title: Fetal asphyctic preconditioning protects against perinatal asphyxia- induced apoptosis and astrogliosis in neonatal brain.
abstract: 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.
authors.affiliation: School for Mental Health and Neuroscience (MHeNS), Faculty of Health, Medicine and Life Sciences, Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands. kimberly.cox@maastrichtuniversity.nl.
authors.forename: Kimberly E M
authors.initials: KE
authors.lastname: Cox-Limpens
authors.forename: Eveline
authors.initials: E
authors.lastname: Strackx
authors.forename: Daniel L A
authors.initials: DL
authors.lastname: Van den Hove
authors.forename: Joris R A
authors.initials: JR
authors.lastname: Van Ekkendonk
authors.forename: Marin de
authors.initials: Md
authors.lastname: Jong
authors.forename: Luc J I
authors.initials: LJ
authors.lastname: Zimmermann
authors.forename: Harry W M
authors.initials: HW
authors.lastname: Steinbusch
authors.forename: Johan S H
authors.initials: JS
authors.lastname: Vles
authors.forename: Antonio W D
authors.initials: AW
authors.lastname: Gavilanes
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D001238:Asphyxia Neonatorum / Q000473:pathology* / Q000517:prevention & control*; D001253:Astrocytes / Q000473:pathology*; D001835:Body Weight; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D009929:Organ Size; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D005904:Glial Fibrillary Acidic Protein