists; D019081:O Antigens; D018341:Receptors, Adrenergic, alpha-2; D053148:Caspase 3; D010751:Phosphopyruvate Hydratase; D019329:Idazoxan