Fetal asphyctic preconditioning protects against perinatal asphyxia- induced apoptosis and astrogliosis in neonatal brain

• Published in: CNS & neurological disorders drug targets Vol. 14; no. 1; p. 33
• Main Authors: Cox-Limpens, Kimberly E M, Strackx, Eveline, Van den Hove, Daniel L A, Van Ekkendonk, Joris R A, Jong, Marin de, Zimmermann, Luc J I, Steinbusch, Harry W M, Vles, Johan S H, Gavilanes, Antonio W D
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 01.01.2015
• Subjects: Age Factors; Analysis of Variance; Animals; Animals, Newborn; Apoptosis - physiology; Asphyxia Neonatorum - pathology; Asphyxia Neonatorum - prevention & control; Astrocytes - pathology; Body Weight; Brain - pathology; Disease Models, Animal; Embryo, Mammalian; Female; Glial Fibrillary Acidic Protein - metabolism; In Situ Nick-End Labeling; Ischemic Preconditioning - methods; Male; Organ Size; Rats; Rats, Sprague-Dawley
• ISSN: 1996-3181
• DOI: 10.2174/1871527314666150116112032

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.