Fetal asphyctic preconditioning protects against perinatal asphyxia- induced apoptosis and astrogliosis in neonatal brain.
2015
Hypoxic-ischemic preconditioning is an endogenous mechanism in which
exposure to a sublethal episode of hypoxia-ischemia protects against a subsequent more
severe episode. Although several postnatal models of hypoxic-ischemic preconditioning have
been established, hardly any perinatal models exist. Therefore, the objective of this study is to
validate a new rodent model. We investigate whether mild fetal asphyxia (FA) as a
preconditioning stimulus, protects against severe perinatal asphyxia (PA) when looking at
neonatal brain histology. FA was induced at embryonic day 17 (E17) by temporarily
clamping the uterine circulation. A caesarean section was performed at E21/22 and PA was
induced by submersing the uterine horns, still containing the fetuses, in a water bath. Brains
were examined for histological changes at either postnatal day 7 or 14. We used terminal
deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining to detect
apoptotic cell death and a glial fibrillary acidic protein (GFAP) staining to detect reactive astrocytes. Interestingly, the
preconditioned group showed significantly less perinatal mortality than non-preconditioned groups. Furthermore,
preconditioned animals had significantly less TUNEL-positive cells and less GFAP-positive cells in striatum, prefrontal
cortex and hippocampus compared to the non-preconditioned animals that underwent PA. Consequently, mild FA might
cause neuroprotection by inducing anti-apoptotic mechanisms and attenuating astrogliosis. Considering the morphological
findings in the neonatal brain from this study, together with previously reported long-term behavioral outcomes in this
model, we can conclude that this is a suitable experimental model to investigate mechanisms of endogenous
neuroprotection in the fetal brain. Identifying these endogenous neuroprotective mechanisms will provide novel potential
targets for future pharmacological intervention in asphyctic newborns.
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