Zinc-Induced Cortical Neuronal Death: Contribution of Energy Failure Attributable to Loss of NAD+ and Inhibition of Glycolysis

• Published in: The Journal of neuroscience Vol. 20; no. 9; pp. 3139 - 3146
• Main Authors: Sheline, Christian T, Behrens, M. Margarita, Choi, Dennis W
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 01.05.2000; Society for Neuroscience
• Subjects: Animals; Cell Death - drug effects; Cell Death - physiology; Cells, Cultured - drug effects; Cerebral Cortex - drug effects; Cerebral Cortex - embryology; Cerebral Cortex - metabolism; Dihydroxyacetone Phosphate - metabolism; Glyceraldehyde-3-Phosphate Dehydrogenases - antagonists & inhibitors; Glyceraldehyde-3-Phosphate Dehydrogenases - metabolism; Glycolysis - drug effects; Glycolysis - physiology; Mice; NAD - drug effects; NAD - metabolism; Neurons - drug effects; Neurons - physiology; Niacinamide - pharmacology; Pyruvic Acid - pharmacology; Zinc - pharmacology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.20-09-03139.2000

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.