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


Journal of Clinical Toxicology

Author(s): Cai AL, Zipfel GJ, Sheline CT

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Abstract Zinc neurotoxicity has been demonstrated in ischemic, seizure, hypoglycemic, and trauma-induced neuronal death where Zn(2+) is thought to be synaptically released and taken up in neighbouring neurons, reaching toxic concentrations. We previously demonstrated that toxicity of extracellular Zn(2+) depended on entry, elevation in intracellular free Zn(2+) ([Zn(2+)](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 Zn(2+) neurotoxicity, and 3-acetylpyridine, which generates inactive NAD(+), potentiated Zn(2+) neurotoxicity. Sirtinol and 2-hydroxynaphthaldehyde, inhibitors of the sirtuin pathway (SIRT proteins are NAD(+)-catabolic protein deacetylases), attenuated both acute and chronic Zn(2+) neurotoxicity. Resveratrol and fisetin (sirtuin activators) potentiated NAD(+) loss and Zn(2+) neurotoxicities. Furthermore, neuronal cultures derived from the Wld(s) mouse, which overexpress the NAD(+) synthetic enzyme nicotinamide mononucleotide adenyl transferase (NMNAT-1), had reduced sensitivity to Zn(2+) 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 Zn(2+) neurotoxicity. This article was published in Eur J Neurosci and referenced in Journal of Clinical Toxicology

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