Pathogenesis of hippocampal neuronal death after hypoxia-ischemia changes during brain development.
Transient hypoxia-ischemia (HI) leads to delayed neuronal death in both mature and immature neurons but the underlying mechanisms are not fully understood. To understand whether the pathogenesis of HI-induced neuronal death is different between mature and immature neurons, we used a rat HI model at postnatal days 7 (P7), 15 (P15), 26 (P26) and 60 (P60) in order to investigate ultrastructural changes and active caspase-3 distribution in HI-injured neurons as a function of developmental age. In P7 pups, despite more than 95% of HI-injured neurons highly expressing active caspase-3, most of these active caspase-3-positive neurons revealed mixed features of apoptosis and necrosis (a chimera type) under electron microscopy (EM). Classical apoptosis was observed only in small populations of HI-injured P7 neurons. Furthermore, in rats older than P7, most HI-injured neurons displayed features of necrotic cell death under EM and, concomitantly, active caspase-3-positive neurons after HI declined dramatically. Classical apoptosis after HI was rarely found in neurons older than P15. In P60 rats, virtually all HI-injured neurons showed the shrinkage necrotic morphology under EM and were negative for active caspase-3. These results strongly suggest that pathogenesis of HI-induced neuronal death is shifting from apoptosis to necrosis during brain development.
Liu
C L
CL
Department of Neurology, University of Miami School of Medicine, PO Box 16960, Miami, FL 33136, USA.
Siesjö
B K
BK
Hu
B R
BR
D000367:Age Factors; D000375:Aging / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000201:enzymology / Q000254:growth & development* / Q000503:physiopathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002452:Cell Count; D016923:Cell Death / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002544:Cerebral Infarction / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000201:enzymology / Q000254:growth & development / Q000503:physiopathology; D020925:Hypoxia-Ischemia, Brain / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D008854:Microscopy, Electron; D009336:Necrosis; D009410:Nerve Degeneration / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000201:enzymology* / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D017208:Rats, Wistar
C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases