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Cerebral Oxygenation and Metabolism After Hypoxia-Ischemia.

ABSTRACT: Perinatal hypoxia-ischemia (HI) is still a significant contributor to mortality and adverse neurodevelopmental outcomes in term and preterm infants. HI brain injury evolves over hours to days, and involves complex interactions between the endogenous protective and pathological processes. Understanding the timing of evolution of injury is vital to guide treatment. Post-HI recovery is associated with a typical neurophysiological profile, with stereotypic changes in cerebral perfusion and oxygenation. After the initial recovery, there is a delayed, prolonged reduction in cerebral perfusion related to metabolic suppression, followed by secondary deterioration with hyperperfusion and increased cerebral oxygenation, associated with altered neurovascular coupling and impaired cerebral autoregulation. These changes in cerebral perfusion are associated with the stages of evolution of injury and injury severity. Further, iatrogenic factors can also affect cerebral oxygenation during the early period of deranged metabolism, and improving clinical management may improve neuroprotection. We will review recent evidence that changes in cerebral oxygenation and metabolism after HI may be useful biomarkers of prognosis.

SUBMITTER: Dhillon SK

PROVIDER: S-EPMC9314655 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Cerebral Oxygenation and Metabolism After Hypoxia-Ischemia.

Dhillon Simerdeep K SK Gunn Eleanor R ER Lear Benjamin A BA King Victoria J VJ Lear Christopher A CA Wassink Guido G Davidson Joanne O JO Bennet Laura L Gunn Alistair J AJ

Frontiers in pediatrics 20220712

Perinatal hypoxia-ischemia (HI) is still a significant contributor to mortality and adverse neurodevelopmental outcomes in term and preterm infants. HI brain injury evolves over hours to days, and involves complex interactions between the endogenous protective and pathological processes. Understanding the timing of evolution of injury is vital to guide treatment. Post-HI recovery is associated with a typical neurophysiological profile, with stereotypic changes in cerebral perfusion and oxygenati ...[more]

PMID: 35903161

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Project description:ObjectiveTo determine whether the NAD+ biosynthetic protein, nicotinamide mononucleotide adenylyltransferase-3 (NMNAT3), is a neuroprotective inducible enzyme capable of decreasing cerebral injury after neonatal hypoxia-ischemia (H-I) and reducing glutamate receptor-mediated excitotoxic neurodegeneration of immature neurons.MethodsUsing NMNAT3-overexpressing mice we investigated whether increases in brain NMNAT3 reduced cerebral tissue loss following H-I. We then employed biochemical methods from injured neonatal brains to examine the inducibility of NMNAT3 and the mechanism of NMNAT3-dependent neuroprotection. Using AAV8-mediated vectors for in vitro neuronal NMNAT3 knockdown, we then examine the endogenous role of this protein on immature neuronal survival prior and following NMDA receptor-mediated excitotoxicity.ResultsNMNAT3 mRNA and protein levels increased after neonatal H-I. In addition, NMNAT3 overexpression decreased cortical and hippocampal tissue loss 7 days following injury. We further show that the NMNAT3 neuroprotective mechanism involves a decrease in calpastatin degradation, and a decrease in caspase-3 activity and calpain-mediated cleavage. Conversely, NMNAT3 knockdown of cortical and hippocampal neurons in vitro caused neuronal degeneration and increased excitotoxic cell death. The neurodegenerative effects of NMNAT3 knockdown were counteracted by exogenous upregulation of NMNAT3.ConclusionsOur observations provide new insights into the neuroprotective mechanisms of NMNATs in the injured developing brain, adding NMNAT3 as an important neuroprotective enzyme in neonatal H-I via inhibition of apoptotic and necrotic neurodegeneration. Interestingly, we find that endogenous NMNAT3 is an inducible protein important for maintaining the survival of immature neurons. Future studies aimed at uncovering the mechanisms of NMNAT3 upregulation and neuroprotection may offer new therapies against the effects of hypoxic-ischemic encephalopathy.

Dataset Information

Cerebral Oxygenation and Metabolism After Hypoxia-Ischemia.

Publications

Cerebral Oxygenation and Metabolism After Hypoxia-Ischemia.

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