title: Zinc-induced cortical neuronal death: contribution of energy failure attributable to loss of NAD(+) and inhibition of glycolysis.
abstract: Excessive zinc influx may contribute to neuronal death after certain insults, including transient global ischemia. In light of evidence that levels of intracellular free Zn(2+) associated with neurotoxicity may be sufficient to inhibit glyceraldehyde-3-phosphate dehydrogenase (GAPDH), experiments were performed looking for reduced glycolysis and energy failure in cultured mouse cortical neurons subjected to lethal Zn(2+) exposure. As predicted, cultures exposed for 3-22 hr to 40 mixroM Zn(2+) developed an early increase in levels of dihydroxy-acetone phosphate (DHAP) and fructose 1,6-bisphosphate (FBP) and a progressive loss of ATP levels, followed by neuronal cell death; furthermore, addition of the downstream glycolytic substrate pyruvate to the bathing medium attenuated the fall in ATP and neuronal death. However, an alternative to direct Zn(2+) inhibition of GAPDH was raised by the observation that Zn(2+) exposure also induced an early decrease in nicotinamide-adenine dinucleotide (NAD(+)) levels, an event itself capable of inhibiting GAPDH. Favoring this indirect mechanism of GAPDH inhibition, the neuroprotective effects of pyruvate addition were associated with normalization of cellular levels of NAD(+), DHAP, and FBP. Zn(2+)-induced neuronal death was also attenuated by addition of the energy substrate oxaloacetate, the activator of pyruvate dehydrogenase, dichloroacetate, or the inhibitors of NAD(+) catabolism, niacinamide or benzamide. Acetyl carnitine, alpha-keto butyrate, lactate, and beta-hydroxy-butyrate did not attenuate Zn(2+)-induced neurotoxicity, perhaps because they could not regenerate NAD(+) or be used for energy production in the presence of glucose.
authors.affiliation: Department of Neurology and Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: C T
authors.initials: CT
authors.lastname: Sheline
authors.forename: M M
authors.initials: MM
authors.lastname: Behrens
authors.forename: D W
authors.initials: DW
authors.lastname: Choi
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D004099:Dihydroxyacetone Phosphate / Q000378:metabolism; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D009243:NAD / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009536:Niacinamide / Q000494:pharmacology; D019289:Pyruvic Acid / Q000494:pharmacology; D015032:Zinc / Q000494:pharmacology*
chemical_list: D009243:NAD; D009536:Niacinamide; D004099:Dihydroxyacetone Phosphate; D019289:Pyruvic Acid; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D015032:Zinc