Iodoacetate protects hippocampal neurons against excitotoxic and oxidative injury: involvement of heat-shock proteins and Bcl-2

Authors

  • Zhihong Guo,

    1. Laboratory of Neurosciences, National Institute on Aging–Gerontology Research Center, Baltimore, Maryland, USA
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  • Jaewon Lee,

    1. Laboratory of Neurosciences, National Institute on Aging–Gerontology Research Center, Baltimore, Maryland, USA
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  • Mark Lane,

    1. Laboratory of Neurosciences, National Institute on Aging–Gerontology Research Center, Baltimore, Maryland, USA
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  • Mark P. Mattson

    1. Laboratory of Neurosciences, National Institute on Aging–Gerontology Research Center, Baltimore, Maryland, USA
    2. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Address correspondence and reprint requests to M. P. Mattson, Laboratory of Neurosciences, National Institute on Aging, GRC 4F01, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA. E-mail: mattsonm@grc.nia.nih.gov

Abstract

Mild metabolic stress may increase resistance of neurons in the brain to subsequent, more severe insults, as demonstrated by the ability of ischemic pre-conditioning and dietary restriction to protect neurons in experimental models of stroke- and age-related neurodegenerative disorders. In the present study we employed iodoacetic acid (IAA), an inhibitor of glyceraldehyde-3-phosphate dehydrogenase, to test the hypothesis that inhibition of glycolysis can protect neurons. Pre-treatment of cultured hippocampal neurons with IAA can protect them against cell death induced by glutamate, iron and trophic factor withdrawal. Surprisingly, protection occurred with concentrations of IAA (2–200 nm) much lower than those required to inhibit glycolysis. Pre-treatment with IAA results in suppression of oxyradical production and stabilization of mitochondrial function in neurons after exposure to oxidative insults. Levels of the stress heat-shock proteins HSP70 and HSP90, and of the anti-apoptotic protein Bcl-2, were increased in neurons exposed to IAA. Our data demonstrate that IAA can stimulate cytoprotective mechanisms within neurons, and suggest the possible use of IAA and related compounds in the prevention and/or treatment of neurodegenerative conditions.

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