Abstract
Oxidative stress and zinc release are both known to contribute to neuronal death after hypoglycemia; however, the cause-effect relationships between these events are not established. Here we found, using a rat model of profound hypoglycemia, that the neuronal zinc release and translocation that occur immediately after hypoglycemia are prevented by the nitric oxide synthase inhibitor 7-nitroindazole but not by overexpression of superoxide dismutase-1 (SOD-1). However, overexpression of SOD-1 prevented activation of poly(ADP-ribose) polymerase-1 (PARP-1) and neuronal death, suggesting that zinc release is upstream of superoxide production. Accordingly, zinc-induced superoxide production was blocked in neuronal cultures by the NADPH oxidase inhibitor apocynin and by genetic deficiency in the p47(phox) subunit of NADPH oxidase. A key role for the vesicular zinc pool in this process was suggested by reduced superoxide formation and neuronal death in mice deficient in zinc transporter 3. Together, these findings suggest a series of events in which nitric oxide production triggers vesicular zinc release, which in turn activates NADPH oxidase and PARP-1. This sequence may also occur in other central nervous system disorders in which zinc, nitric oxide, and oxidative stress have been linked.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Animals, Genetically Modified
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Carrier Proteins / metabolism
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Cation Transport Proteins / metabolism
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Cell Death / physiology*
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Cells, Cultured
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Enzyme Inhibitors / pharmacology
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Glucose / pharmacology
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Hypoglycemia / complications
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Hypoglycemia / metabolism
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Hypoglycemia / pathology*
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Membrane Proteins / metabolism
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Membrane Transport Proteins
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Mice
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Mice, Inbred C57BL
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Mice, Mutant Strains
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NADPH Oxidases / genetics
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NADPH Oxidases / metabolism
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Neurons / metabolism
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Neurons / pathology*
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Nitric Oxide / metabolism*
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Nitric Oxide Synthase / antagonists & inhibitors
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Nitric Oxide Synthase / metabolism
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases / metabolism
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Rats
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Rats, Sprague-Dawley
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Superoxide Dismutase / genetics
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Superoxide Dismutase / metabolism
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Superoxide Dismutase-1
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Superoxides / metabolism*
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Zinc / metabolism*
Substances
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Carrier Proteins
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Cation Transport Proteins
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Enzyme Inhibitors
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Membrane Proteins
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Membrane Transport Proteins
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Slc30a3 protein, mouse
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zinc transporter 3, rat
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Superoxides
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Nitric Oxide
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Nitric Oxide Synthase
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Sod1 protein, mouse
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Sod1 protein, rat
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Superoxide Dismutase
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Superoxide Dismutase-1
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NADPH Oxidases
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neutrophil cytosolic factor 1
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Parp1 protein, mouse
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Parp1 protein, rat
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases
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Glucose
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Zinc