Trophic deprivation mediated neuronal death is important during development, acute brain or nerve trauma, and neurodegeneration. Serum deprivation (SD) approximates trophic deprivation in vitro, and an in vivo model is 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 previously showed that neurotoxicity of extracellular Zn 2+ required entry, elevation in [Zn 2+ ] i , 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 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) VCA induces Zn 2+ staining and death only in ipsilateral LGNd neurons, and a 1ppm Zn 2+ diet attenuated injury; 6) Finally, NAD + synthesis and levels are involved because 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.
Keywordsvisual cortex ablation; mouse; pyruvate; sirtuin; dorsal lateral geniculate nucleus Target deprivation mediated neuronal death plays a large role during development, trauma, and neurodegeneration. In the developing nervous system, 20-80% of all neurons produced during embryogenesis die before reaching adulthood as a result of competition between neurons for innervation of their targets. This results in matching of the size of the target cell population with the number of innervating neurons (Oppenheim, 1991;Purves et al., 1988). Target deprivation mediated neuronal death is apoptotic and occurs by programmed cell death (PCD) (Deshmukh & Johnson, 1997;Martin et al., 1998). PCD is required for the * corresponding author, FAX: (504) 568-5801, telephone: (504) 599-0880, csheli@lsuhsc.edu.
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Author ManuscriptEur J Neurosci. Author manuscript; available in PMC 2011 September 1. Serum Deprivation Models Target Deprivation, and Both Induce an
Oxidative InjuryWe and others have shown that serum deprivation (SD) induces substantial oxidative stress leading to partial ATP depletion, K + loss involving inhibition of the Na + /K + ATPase, and the apoptotic cascade . We...