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.

Brain caspase-3 and intestinal FABP responses in preterm and term rats submitted to birth asphyxia

“…TA subgroup showed lower IW and IW/BW compared to all other term subgroups. This result could be explained by the severity of the injury induced by asphyxia and were similar to previous publications that obtained decreased BW neonates in the model of perinatal and intrauterine asphyxia ( 22 , 23 ).…”

Acylethanolamides and endocannabinoid signaling system in dorsal striatum of rats exposed to perinatal asphyxia

“…[31] demonstrated that organotypic striatum cultures exposed to hypoxia present an increase in GFAP levels. It has been also shown that this tissue presents astrogliosis after hypoxia-ischemia in a rodent model [32]. As expected, we observed a higher number of GFAP-positive cells in the striatum of asphyctic animals (see Fig.…”

Pretreatment with Group II Metabotropic Glutamate Receptor Agonist LY379268 Protects Neonatal Rat Brains from Oxidative Stress in an Experimental Model of Birth Asphyxia

“…These mechanisms may be triggered by preconditioning with a sublethal stress that induces resistance to subsequent lethal stress. Preconditioning with ischemia, hypoxia, mild oxidative stress, or oxidative phosphorylation inhibition can activate ischemic tolerance when applied below the damage threshold [ 5 , 6 , 7 ]. However, as perinatal H-I is unpredictable and such manipulations may be potentially dangerous, they seem not to have a credible translational potential in clinical practice [ 4 ].…”