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Zinc neurotoxicity is dependent on intracellular NAD+ levels and the sirtuin pathway

Authors

  • Ai-Li Cai,

    1. Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO, USA
    2. The Hope Center for Neurological Disorders, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA
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  • Gregory J. Zipfel,

    1. Department of Neurosurgery, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO, USA
    2. The Hope Center for Neurological Disorders, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA
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  • Christian T. Sheline

    1. Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO, USA
    2. The Hope Center for Neurological Disorders, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA
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Dr Christian T. Sheline, as above.
E-mail: shelinec@neuro.wustl.edu

Abstract

Zinc neurotoxicity has been demonstrated in ischemic, seizure, hypoglycemic, and trauma-induced neuronal death where Zn2+ is thought to be synaptically released and taken up in neighbouring neurons, reaching toxic concentrations. We previously demonstrated that toxicity of extracellular Zn2+ depended on entry, elevation in intracellular free Zn2+ ([Zn2+]i), a reduction in NAD+ and ATP levels, and dysfunction of glycolysis and cellular metabolism. We suggested that PARP-1 activation alone can not explain this loss of neuronal NAD+. NAD+ was recently demonstrated to permeate neurons and glia, and we have now shown that exogenous NAD+ can reduce Zn2+ neurotoxicity, and 3-acetylpyridine, which generates inactive NAD+, potentiated Zn2+ neurotoxicity. Sirtinol and 2-hydroxynaphthaldehyde, inhibitors of the sirtuin pathway (SIRT proteins are NAD+-catabolic protein deacetylases), attenuated both acute and chronic Zn2+ neurotoxicity. Resveratrol and fisetin (sirtuin activators) potentiated NAD+ loss and Zn2+ neurotoxicities. Furthermore, neuronal cultures derived from the Wlds mouse, which overexpress the NAD+ synthetic enzyme nicotinamide mononucleotide adenyl transferase (NMNAT-1), had reduced sensitivity to Zn2+ neurotoxicity. Finally, nicotinamide was demonstrated to attenuate CA1 neuronal death after 10 min of global ischemia in rat even if administered 1 h after the insult. Together with previous data, these results further implicate NAD+ levels in Zn2+ neurotoxicity.

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