Differential neuronal fates in the CA1 hippocampus after hypoxia in newborn and 7‐day‐old rats: Effects of pre‐treatment with MK‐801

Abstract

The brain displays an age-dependent sensitivity to ischemic insults. However, the consequences of oxygen deprivation per se in the developing brain remain unclear, and the role of glutamate excitotoxicity via N-methyl-D-aspartate (NMDA) receptors is controversial. To gain a better understanding of the mechanisms involved in the cerebral response to severe hypoxia, cell damage was temporally monitored in the CA1 hippocampus of rat pups transiently exposed to in vivo hypoxia (100% N2) at either 24 h or 7 days of age. Also, the influence of a pre-treatment with the NMDA receptor antagonist MK-801 (5 mg/kg, i.p.) was examined. At both ages, morphometric analyses and cell counts showed hypoxia-induced significant neuronal loss (30-35%) in the pyramidal layer, with injury appearing more rapidly in rats exposed at 7 days. Morphological alterations of 4,6-diamidino-2-phenylindole (DAPI)-labeled nuclei, DNA fragmentation patterns on agarose gels, as well as expression profiles of the apoptosis-related regulatory proteins Bax and Bcl-2 showed that apoptosis was prevalent in younger animals, whereas only necrosis was detected in hippocampi of rats treated at 7 days. Moreover, pre-treatment with MK-801 was ineffective in protecting hippocampal neurons from hypoxic injury in newborn rats, but significantly reduced necrosis in older subjects. These data confirm that hypoxia alone may trigger neuronal death in vivo, and the type of cell death is strongly influenced by the degree of brain maturity. Finally, NMDA receptors are not involved in the apoptotic consequences of hypoxia in the newborn rat brain, but they were found to mediate necrosis at 7 days of age.

The effect of prenatal hypoxia on brain development: short‐ and long‐term consequences demonstrated in rodent models

“…In addition to these inter‐animal differences, the intensity and duration of the H/HI influences the severity of the damage (Ten et al , 2003). With short exposure to H/HI, brain regions are indistinguishable from comparable regions in sham treated animals, although careful analysis can reveal significant cell loss (Tashima et al , 2001; Grojean, Pourié, Vert & Daval, 2003a). In these cases, detailed analysis of the cortical regions showed cell loss following prenatal E17, E18 HI, or P1 H detectable about three to four days after the insult (Tashima et al , 2001; Grojean et al , 2003a).…”

“…With short exposure to H/HI, brain regions are indistinguishable from comparable regions in sham treated animals, although careful analysis can reveal significant cell loss (Tashima et al , 2001; Grojean, Pourié, Vert & Daval, 2003a). In these cases, detailed analysis of the cortical regions showed cell loss following prenatal E17, E18 HI, or P1 H detectable about three to four days after the insult (Tashima et al , 2001; Grojean et al , 2003a). In addition to cell loss, prenatal H resulted in shrinkage of the hippocampal CA1 neurons apical and basal dendritic tree and a decreased number of branches and branching points in the granular cells of the dentate gyrus (Dieni & Rees, 2003).…”

“…However, the resultant cell death pathway, either apoptosis or necrosis, depends on the age of the animal. During embryonic and perinatal rodent development, apoptosis is the main process of cell death following HI, while, at later ages, necrosis is the dominant process (Grojean et al , 2003a; Liu, Siesjö & Hu, 2004). The type of cell death following HI is of great interest for researchers developing treatments, meaning that considerable attention has been focused on this issue.…”

Oxygen and Glucose Deprivation in an Organotypic Hippocampal Slice Model of the Developing Rat Brain: The Effects on N-Methyl-d-Aspartate Subunit Composition

“…The NR2B predominance early in development is an adaptive response that protects the fetus during hypoxic conditions normally seen in utero (20–21). However, the response of the NMDA receptor subunit composition to acute hypoxia has not been demonstrated fully in a developing brain model (14, 19, 22–26). …”

Maternal hypoxia during pregnancy induces fetal neurodevelopmental brain damage: Partial protection by magnesium sulfate

“…Cell death in the sub‐ and cortical plate regions (McQuillen et al, 2003), due to apoptosis or necrosis, has been reported to be a result of HI, depending on the age of the exposed newborn (Grojean et al, 2003). The reduction in cell density observed in adult offspring cerebral cortexes in our study might be related to the long‐lasting outcome of earlier hypoxic experience.…”