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The Journal of Neuroscience, May 1, 2000, 20(9):3139-3146
Zinc-Induced Cortical Neuronal Death: Contribution of Energy Failure Attributable to Loss of NAD+ and Inhibition of Glycolysis
Christian T. Sheline, M. Margarita Behrens, and Dennis W. Choi Department of Neurology and Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri 63110
Excessive zinc influx may contribute to neuronal death after certain insults, including transient global ischemia. In light of evidence that levels of intracellular free Zn2+ 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 Zn2+ exposure. As predicted, cultures exposed for 3-22 hr to 40 µM Zn2+ 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 Zn2+ inhibition of GAPDH was raised by the observation that Zn2+ 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. Zn2+-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,
-keto butyrate, lactate, and
-hydroxy-butyrate did not attenuate Zn2+-induced neurotoxicity, perhaps because they could not regenerate NAD+ or be used for energy production in the presence of glucose.
Key words: pyruvate; niacinamide; energy depletion; PARS; ATP levels; GAPDH inhibition
Copyright © 2000 Society for Neuroscience 0270-6474/00/2093139-08$05.00/0
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