Pyruvate improves recovery after PARP-1-associated energy failure induced by oxidative stress in neonatal rat cerebrocortical slices

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Abstract

Previous neuron and glial cell culture studies of excessive poly (ADP-ribose) polymerase (PARP-1) activation found NAD+ depletion, glycolytic arrest, and cell death that could be avoided by exogenous tricarboxylic acid cycle (TCA) metabolites, especially pyruvate (pyr). Pyruvate neuroprotection has been attributed to cytosolic NAD+ replenishment, TCA metabolism, and antioxidant activity. We investigated the first two mechanisms in respiring cerebrocortical slices after a 1-h H2O 2 exposure to activate PARP-1. H2O2 was followed by a 4-h recovery with oxy-artificial cerebrospinal fluid superfusion having either: (1) no glucose (glc) or pyruvate; (2) 10 mmol/L glc only; (3) 10 mmol/L pyruvate only; (4) both 10 mmol/L glc and 10 mmol/L pyruvate. Poly-ADP-ribosylation was quantified from Western blots and immunohistochemistry. Perchloric acid extracts were quantified with 14.1 T 31P nuclear magnetic resonance spectroscopy. Just after H 2O2 exposure, ATP and NAD+ decreased by ≈50%, PCr decreased by 75%, and the ADP/ATP ratio approximately doubled. ATP and NAD+ changes, but not PCr changes, were nearly eliminated if PARP inhibitors accompanied the H2O2. Recovery with both pyruvate and glc was better than with glc alone, having higher ATP (0.161 versus 0.075, P<0.01) and PCr levels (0.144 versus 0.078, P<0.01), and higher viable cell counts in TUNEL and Fluoro-Jade B staining. Two-dimensional [ 1H-13C] HSQC spectra showed metabolism during recovery of 13C glc or pyr. Pyruvate metabolism was primarily via pyruvate dehydrogenase, with some via pyruvate carboxylation. Pyruvate superfusion of PARP-injured brain slices helps replenish NAD+ while providing metabolic fuel. Although this augments recovery, a strong antioxidant role for pyruvate has not been ruled out. © 2007 ISCBFM All rights reserved.

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CITATION STYLE

APA

Zeng, J., Yang, G. Y., Ying, W., Kelly, M., Hirai, K., James, T. L., … Litt, L. (2007). Pyruvate improves recovery after PARP-1-associated energy failure induced by oxidative stress in neonatal rat cerebrocortical slices. Journal of Cerebral Blood Flow and Metabolism, 27(2), 304–315. https://doi.org/10.1038/sj.jcbfm.9600335

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