title: Serum or target deprivation-induced neuronal death causes oxidative neuronal accumulation of Zn2+ and loss of NAD+.
abstract: Trophic deprivation-mediated neuronal death is important during development, after acute brain or nerve trauma, and in neurodegeneration. Serum deprivation (SD) approximates trophic deprivation in vitro, and an in vivo model is provided by neuronal death in the mouse dorsal lateral geniculate nucleus (LGNd) after ablation of the visual cortex (VCA). Oxidant-induced intracellular Zn(2+) release ([Zn(2+) ](i) ) from metallothionein-3 (MT-III), mitochondria or 'protein Zn(2+) ', was implicated in trophic deprivation neurotoxicity. We have previously shown that neurotoxicity of extracellular Zn(2+) required entry, increased [Zn(2+) ](i) , and reduction of NAD(+) and ATP levels causing inhibition of glycolysis and cellular metabolism. Exogenous NAD(+) and sirtuin inhibition attenuated Zn(2+) neurotoxicity. Here we show that: (1) Zn(2+) is released intracellularly after oxidant and SD injuries, and that sensitivity to these injuries is proportional to neuronal Zn(2+) content; (2) NAD(+) loss is involved - restoration of NAD(+) using exogenous NAD(+) , pyruvate or nicotinamide attenuated these injuries, and potentiation of NAD(+) loss potentiated injury; (3) neurons from genetically modified mouse strains which reduce intracellular Zn(2+) content (MT-III knockout), reduce NAD(+) catabolism (PARP-1 knockout) or increase expression of an NAD(+) synthetic enzyme (Wld(s) ) each had attenuated SD and oxidant neurotoxicities; (4) sirtuin inhibitors attenuated and sirtuin activators potentiated these neurotoxicities; (5) visual cortex ablation (VCA) induces Zn(2+) staining and death only in ipsilateral LGNd neurons, and a 1 mg/kg Zn(2+) diet attenuated injury; and finally (6) NAD(+) synthesis and levels are involved given that LGNd neuronal death after VCA was dramatically reduced in Wld(s) animals, and by intraperitoneal pyruvate or nicotinamide. Zn(2+) toxicity is involved in serum and trophic deprivation-induced neuronal death.
authors: Department of Ophthalmology and the Neuroscience Center of Excellence, LSU Health Sciences Center, 2020 Gravier Street, Suite D, New Orleans, LA 70112, USA. csheli@lsuhsc.edu
authors: Christian T
authors: CT
authors: Sheline
authors: Ai-Li
authors: AL
authors: Cai
authors: Julia
authors: J
authors: Zhu
authors: Chunxiao
authors: C
authors: Shi
mesh_terms: D000818:Animals; D002413:Cations, Divalent / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D005829:Geniculate Bodies / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009243:NAD / Q000172:deficiency*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology*; D012709:Serum Albumin / Q000172:deficiency*; D056564:Sirtuin 1 / Q000502:physiology; D015032:Zinc / Q000378:metabolism*
chemical_list: D002413:Cations, Divalent; D012709:Serum Albumin; D009243:NAD; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D015032:Zinc