Pathophysiology of perinatal asphyxia: can we predict and improve individual outcomes?

Abstract

Perinatal asphyxia occurs still with great incidence whenever delivery is prolonged, despite improvements in perinatal care. After asphyxia, infants can suffer from short- to long-term neurological sequelae, their severity depend upon the extent of the insult, the metabolic imbalance during the re-oxygenation period and the developmental state of the affected regions. Significant progresses in understanding of perinatal asphyxia pathophysiology have achieved. However, predictive diagnostics and personalised therapeutic interventions are still under initial development. Now the emphasis is on early non-invasive diagnosis approach, as well as, in identifying new therapeutic targets to improve individual outcomes. In this review we discuss (i) specific biomarkers for early prediction of perinatal asphyxia outcome; (ii) short and long term sequelae; (iii) neurocircuitries involved; (iv) molecular pathways; (v) neuroinflammation systems; (vi) endogenous brain rescue systems, including activation of sentinel proteins and neurogenesis; and (vii) therapeutic targets for preventing or mitigating the effects produced by asphyxia.

Figures

Fig. 1

Perinatal asphyxia reduces neurite branching of primary cultured pyramidal neurons from hippocampus. Asphyxia was induced by immersing foetuses-containing uterine horns, removed from ready-to-deliver rats into a water bath at 37°C for 21 min. The cultures were prepared 6 h after delivery. After 14 days in vitro, the cultures were fixed with a formalin solution for assaying neuronal and astroglial phenotype using antibodies against microtubule associated protein-2 (MAP-2, red) and glial fibrillary acidic protein (GFAP, green) respectively, counterstained with 4′,6-diamidino-2-phenylindole (DAPI, blue), a DNA marker. A fluorescent photomicrograph of cultures from a caesarean-delivered control (a), and asphyxia-exposed (b) rats, showing MAP-2 (red) and GPAP (green) positive cells is shown. A significant decrease on neurite branching is observed in asphyctic cultures (b), principally evident in neurites of secondary and tertiary order. Moreover, a relationship between neurons and astrocytes can be observed in both experimental conditions, being more pronounced in astrocytes from asphyctic condition. Scale bar: 20 μm. Taken from Rojas-Mancilla et al., in preparation

Fig. 2

Neuropathological mechanisms induced by perinatal asphyxia in the neonatal brain. Following PA, energy failure leads to a shift from aerobic to anaerobic metabolism, resulting in a decreased rate of ATP and other energy compounds, lactate accumulation, decreased pH, and finally, over-production of reactive oxygen species (ROS). An ATP deficit leads to dissipation of ion gradients and membrane depolarisation, due to pumps decreased protein phosphorylation, with a subsequent increase in extracellular glutamate concentration. This results in over-activation of glutamate receptors inducing a massive influx of Ca2+ into cells, which activates proteases, lipases, endonucleases, and nitric oxide synthases that degrade the cytoskeleton and extracellular matrix proteins, producing membrane lipid peroxidation, peroxynitrites, and other free radicals. These events elicit a cascade of downstream intracellular processes that finally lead to excitotoxic neuronal damage and cell death. At the same time, antioxidative mechanisms get involved and DNA damage triggers the activation of sentinel proteins that maintain genome integrity, such as poly (ADP-ribose) polymerases (PARPs), but when overactivated, leads to further energy depletion and cell death. Depending upon time after asphyctic injury, re-oxygenation can lead to improper homeostasis, prolonging the energy deficit and/or generating oxidative stress. Oxidative stress has been associated with inactivation of a number of metabolic repair enzymes and further activation of degradatory enzymes, thus extending and maintaining damage. After acute damage, proliferation and sprouting are diminished, in agreement with a decrease in activity of Protein kinase C (PKC) and cyclin-dependent kinase (Cdk) observed after PA. But at long-term, release of neurotrophic factors promotes neurogenesis and neuritogenesis