Metabolomic Analysis of Cerebrospinal Fluid Indicates Iron Deficiency Compromises Cerebral Energy Metabolism in the Infant Monkey

Rao, Raghavendra; Ennis, Kathleen; Öz, Gülin; Lubach, Gabriele R.; Georgieff, Michael; Coe, Christopher L.

doi:10.1007/s11064-012-0950-7

Cited by 26 publications

(25 citation statements)

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“…Induction of ID by adding the iron chelator desferrioxamine (DFO) to the human cell line K-562 also results in an increase in lactate to compensate for the ATP loss in the TCA cycle (29). A decrease in the citrate/lactate ratio of cerebrospinal fluid has previously been shown in dietary IDA monkeys (30). While lactate can be used by the brain for energy, the finding of increased steady-state, intracellular lactate levels suggests an accumulation of this by-product of anaerobic glycolysis.…”

Section: Discussionmentioning

confidence: 60%

Phlebotomy-induced anemia alters hippocampal neurochemistry in neonatal mice

et al. 2015

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Background Phlebotomy-induced anemia (PIA) is common in preterm infants. The hippocampus undergoes rapid differentiation during late fetal/early neonatal life and relies on adequate oxygen and iron to support oxidative metabolism necessary for development. Anemia shortchanges these two critical substrates, potentially altering hippocampal development and function. Methods PIA (hematocrit <25%) was induced in neonatal mice pups from postnatal day (P)3 to P14. Neurochemical concentrations in the hippocampus were determined using in vivo 1H NMR spectroscopy at 9.4T and compared with control animals at P14. Gene expression was assessed using qRT-PCR. Results PIA decreased brain iron concentration, increased hippocampal lactate and creatine concentrations, and decreased phosphoethanolamine (PE) concentration and the phosphocreatine/creatine ratio. Hippocampal transferrin receptor (Tfrc) gene expression was increased, while the expression of calcium/calmodulin-dependent protein kinase type II alpha (CamKIIα) was decreased in PIA mice. Conclusion This clinically relevant model of neonatal anemia alters hippocampal energy and phospholipid metabolism and gene expression during a critical developmental period. Low target hematocrits for preterm neonates in the NICU may have potential adverse neural implications.

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Section: Discussionmentioning

confidence: 60%

Phlebotomy-induced anemia alters hippocampal neurochemistry in neonatal mice

et al. 2015

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“…Different approaches have been used to this end, including the evaluation of plasma, urine, cerebral spinal fluid, and magnetic resonance spectroscopy of brain [8,20,25,26]. The metabolomic profile is composed of products of cellular and physiologic metabolism, products of specific biochemical pathways that the organism has used to promote survival in any given circumstance.…”

Section: Discussionmentioning

confidence: 99%

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

Chun

McPherson

Marney³

et al. 2015

Dev Neurosci

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Biomarkers that indicate the severity of hypoxic-ischemic brain injury and response to treatment and that predict neurodevelopmental outcomes are urgently needed to improve the care of affected neonates. We hypothesize that sequentially obtained plasma metabolomes will provide indicators of brain injury and repair, allowing for the prediction of neurodevelopmental outcomes. A total of 33 Macaca nemestrina underwent 0, 15 or 18 min of in utero umbilical cord occlusion (UCO) to induce hypoxic-ischemic encephalopathy and were then delivered by hysterotomy, resuscitated and stabilized. Serial blood samples were obtained at baseline (cord blood) and at 0.1, 24, 48, and 72 h of age. Treatment groups included nonasphyxiated controls (n = 7), untreated UCO (n = 11), UCO + hypothermia (HT; n = 6), and UCO + HT + erythropoietin (n = 9). Metabolites were extracted and analyzed using comprehensive two-dimensional gas chromatography coupled with time-of-flight mass spectrometry and quantified by PARAFAC (parallel factor analysis). Using nontargeted discovery-based methods, we identified 63 metabolites as potential biomarkers. The changes in metabolite concentrations were characterized and compared between treatment groups. Further comparison determined that 8 metabolites (arachidonic acid, butanoic acid, citric acid, fumaric acid, lactate, malate, propanoic acid, and succinic acid) correlated with early and/or long-term neurodevelopmental outcomes. The combined outcomes of death or cerebral palsy correlated with citric acid, fumaric acid, lactate, and propanoic acid. This change in circulating metabolome after UCO may reflect cellular metabolism and biochemical changes in response to the severity of brain injury and have potential to predict neurodevelopmental outcomes.

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“…The impact of early-life IDA on the metabolic composition of cerebrospinal fluid (CSF) from rhesus monkeys was assessed using a 1 H NMR spectroscopy-based metabolomic approach [ 83 ]. Suppression of TCA cycle activity in the intrathecal compartment was indicated during the anemia period by lower citrate: pyruvate and citrate: lactate ratios and a higher pyruvate: glutamine ratio in the IDA infants compared to the iron sufficient animals.…”

Section: Metabolic Phenotyping Of Malnutrition During the First 1000 mentioning

confidence: 99%

Metabolic phenotyping of malnutrition during the first 1000 days of life

Mayneris‐Perxachs

Swann

2018

Eur J Nutr

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Nutritional restrictions during the first 1000 days of life can impair or delay the physical and cognitive development of the individual and have long-term consequences for their health. Metabolic phenotyping (metabolomics/metabonomics) simultaneously measures a diverse range of low molecular weight metabolites in a sample providing a comprehensive assessment of the individual's biochemical status. There are a growing number of studies applying such approaches to characterize the metabolic derangements induced by various forms of early-life malnutrition. This includes acute and chronic undernutrition and specific micronutrient deficiencies. Collectively, these studies highlight the diverse and dynamic metabolic disruptions resulting from various forms of nutritional deficiencies. Perturbations were observed in many pathways including those involved in energy, amino acid, and bile acid metabolism, the metabolic interactions between the gut microbiota and the host, and changes in metabolites associated with gut health. The information gleaned from such studies provides novel insights into the mechanisms linking malnutrition with developmental impairments and assists in the elucidation of candidate biomarkers to identify individuals at risk of developmental shortfalls. As the metabolic profile represents a snapshot of the biochemical status of an individual at a given time, there is great potential to use this information to tailor interventional strategies specifically to the metabolic needs of the individual.

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Metabolomic Analysis of Cerebrospinal Fluid Indicates Iron Deficiency Compromises Cerebral Energy Metabolism in the Infant Monkey

Cited by 26 publications

References 50 publications

Phlebotomy-induced anemia alters hippocampal neurochemistry in neonatal mice

Phlebotomy-induced anemia alters hippocampal neurochemistry in neonatal mice

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

Metabolic phenotyping of malnutrition during the first 1000 days of life

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