Abstract
Labor and delivery entail a complex and sequential metabolic and physiologic cascade, culminating in most circumstances in successful childbirth, although delivery can be a risky episode if oxygen supply is interrupted, resulting in perinatal asphyxia (PA). PA causes an energy failure, leading to cell dysfunction and death if re-oxygenation is not promptly restored. PA is associated with long-term effects, challenging the ability of the brain to cope with stressors occurring along with life. We review here relevant targets responsible for metabolic cascades linked to neurodevelopmental impairments, that we have identified with a model of global PA in rats. Severe PA induces a sustained effect on redox homeostasis, increasing oxidative stress, decreasing metabolic and tissue antioxidant capacity in vulnerable brain regions, which remains weeks after the insult. Catalase activity is decreased in mesencephalon and hippocampus from PA-exposed (AS), compared to control neonates (CS), in parallel with increased cleaved caspase-3 levels, associated with decreased glutathione reductase and glutathione peroxidase activity, a shift towards the TIGAR-dependent pentose phosphate pathway, and delayed calpain-dependent cell death. The brain damage continues long after the re-oxygenation period, extending for weeks after PA, affecting neurons and glial cells, including myelination in grey and white matter. The resulting vulnerability was investigated with organotypic cultures built from AS and CS rat newborns, showing that substantia nigra TH-dopamine-positive cells from AS were more vulnerable to 1 mM of H2O2 than those from CS animals. Several therapeutic strategies are discussed, including hypothermia; N-acetylcysteine; memantine; nicotinamide, and intranasally administered mesenchymal stem cell secretomes, promising clinical translation.
Highlights
Molecular & Clinical Pharmacology Program, ICBM, Faculty of Medicine, University of Chile, School of Pharmacy, Faculty of Medicine, Universidad Andres Bello, Santiago 8370149, Chile; Center for Regenerative Medicine, Faculty of Medicine-Clínica Alemana, Universidad del Desarrollo, Department of Neuroscience, Faculty of Medicine, University of Chile, Santiago 8380453, Chile
Hypoxia leads to the generation of reactive oxygen (ROS) and nitrogen (RNS) species, which inhibit prolylhydroxylases that under normoxia metabolize the oxygen sensor Hypoxia Inducible Factor1alpha (HIF-1α), to be poly-ubiquitinated by the von Hippel-Lindau tumor-suppressing factor, and eliminated by the proteasome [19], a discovery that led to the Nobel
We studied the effect of perinatal asphyxia (PA) on redox homeostasis during the first weeks after birth, monitoring mesencephalon, telencephalon, and hippocampus, brain areas shown to be susceptible to hypoxia and ischemic insults [62,66,91,92]
Summary
Pregnancy lasts 9 months, a period that is divided into three trimesters: the first trimester, from conception up to the time when the embryo and placenta are formed; the second trimester, when the movements of the fetus may already be felt, and the third trimester, starting at week 28, culminating with childbirth. Pregnancy culminates at the time when labor begins, entailing a complex interchange of molecules generated by uterine and extrauterine tissue. Labor and delivery involve a complex and sequential metabolic and physiologic cascade, culminating in most circumstances in successful childbirth. Delivery can be a risky event, mainly when there is a metabolic and/or a blood perfusion deficit, including a drop in maternal blood pressure during labor, preceding delivery, or during and/or after delivery, when the required spontaneous pulmonary respiration by the newborn is delayed or interrupted, leading to reduced transfer of oxygen to tissue and cells, and hypoxia, either due to a dysfunction of respiratory and heart rate by the mother at the prenatal stage, or by the newborn after delivery, resulting in a drop of oxygen saturation. Interruption of oxygen transference leads to perinatal asphyxia (PA), a medical condition occurring at labor, delivery, and/or neonatal stages, affecting most of the infant’s organs, but the brain being the most concerned target. If re-oxygenation is re-established, PA can lead to long-term consequences [8], including long-lasting neuropsychiatric dysfunctions when children reach critical developmental stages [9,10]
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