Zinc neurotoxicity is dependent on intracellular NAD levels and the sirtuin pathway.
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.
Cai
Ai-Li
AL
Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO, USA.
Zipfel
Gregory J
GJ
Sheline
Christian T
CT
D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002545:Brain Ischemia / Q000473:pathology; D002478:Cells, Cultured; D005419:Flavonoids / Q000494:pharmacology; D044948:Flavonols; D007473:Ion Channels / Q000502:physiology; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D009243:NAD / Q000378:metabolism*; D009281:Naphthalenes / Q000494:pharmacology; D009431:Neural Conduction / Q000502:physiology; D020258:Neurotoxicity Syndromes / Q000378:metabolism* / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity; D009536:Niacinamide / Q000494:pharmacology; D011725:Pyridines / Q000633:toxicity; D051381:Rats; D020318:Rats, Long-Evans; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology; D015533:Transcriptional Activation / Q000502:physiology; D015032:Zinc / Q000633:toxicity*
C482304:2-hydroxynaphthaldehyde; D000447:Aldehydes; D000975:Antioxidants; D005419:Flavonoids; D044948:Flavonols; D007473:Ion Channels; D009281:Naphthalenes; D009498:Neurotoxins; D011725:Pyridines; D013267:Stilbenes; C010835:3-acetylpyridine; D009243:NAD; D009536:Niacinamide; D037761:Sirtuins; D015032:Zinc; C017875:fisetin; D000077185:Resveratrol