Perinatal asphyxia: CNS development and deficits with delayed onset

Abstract

Perinatal asphyxia constitutes a prototype of obstetric complications occurring when pulmonary oxygenation is delayed or interrupted. The primary insult relates to the duration of the period lacking oxygenation, leading to death if not re-established. Re-oxygenation leads to a secondary insult, related to a cascade of biochemical events required for restoring proper function. Perinatal asphyxia interferes with neonatal development, resulting in long-term deficits associated to mental and neurological diseases with delayed clinical onset, by mechanisms not yet clarified. In the experimental scenario, the effects observed long after perinatal asphyxia have been explained by overexpression of sentinel proteins, such as poly(ADP-ribose) polymerase-1 (PARP-1), competing for NAD+ during re-oxygenation, leading to the idea that sentinel protein inhibition constitutes a suitable therapeutic strategy. Asphyxia induces transcriptional activation of pro-inflammatory factors, in tandem with PARP-1 overactivation, and pharmacologically induced PARP-1 inhibition also down-regulates the expression of proinflammatory cytokines. Nicotinamide has been proposed as a suitable PARP-1 inhibitor. Its effect has been studied in an experimental model of global hypoxia in rats. In that model, the insult is induced by immersing rat fetus into a water bath for various periods of time. Following asphyxia, the pups are delivered, treated, and nursed by surrogate dams, pending further experiments. Nicotinamide rapidly distributes into the brain following systemic administration, reaching steady state concentrations sufficient to inhibit PARP-1 activity for several hours, preventing several of the long-term consequences of perinatal asphyxia, supporting the idea that nicotinamide constitutes a lead for exploring compounds with similar or better pharmacological profiles.

Maternal Oxytocin Administration Before Birth Influences the Effects of Birth Anoxia on the Neonatal Rat Brain

“…Following this, pups were born by C-section (CS) alone or by CS with an added period of anoxia (6 or 15 min), using a well-characterized model of global birth anoxia as previously described by our and others' laboratories [e.g. 19,20]. Pups were sacrificed at various times after birth and their brains taken for biochemical measurements.…”

“…Therefore in the current study, we tested if administering oxytocin to pregnant dams before birth affects the neonatal brain response to hypoxia, using an in vivo rat model of global birth hypoxia. In this model, pregnant rat dams are administered oxytocin on the expected day of birth; following this, the entire intact uterus containing rat pups is isolated via an abdominal incision [Cesarean section (Csection)] and submerged in saline for several minutes to mimic an acute anoxic episode, followed by delivery of pups [19,20]. We also assessed effects of injecting oxytocin directly to postnatal day 2 (P2) rat pups followed by exposure to 10 min of anoxia, to determine if oxytocin can have direct effects on the neonate, independent of maternal effects.…”

Characterization of mitochondrial bioenergetics in neonatal anoxic model of rats

“…It is considered as a global clinical problem. It has been implicated to cause motor and cognitive alterations in neonates of variable severity like cerebral palsy, epilepsy, dystonia in the early age and attention deficit disorder, mental retardation and other neuropsychiatric syndromes at school age (Herrera-Marschitz et al 2014;Strata et al 2004). …”

“…This critical requirement is compromised during anoxic injury triggering cascade of biochemical events which lead to excitotoxicity and influx of Ca 2+ ions. This results in overproduction of nitric oxide (NO) apart from other reactive oxygen species (ROS) within the mitochondria (Magistretti and Allaman 2013;Sun and Gilboe 1994;Herrera-Marschitz et al 2014). These mitochondrial events lead to opening of membrane permeability transition pore and release of proapoptotic proteins like cytochrome c which ultimately cause mitochondrial dysfunction and cell death (Morin et al 2003).…”

Urinary gas chromatography mass spectrometry metabolomics in asphyxiated newborns undergoing hypothermia: from the birth to the first month of life

“…The timing of the organ insult is a key factor influencing the extension and the pattern of the damage and, in turn the clinical outcome. The brain is the most injured organ by perinatal asphyxia (6); almost all of the oxygen consumed by the human brain is utilized for the oxidation of glucose, which in turn is the only significant substrate for energy in cerebral metabolism. In detail, the aerobic glycolysis generates pyruvate; subsequently, pyruvate enters into the citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, within mitochondria, ultimately generating adenosine triphosphate (ATP).…”