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Zeng J, Yang GY, Ying W, Kelly M, Hirai K, James TL, Swanson RA, Litt L: Pyruvate improves recovery after PARP-1-associated energy failure induced by oxidative stress in neonatal rat cerebrocortical slices. J Cereb Blood Flow Metab. 2007 Feb;27(2):304-15. Epub 2006 May 24.
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 H (2) O (2) exposure to activate PARP-1. H (2) O (2) 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 (31) P nuclear magnetic resonance spectroscopy. Just after H (2) O (2) exposure, ATP and NAD (+) decreased by approximately 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 H (2) O (2). 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 [(1) H-(13) C] HSQC spectra showed metabolism during recovery of (13) C 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. |
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