Sequential release of nitric oxide, zinc, and superoxide in hypoglycemic neuronal death

J Cereb Blood Flow Metab. 2008 Oct;28(10):1697-706. doi: 10.1038/jcbfm.2008.61. Epub 2008 Jun 11.


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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Carrier Proteins / metabolism
  • Cation Transport Proteins / metabolism
  • Cell Death / physiology*
  • Cells, Cultured
  • Enzyme Inhibitors / pharmacology
  • Glucose / pharmacology
  • Hypoglycemia / complications
  • Hypoglycemia / metabolism
  • Hypoglycemia / pathology*
  • Membrane Proteins / metabolism
  • Membrane Transport Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism
  • Neurons / metabolism
  • Neurons / pathology*
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase / metabolism
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Superoxide Dismutase-1
  • Superoxides / metabolism*
  • Zinc / metabolism*


  • Carrier Proteins
  • Cation Transport Proteins
  • Enzyme Inhibitors
  • Membrane Proteins
  • Membrane Transport Proteins
  • Slc30a3 protein, mouse
  • zinc transporter 3, rat
  • Superoxides
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Sod1 protein, mouse
  • Sod1 protein, rat
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • NADPH Oxidases
  • neutrophil cytosolic factor 1
  • Parp1 protein, mouse
  • Parp1 protein, rat
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • Glucose
  • Zinc