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Molecular Medicine

, Volume 13, Issue 7–8, pp 344–349 | Cite as

Zinc Inhibits Astrocyte Glutamate Uptake by Activation of Poly(ADP-ribose) Polymerase-1

  • Sang Won Suh
  • Koji Aoyama
  • Conrad C. Alano
  • Christopher M. Anderson
  • Aaron M. Hamby
  • Raymond A. Swanson
Proceedings

Abstract

Several processes by which astrocytes protect neurons during ischemia are now well established. However, less is known about how neurons themselves may influence these processes. Neurons release zinc (Zn2+) from presynaptic terminals during ischemia, seizure, head trauma, and hypoglycemia, and modulate postsynaptic neuronal function. Peak extracellular zinc may reach concentrations as high as 400 µM. Excessive levels of free, ionic zinc can initiate DNA damage and the subsequent activation of poly(ADP-ribose) polymerase 1 (PARP-1), which in turn lead to NAD+ and ATP depletion when DNA damage is extensive. In this study, cultured cortical astrocytes were used to explore the effects of zinc on astrocyte glutamate uptake, an energy-dependent process that is critical for neuron survival. Astrocytes incubated with 100 or 400 µM of zinc for 30 min showed significant decreases in ATP levels and glutamate uptake capacity. These changes were prevented by the PARP inhibitors benzamide or DPQ (3,4-dihydro-5-(4-(1-piperidinyl)butoxyl)-1(2H)-isoquinolinone) or PARP-1 gene deletion (PARP-1 KO). These findings suggest that release of Zn2+ from neurons during brain insults could induce PARP-1 activation in astrocytes, leading to impaired glutamate uptake and exacerbation of neuronal injury.

Notes

Acknowledgments

This work was supported by the Department of Veterans Affairs and by the National Institutes of Health grant RO1 NS41421 (R.A.S.). We thank Elizabeth Gum, Jennifer Bergher, and Jillian Silva for expert technical assistance.

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Copyright information

© Feinstein Institute for Medical Research 2007

Authors and Affiliations

  • Sang Won Suh
    • 1
    • 2
  • Koji Aoyama
    • 1
    • 2
  • Conrad C. Alano
    • 1
    • 2
  • Christopher M. Anderson
    • 1
    • 2
  • Aaron M. Hamby
    • 1
    • 2
  • Raymond A. Swanson
    • 1
    • 2
  1. 1.Department of Neurology (127)University of CaliforniaSan FranciscoUSA
  2. 2.Department of Neurology (127)Veterans Affairs Medical CenterSan FranciscoUSA

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