Metabolomic Analysis of the Effect of Postnatal Hypoxia on the Retina in a Newly Born Piglet Model

Solberg, Rønnaug; Escobar, Javier; Arduini, Alessandro; Torres-Cuevas, Isabel; Lahoz, Agustín; Sastre, Juan; Saugstad, Ola Didrik; Vento, Máximo; Kuligowski, Julia; Quintás, Guillermo

doi:10.1371/journal.pone.0066540

Cited by 19 publications

(19 citation statements)

References 44 publications

(57 reference statements)

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“…Hence, metabolomics evidenced a substantial increase in free fatty acids also at the end of hypoxia. The increase of cytidine and uridine derivatives, free fatty acids, and choline in plasma supports the idea that the Kennedy pathway and the transport of such metabolites are significantly altered during intense and prolonged hypoxia and could be used as early biomarkers of relevant alterations in cell metabolism (10,11). In addition, we found that levels of hypoxanthine, a hallmark of hypoxia (17,18), as well as other intermediates of purine catabolism including 8-hydroxyadenine, inosine, 6,8-dihydroxypurine, guanine, and uric acid were increased in plasma of the hypoxic newborn piglets.…”

Section: Biological Interpretation Of the Metabolic Alterations Obsermentioning

confidence: 63%

“…Moreover, a recent study investigated metabolic changes in piglets' retina after an intense period of hypoxia (10). Untargeted liquid chromatography-time of flight mass spectrometry (LC-TOFMS) revealed that there was a significant increase in cytidine di-phosphate-choline, a precursor of phosphocholine in the retina after hypoxia (11).…”

Section: Metabolome In Hypoxia and Reoxygenationmentioning

confidence: 99%

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Changes of the plasma metabolome of newly born piglets subjected to postnatal hypoxia and resuscitation with air

et al. 2016

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Background: Perinatal hypoxic-ischemic brain damage is a major cause of mortality and morbidity in the neonatal period. Currently, limited ranges of biochemical tests assessing the intensity and duration of hypoxia are ready for clinical use. However, the need to initiate hypothermia therapy early after the clinical suspicion of hypoxic-ischemic encephalopathy requires the availability of early and reliable hypoxia markers. We have sought these biomarkers in an experimental model of hypoxia reoxygenation. Methods: Hypoxia and hypotension were induced in newborn piglets following a standardized model and reoxygenation was carried out using room air (RA). An untargeted liquid chromatography-time of flight mass spectrometry (LC-TOFMS) approach was used to assess changes in the metabolomic profile of plasma samples after intense hypoxia and upon reoxygenation. results: At the end of hypoxia, the plasma metabolome showed an increased plasma concentration of analytes reflecting a metabolic adaptation to prolonged anaerobiosis. However, after resuscitation, metabolite levels returned to the starting values. conclusion: Severe hypoxia induces early, significant, and transient changes of specific metabolites in the plasma metabolome, which represent a snapshot of the biochemical adaptation of mammals to intense hypoxia. These metabolites could have applicability in predicting the severity of hypoxia in the clinical setting. P erinatal hypoxia-ischemia (HI) is an injurious event that may precipitate a cascade of biochemical processes, which can lead to multiorgan failure including neuronal cell death evolving for hours, days, or even months (1). At present, clinical assessment which includes Apgar score, serum blood gases, and lactate analysis lack desired reliability both in the assessment of a good postnatal adaptation and to predict long-term neurocognitive outcome (2,3). Both, amplitude-integrated electroencephalography and magnetic resonance imaging offer valuable information that can be predictive of outcome; however, they do not have the sensitivity needed to inform treatment. Moreover, in many centers, there is no easy access to these technologies (4). Therapeutic hypothermia has significantly improved prognosis of a substantial number of asphyxiated babies evolving to hypoxic-ischemic encephalopathy. However, the need to promptly initiate therapeutic hypothermia after the hypoxic-ischemic (< 6 h) insult urges the need for diagnostic tools, which rapidly and reliably assess the degree of hypoxia thus helping to stratify patients and adopt clinical decisions (5). Biochemical evaluation of the severity of birth asphyxia has been traditionally performed using blood gases and lactate concentrations in cord blood at birth. However, in a study by Solberg et al. (6), changes in metabolites during neonatal hypoxia were analyzed and correlated with the duration of hypoxia using targeted metabolomics. Although blood lactate, pH, and base excess increased in the first minutes after hypoxia, there was no significant correlati...

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Section: Biological Interpretation Of the Metabolic Alterations Obsermentioning

confidence: 63%

Section: Metabolome In Hypoxia and Reoxygenationmentioning

confidence: 99%

Changes of the plasma metabolome of newly born piglets subjected to postnatal hypoxia and resuscitation with air

et al. 2016

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“…32 Signaling pathways like apoptosis and angiogenesis are triggered by oxidative stress, possibly explaining the pathologic features of vascular development in ROP. 32,33 Several studies of hypoxia and hypoxia-reoxygenation also show tight connections to accumulation of oxidative stress, thereby initiating both gene and protein expression [33][34][35][36] as well as metabolites 37 in different eye structures.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia–Reoxygenation Affects Whole-Genome Expression in the Newborn Eye

Wollen

Kwinta

Bik-Multanowski

et al. 2014

Invest. Ophthalmol. Vis. Sci.

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“…Data presented in Table 1 demonstrate that physiological variables do not provide sufficient predictive capacity as they return to normal values during resuscitation. In this study we assessed and compared the evolution of four metabolites, namely choline, betaine, cytidine and uridine, which have been identified as potential biomarkers of hypoxia in previous studies13192021. Levels of lactate, which are currently considered the gold standard for assessing asphyxia in the clinics, were used throughout this work as reference for comparison.…”

Section: Discussionmentioning

confidence: 99%

“…In a previous targeted metabolomic study in newborn piglets plasma it was shown that the duration and intensity of hypoxia were more accurately reflected by ratios of alanine to branched-chained amino acids (BCAA) and glycine to BCAA than by the traditionally employed plasma lactate concentration12. With the aim of discovering early biomarkers Solberg et al 13. carried out an untargeted metabolomics study involving the analysis of retinal tissue samples from a piglet model of perinatal asphyxia.…”

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confidence: 99%

Assessment of phospholipid synthesis related biomarkers for perinatal asphyxia: a piglet study

Sánchez-Illana

Solberg

Lliso

et al. 2017

Sci Rep

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The prompt and reliable identification of infants at risk of hypoxic-ischemic encephalopathy secondary to perinatal asphyxia in the first critical hours is important for clinical decision-making and yet still remains a challenge. This work strives for the evaluation of a panel of metabolic biomarkers that have been associated with the hypoxic-ischemic insult in the perinatal period. Plasma and urine samples from a consolidated newborn piglet model of hypoxia and withdrawn before and at different time points after a hypoxic insult were analyzed and compared to a control group. Time-dependent metabolic biomarker profiles were studied and observed patterns were similar to those of lactate levels, which are currently considered the gold standard for assessing hypoxia. Class prediction performance could be improved by the use of a combination of the whole panel of determined metabolites in plasma as compared to lactate values. Using a multivariate model including lactate together with the studied metabolic biomarkers allowed to improve the prediction performance of duration of hypoxia time, which correlates with the degree of brain damage. The present study evidences the usefulness of choline and related metabolites for improving the early assessment of the severity of the hypoxic insult.

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Metabolomic Analysis of the Effect of Postnatal Hypoxia on the Retina in a Newly Born Piglet Model

Cited by 19 publications

References 44 publications

Changes of the plasma metabolome of newly born piglets subjected to postnatal hypoxia and resuscitation with air

Changes of the plasma metabolome of newly born piglets subjected to postnatal hypoxia and resuscitation with air

Hypoxia–Reoxygenation Affects Whole-Genome Expression in the Newborn Eye

Assessment of phospholipid synthesis related biomarkers for perinatal asphyxia: a piglet study

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