Neonatal hypoxia triggers transient apoptosis followed by neurogenesis in the rat CA1 hippocampus.
Continuous generation of new neurons has been demonstrated in the adult mammalian brain, and this process was shown to be stimulated by various pathologic conditions, including cerebral ischemia. Because brain oxygen deprivation is particularly frequent in neonates and represents the primary event of asphyxia, we analyzed long-term consequences of transient hypoxia in the newborn rat. Within 24 h after birth, animals were exposed to 100% N(2) for 20 min at 36 degrees C, and temporal changes in the vulnerable CA1 hippocampus were monitored. Cell density measurements revealed delayed cell death in the pyramidal cell layer reflecting apoptosis, as shown by characteristic nuclear morphology and expression levels of Bcl-2, Bax, and caspase-3. Neuronal loss was confirmed by reduced density of neuron-specific enolase (NSE)-labeled cells, and peaked by 1 wk post insult, to reach 27% of total cells. A gradual recovery then occurred, and no significant difference in cell density could be detected between controls and hypoxic rats at postnatal d 21. Repeated injections of bromodeoxyuridine (50 mg/kg) showed that newly divided cells expressing neuronal markers increased by 225% in the germinative subventricular zone, and they tended to migrate along the posterior periventricle toward the hippocampus. Therefore, transient hypoxia in the newborn rat triggered apoptosis in the CA1 hippocampus followed by increased neurogenesis and apparent anatomical recovery, suggesting that the developing brain may have a high capacity for self-repair.
Daval
Jean-Luc
JL
INSERM EMI 0014, Faculté de Médecine, 9 avenue de la Forêt de Haye, B.P. 184, 54505 Vandoeuvre-les-Nancy Cedex, France. Jean-Luc.Daval@nancy.inserm.fr
Pourié
Grégory
G
Grojean
Stéphanie
S
Lièvre
Valerie
V
Strazielle
Catherine
C
Blaise
Sébastien
S
Vert
Paul
P
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000033:anatomy & histology / Q000502:physiology*; D002534:Hypoxia, Brain; D009474:Neurons / Q000166:cytology* / Q000378:metabolism / Q000502:physiology*; D011247:Pregnancy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051028:bcl-2-Associated X Protein
C494828:Bax protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D003576:Electron Transport Complex IV; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases