Serial Plasma Metabolites Following Hypoxic-Ischemic Encephalopathy in a Nonhuman Primate Model

Chun, Pattaraporn Tanya; McPherson, Ronald J.; Marney, Luke C.; Zangeneh, Sahar Z.; Parsons, Brendon A.; Shojaie, Ali; Synovec, Robert E.; Juul, Sandra E.

doi:10.1159/000370147

Cited by 26 publications

(34 citation statements)

References 43 publications

(53 reference statements)

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“…For example, preterm infants with CNS insults are prone to cumulative injuries from additional postnatal problems such as sepsis and seizures, and serum biomarkers could guide the duration of treatment for CNS protection. The need for serum biomarkers for preterm infants, as well as infants with other perinatal CNS insults is well recognized [61–63]. …”

Section: Discussionmentioning

confidence: 99%

Erythropoietin Modulates Cerebral and Serum Degradation Products from Excess Calpain Activation following Prenatal Hypoxia-Ischemia

Jantzie

Winer²,

Corbett³

et al. 2015

Dev Neurosci

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Preterm infants suffer central nervous system (CNS) injury from hypoxia-ischemia and inflammation - termed encephalopathy of prematurity. Mature CNS injury activates caspase and calpain proteases. Erythropoietin (EPO) limits apoptosis mediated by activated caspases, but its role in modulating calpain activation has not yet been investigated extensively following injury to the developing CNS. We hypothesized that excess calpain activation degrades developmentally regulated molecules essential for CNS circuit formation, myelination and axon integrity, including neuronal potassium-chloride co-transporter (KCC2), myelin basic protein (MBP) and phosphorylated neurofilament (pNF), respectively. Further, we predicted that post-injury EPO treatment could mitigate CNS calpain-mediated degradation. Using prenatal transient systemic hypoxia-ischemia (TSHI) in rats to mimic CNS injury from extreme preterm birth, and postnatal EPO treatment with a clinically relevant dosing regimen, we found sustained postnatal excess cortical calpain activation following prenatal TSHI, as shown by the cleavage of alpha II-spectrin (αII-spectrin) into 145-kDa αII-spectrin degradation products (αII-SDPs) and p35 into p25. Postnatal expression of the endogenous calpain inhibitor calpastatin was also reduced following prenatal TSHI. Calpain substrate expression following TSHI, including cortical KCC2, MBP and NF, was modulated by postnatal EPO treatment. Calpain activation was reflected in serum levels of αII-SDPs and KCC2 fragments, and notably, EPO treatment also modulated KCC2 fragment levels. Together, these data indicate that excess calpain activity contributes to the pathogenesis of encephalopathy of prematurity. Serum biomarkers of calpain activation may detect ongoing cerebral injury and responsiveness to EPO or similar neuroprotective strategies.

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Section: Discussionmentioning

confidence: 99%

Erythropoietin Modulates Cerebral and Serum Degradation Products from Excess Calpain Activation following Prenatal Hypoxia-Ischemia

Jantzie

Winer²,

Corbett³

et al. 2015

Dev Neurosci

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“…Juul et al extensively explored PA in a non-human primate model, namely Macaca Nemestrina, using two-dimensional gas chromatography with time-of-flight mass spectrometry (GC×GC-TOFMS) [41][42][43]. In their first work, asphyxia was induced in utero by clamping the umbilical cord blood for 15 or 18 min before delivery [41].…”

Section: Animal Modelsmentioning

confidence: 99%

“…In a following study, the authors used the same model, withdrawing four arterial blood sample at defined timepoints (5 min, 24, 48, and 72 h) after delivery [42]. Moreover, the asphyxiated newborns were randomized to three treatments groups: The first no treatment, the second standard TH, and the third standard TH plus EPO.…”

Section: Animal Modelsmentioning

confidence: 99%

Exploring Perinatal Asphyxia by Metabolomics

et al. 2020

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Brain damage related to perinatal asphyxia is the second cause of neuro-disability worldwide. Its incidence was estimated in 2010 as 8.5 cases per 1000 live births worldwide, with no further recent improvement even in more industrialized countries. If so, hypoxic-ischemic encephalopathy is still an issue of global health concern. It is thought that a consistent number of cases may be avoided, and its sequelae may be preventable by a prompt and efficient physical and therapeutic treatment. The lack of early, reliable, and specific biomarkers has up to now hampered a more effective use of hypothermia, which represents the only validated therapy for this condition. The urge to unravel the biological modifications underlying perinatal asphyxia and hypoxic-ischemic encephalopathy needs new diagnostic and therapeutic tools. Metabolomics for its own features is a powerful approach that may help for the identification of specific metabolic profiles related to the pathological mechanism and foreseeable outcome. The metabolomic profiles of animal and human infants exposed to perinatal asphyxia or developing hypoxic-ischemic encephalopathy have so far been investigated by means of 1 H nuclear magnetic resonance spectroscopy and mass spectrometry coupled with gas or liquid chromatography, leading to the identification of promising metabolomic signatures. In this work, an extensive review of the relevant literature was performed.trigger several changes at molecular and cellular levels, which may end in cell death and in local/systemic inflammation. The shortage of oxygen, which acts as final electron acceptor in the electron transport chain (ETC) during aerobic respiration, induced by hypoxia and by ischemia, boosts reactive oxygen species (ROS) generation at the cellular level. Generated ROS attack surrounds components at both the mitochondrial and cellular level, leading to mitochondrial dysfunction and permanent damage to cells. The pathogenesis of HIE is strongly influenced by the failure of several potent fetal compensatory mechanisms to cope with the 'physiological' hypoxia during pregnancy and delivery. The final clinical outcome of such an insult is a wide spectrum of neurological deficits, ranging from behavioral and motor impairments to general developmental delays to seizures related to structural brain damage.The severity of the clinical picture of HIE infants is the final result of an uneven combination of several factors, and among them the length and strength of hypoxic insult, together with fetal metabolic conditions before the hypoxia onset. For this reason, the pathological effects are complex to forecast, and they evolve over time. They may be related to two main pathological phases: A primary and a secondary energy failure. Primary energy failure is the first biological effect of both hypoxia and a reduction of cerebral blood flow and it mainly takes place before birth. While the impairment of blood flow is responsible for the progressive reduction of glucose availability needed to fuel brain cells' metabo...

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“…Fluid-based metabolomics is an increasingly popular area of research in perinatal medicine, with studies related to neonatal encephalopathy and chorioamnionitis [26,[50][51][52] . Attempts have even been made to correlate metabolic changes with neuropathology in a sheep model of inflammation-driven perinatal brain injury [53] .…”

Section: Time-series Analysismentioning

confidence: 99%

Persistently Altered Metabolic Phenotype following Perinatal Excitotoxic Brain Injury

Blaise

Schwendimann

Chhor³

et al. 2017

Dev Neurosci

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Excitotoxicity plays a key role during insults to the developing brain such as neonatal encephalopathy, stroke, and encephalopathy of prematurity. Such insults affect many thousands of infants each year. Excitotoxicity causes frank lesions due to cell death and gliosis and disturbs normal developmental process, leading to deficits in learning, memory, and social integration that persist into adulthood. Understanding the underlying processes of the acute effects of excitotoxicity and its persistence during brain maturation provides an opportunity to identify mechanistic or diagnostic biomarkers, thus enabling and designing possible therapies. We applied mass spectrometry to provide metabolic profiles of brain tissue and plasma over time following an excitotoxic lesion (intracerebral ibotenate) to the neonatal (postnatal day 5) mouse brain. We found no differences between the plasma from the control (PBS-injected) and excitotoxic (ibotenate-injected) groups over time (on postnatal days 8, 9, 10, and 30). In the brain, we found that variations in amino acids (arginine, glutamine, phenylananine, and proline) and glycerophospholipids were sustaining acute and delayed (tertiary) responses to injury. In particular, the effect of the excitotoxic lesion on the normal profile of development was linked to alterations in a fingerprint of glycerophospolipids and amino acids. Specifically, we identified increases in the amino acids glutamine, proline, serine, threonine, tryptophan, valine, and the sphingolipid SM C26:1, and decreases in the glycerophospholipids, i.e., the arachidonic acid-containing phosphatidylcholine (PC aa) C30:2 and the PC aa C32:3. This study demonstrates that metabolic profiling is a useful approach to identify acute and tertiary effects in an excitotoxic lesion model, and generating a short list of targets with future potential in the hunt for identification, stratification, and possibly therapy.

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Serial Plasma Metabolites Following Hypoxic-Ischemic Encephalopathy in a Nonhuman Primate Model

Cited by 26 publications

References 43 publications

Erythropoietin Modulates Cerebral and Serum Degradation Products from Excess Calpain Activation following Prenatal Hypoxia-Ischemia

Erythropoietin Modulates Cerebral and Serum Degradation Products from Excess Calpain Activation following Prenatal Hypoxia-Ischemia

Exploring Perinatal Asphyxia by Metabolomics

Persistently Altered Metabolic Phenotype following Perinatal Excitotoxic Brain Injury

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