Antioxidant effect of ethyl pyruvate in respiring neonatal cerebrocortical slices after H2O2 stress

Liu, J.; Segal, Mark R.; Yoo, Seungho; Yang, Guo‐Yuan; James, Thomas Leroy; Litt, Lawrence

doi:10.1016/j.neuint.2008.10.009

Cited by 17 publications

(15 citation statements)

References 26 publications

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“…To circumvent this issue, Sims et al [17] formulated a stable derivative of pyruvate, namely ethyl pyruvate (EP), in a calcium-and potassium-containing balanced salt solution. Recently, EP has been shown to afford protection against oxidative injury in various disease processes, including neurodegenerative disorders [18][19][20][21]. Although the antioxidant properties of EP appear to be responsible, at least partially, for its neuroprotective effects, it remains unclear whether the neuroprotective effects of EP may also occur through other mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Ethyl Pyruvate Inhibits Peroxynitrite-induced DNA Damage and Hydroxyl Radical Generation: Implications for Neuroprotection

et al. 2009

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Ethyl pyruvate (EP) has recently been reported to afford protection against neurodegenerative disorders. However, the mechanism underlying EP-mediated neuroprotection remains to be elucidated. Because peroxynitrite has been extensively implicated in the pathogenesis of various forms of neurodegenerative disorders via its cytotoxic effects, this study was undertaken to investigate whether the neuroprotective effect of EP is associated with inhibition of peroxynitrite-induced DNA strand breaks, a critical event leading to peroxynitrite elicited cytotoxicity. Incubation of phiX-174 plasmid DNA with 3-morpholinosydnonimine (SIN-1), a peroxynitrite generator, led to the formation of both single- and double-stranded DNA breaks in a concentration- and time- dependent manner. The presence of EP (0.5-10 mM) was found to significantly inhibit SIN-1-induced DNA strand breaks in a concentration-dependent fashion. The consumption of oxygen induced by 250 microM SIN-1 was found to be decreased in the presence of EP (0.5-10 mM), indicating that EP might affect the auto-oxidation of SIN-1. It was observed that incubation of the plasmid DNA with authentic peroxynitrite caused significant DNA strand breaks, which could also be dramatically inhibited by EP (0.5-10 mM). EPR spectroscopy in combination with spin-trapping technique using 5,5-dimethylpyrroline-N- oxide (DMPO) as a spin trap demonstrated the formation of DMPO-hydroxyl radical adducts (DMPO-OH) from authentic peroxynitrite, and that EP at 0.5-10 mM inhibited the adduct signal in a concentration-dependent manner. Taken together, these results demonstrate for the first time that EP can inhibit peroxynitrite-mediated DNA damage and hydroxyl radical generation.

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Section: Introductionmentioning

confidence: 99%

Ethyl Pyruvate Inhibits Peroxynitrite-induced DNA Damage and Hydroxyl Radical Generation: Implications for Neuroprotection

et al. 2009

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“…29 As well it suggests that better preservation of astrocyte metabolism might be a marker or even a cause of immediate hypothermia’s treatment advantage, and also possibly the mechanism for our earlier study’s finding from ELISA cell death assays that showed better protection from immediate hypothermia, also by a factor of two. 19 …”

Section: Discussionmentioning

confidence: 99%

“…Details of the brain slice preparation were described previously. 17–19 Briefly, in each experiment 20 cerebrocortical slices (350 μm thickness) were obtained from 10 isoflurane-anesthetized 7-day-old Sprague-Dawley rat litter-mates of either sex, and then immediately placed in a superfusion chamber containing fresh, oxygenated artificial cerebrospinal fluid (oxy-ACSF, 3 mL/min flow) whose nutrient was 10 mM glucose. At 1 h before beginning OGD, 10 mM glucose in oxy-ACSF was replaced with 5 mM [1- 13 C]glucose and 5 mM [1,2- 13 C]acetate, which continued during OGD and thereafter for 6 h. The superfusion chamber was partially submerged in a water bath having a combined circulator-temperature control that maintained temperatures at either 37°C (normothermic) or 32°C (hypothermic).…”

Section: Methodsmentioning

confidence: 99%

13C NMR Metabolomic Evaluation of Immediate and Delayed Mild Hypothermia in Cerebrocortical Slices after Oxygen–Glucose Deprivation

Liu¹,

Segal

Kim

et al. 2013

Anesthesiology

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Background Mild brain hypothermia (32°C–34°C) after human neonatal asphyxia improves neurodevelopmental outcomes. Astrocytes but not neurons have pyruvate carboxylase (PC) and an acetate uptake transporter. 13C NMR spectroscopy of rodent brain extracts after administering [1-13C]glucose and [1,2-13C]acetate can distinguish metabolic differences between glia and neurons, and tricarboxylic acid cycle (TCA cycle) entry via pyruvate dehydrogenase (PDH) and PC. Methods Neonatal rat cerebrocortical slices receiving a 13C-acetate/glucose mixture underwent a 45-min asphyxia simulation via oxygen-glucose-deprivation (OGD) followed by 6 h of recovery. Protocols in three groups of N = 3 experiments were identical except for temperature management. The three temperature groups were: normothermia (37°C), hypothermia (32°C for 3.75 h beginning at OGD start), and delayed hypothermia (32°C for 3.75 h, beginning 15 min after OGD start). Multivariate analysis of nuclear magnetic resonance metabolite quantifications included principal component analyses and the L1-Penalized Regularized Regression algorithm known as the Least Absolute Shrinkage and Selection Operator (LASSO). Results The most significant metabolite difference (p < 0.0056) was [2-13C]glutamine’s higher final/control ratio for the Hypothermia group (1.75 ± 0.12) compared to ratios for the Delayed (1.12 ± 0.12) and Normothermia group (0.94 ± 0.06), implying a higher PC/PDH ratio for glutamine formation. LASSO found the most important metabolites associated with adenosine triphosphate preservation: [3,4-13C]glutamate—produced via PDH entry, [2-13C]taurine--an important osmolyte, and phosphocreatine. Final principal component analyses scores plots suggested separate cluster formation for the hypothermia group, but with insufficient data for statistical significance. Conclusions Starting mild hypothermia simultaneously with OGD, compared with delayed starting or no hypothermia, has higher PC throughput, suggesting that better glial integrity is one important neuroprotection mechanism of earlier hypothermia.

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“…Perchloric acid extraction was done as in earlier studies (24,25,26). In brief, to obtain extracts for one NMR tube for a given time point, two frozen brains of sibling P7 mice in the same experimental group and time point were ground together under liquid nitrogen in a precooled mortar and then extracted using 30 ml/g (dry mass) of ice-cold 12% perchloric acid.…”

Section: Methodsmentioning

confidence: 99%

1H nuclear magnetic resonance brain metabolomics in neonatal mice after hypoxia–ischemia distinguished normothermic recovery from mild hypothermia recoveries

et al. 2013

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Background:Mild brain hypothermia (31–34 °C) after neonatal hypoxia–ischemia (HI) improves neurodevelopmental outcomes in human and animal neonates. Using an asphyxia model with neonatal mice treated with mild hypothermia after HI, we investigated whether 1H nuclear magnetic resonance (NMR) metabolomics of brain extracts could suggest biomarkers and distinguish different treatments and outcome groups.Methods:At postnatal day 7 (P7), CD1 mice underwent right carotid artery occlusion, 30 min of HI (8% oxygen), and 3.5 h of either hypothermia (31 °C) or normothermia (37 °C). Whole brains were frozen immediately after HI, immediately after 3.5 h of hypothermia or normothermia treatments, and 24 h later. Perchloric acid extractions of 36 metabolites were quantified by 900 MHz 1H NMR spectroscopy. Multivariate analyses included principal component analyses (PCA) and a novel regression algorithm. Histological injury was quantified after HI at 5 d.Results:PCA scores plots separated normothermia/HI animals from hypothermia/HI and control animals, but more data are required for multivariate models to be predictive. Loadings plots identified 11 significant metabolites, whereas the regression algorithm identified 6. Histological injury scores were significantly reduced by hypothermia.Conclusion:Different treatment and outcome groups are identifiable by 1H NMR metabolomics in a neonatal mouse model of mild hypothermia treatment of HI.

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Antioxidant effect of ethyl pyruvate in respiring neonatal cerebrocortical slices after H2O2 stress

Cited by 17 publications

References 26 publications

Ethyl Pyruvate Inhibits Peroxynitrite-induced DNA Damage and Hydroxyl Radical Generation: Implications for Neuroprotection

Ethyl Pyruvate Inhibits Peroxynitrite-induced DNA Damage and Hydroxyl Radical Generation: Implications for Neuroprotection

13C NMR Metabolomic Evaluation of Immediate and Delayed Mild Hypothermia in Cerebrocortical Slices after Oxygen–Glucose Deprivation

1H nuclear magnetic resonance brain metabolomics in neonatal mice after hypoxia–ischemia distinguished normothermic recovery from mild hypothermia recoveries

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