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

Morales P, Bustamante D, Espina-Marchant P, Neira-Peña T, Gutiérrez-Hernández MA, Allende-Castro C, Rojas-Mancilla E - EPMA J (2011)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Programme of Molecular & Clinical Pharmacology, ICBM, Medical Faculty, University of Chile, PO Box 70.000, Santiago 7, Chile.

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.

No MeSH data available.


Related in: MedlinePlus

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
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Fig2: 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

Mentions: Energy failure occurring in PA leads a radical shift from an aerobic to a less efficient anaerobic metabolism, resulting in a decreased rate of ATP and phosphocreatine formation [67–69], lactate accumulation [70, 71], decreased pH [67, 72], decreased protein phosphorylation [69, 73–75]; and finally, over-production of reactive oxygen species (ROS) [76–80] that result in cell death. Deficit in ATP production leads to loss of resting membrane potential [81], disturbances in ionic homeostasis, membrane depolarisation [82], and an increase in extracellular glutamate concentration [70, 83] as shown in Fig. 2. This results in over-activation of the ionotropic NMDA (N-methyl-D-aspartic acid), AMPA/KA (Alpha-amino acid-3-hydroxy-5-methyl-4-isoxazolepropionic acid/Kainic acid) receptors as well as the G-protein-linked metabotropic glutamate receptors (mGluR) [82, 84, 85], inducing a massive influx of Ca2+ into cells. The increase in cytosolic Ca2+, in turn, 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 [44, 57, 86, 87]. These events [88–91] elicit a cascade of downstream intracellular processes that finally lead to excitotoxic neuronal damage [92–94] and cell death (see Fig. 2).Fig. 2


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

Morales P, Bustamante D, Espina-Marchant P, Neira-Peña T, Gutiérrez-Hernández MA, Allende-Castro C, Rojas-Mancilla E - EPMA J (2011)

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
© Copyright Policy
Related In: Results  -  Collection

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Fig2: 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
Mentions: Energy failure occurring in PA leads a radical shift from an aerobic to a less efficient anaerobic metabolism, resulting in a decreased rate of ATP and phosphocreatine formation [67–69], lactate accumulation [70, 71], decreased pH [67, 72], decreased protein phosphorylation [69, 73–75]; and finally, over-production of reactive oxygen species (ROS) [76–80] that result in cell death. Deficit in ATP production leads to loss of resting membrane potential [81], disturbances in ionic homeostasis, membrane depolarisation [82], and an increase in extracellular glutamate concentration [70, 83] as shown in Fig. 2. This results in over-activation of the ionotropic NMDA (N-methyl-D-aspartic acid), AMPA/KA (Alpha-amino acid-3-hydroxy-5-methyl-4-isoxazolepropionic acid/Kainic acid) receptors as well as the G-protein-linked metabotropic glutamate receptors (mGluR) [82, 84, 85], inducing a massive influx of Ca2+ into cells. The increase in cytosolic Ca2+, in turn, 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 [44, 57, 86, 87]. These events [88–91] elicit a cascade of downstream intracellular processes that finally lead to excitotoxic neuronal damage [92–94] and cell death (see Fig. 2).Fig. 2

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Programme of Molecular & Clinical Pharmacology, ICBM, Medical Faculty, University of Chile, PO Box 70.000, Santiago 7, Chile.

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.

No MeSH data available.


Related in: MedlinePlus