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Serum or target deprivation‐induced neuronal death causes oxidative neuronal accumulation of Zn 2+ and loss of NAD +
Author(s) -
Sheline Christian T.,
Cai AiLi,
Zhu Julia,
Shi Chunxiao
Publication year - 2010
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2010.07372.x
Subject(s) - nad+ kinase , neurotoxicity , nicotinamide adenine dinucleotide , neurodegeneration , programmed cell death , intracellular , sirtuin 1 , biology , neuroprotection , biochemistry , sirtuin , chemistry , microbiology and biotechnology , medicine , pharmacology , downregulation and upregulation , enzyme , apoptosis , toxicity , disease , gene
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.