Paradoxical mitochondrial oxidation in perinatal hypoxic-ischemic brain damage.
Measurements of cytoplasmic and mitochondrial markers of the oxidation-reduction (redox) state of brain tissue were conducted in a perinatal animal model of cerebral hypoxia-ischemia to ascertain underlying biochemical mechanisms whereby ischemia (reduced oxygen and substrate supply) causes brain damage. Seven-day postnatal rats underwent unilateral common carotid artery ligation followed by exposure to 8% oxygen at 37 degrees C for 3 h. During the course of hypoxia-ischemia, the rat pups were quick frozen in liquid nitrogen and their brains processed for the enzymatic, fluorometric measurement of cerebral metabolites necessary for the calculation of intracellular pH and cytoplasmic and mitochondrial redox states. The results showed an early mitochondrial reduction followed by re-oxidation during the course of hypoxia-ischemia. The oxidation reflected a partial depletion in accumulated reducing equivalents and coincides temporally with the duration of hypoxia-ischemia required to convert selective neuronal necrosis into cerebral infarction. The findings suggest that perinatal cerebral hypoxia-ischemia is characterized more by a limitation of substrate than of oxygen supply to the brain, which may explain why glucose supplementation of the immature animal improves neuropathologic outcome, in contrast to adults.
Yager
J Y
JY
Department of Pediatrics, Royal University Hospital, Saskatoon, Saskatchewan, Canada.
Brucklacher
R M
RM
Vannucci
R C
RC
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D002545:Brain Ischemia / Q000201:enzymology / Q000378:metabolism*; D003593:Cytoplasm / Q000201:enzymology / Q000378:metabolism; D005260:Female; D006019:Glycolysis / Q000502:physiology; D006863:Hydrogen-Ion Concentration; D006884:Hydroxybutyrate Dehydrogenase / Q000378:metabolism; D002534:Hypoxia, Brain / Q000201:enzymology / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D010084:Oxidation-Reduction; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
D009243:NAD; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D006884:Hydroxybutyrate Dehydrogenase