The role of PARP activation in glutamate-induced necroptosis in HT-22 cells

Brain Res. 2010 Jul 9;1343:206-12. doi: 10.1016/j.brainres.2010.04.080. Epub 2010 May 6.

Abstract

Oxidative cell death contributes to neuronal cell death in many neurological diseases such as stroke, brain trauma, and Alzheimer's disease. In this study, we explored the involvement of poly(ADP-ribose)-polymerase (PARP) in oxidative stress-induced necroptosis. We showed that PJ34, a potent and specific inhibitor of PARP, can completely inhibit glutamate-induced necroptosis in HT-22 cells. This protective effect was still observed 8h after glutamate exposure followed by PJ34 treatment. These results suggest that PARP activation plays a critical role in glutamate-induced necroptosis. We also examined the interaction between PARP and a necroptosis inhibitor called necrostatin-1 (Nec-1). Previously, we showed that Nec-1 protects against glutamate-induced oxytosis by inhibiting the translocation of cellular apoptosis-inducing factor (AIF), a downstream target of PARP-1 activation. In this study, Nec-1 reduced PARP activity but had no effect on the expression of PARP-1 in cells treated with glutamate. Nec-1 also did not protect against cell death mediated by the PARP activator N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), although PJ34 did protect against MNNG-mediated cell death. These findings suggest that Nec-1 is not a direct PARP inhibitor and that its signaling target is located upstream of PARP.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Apoptosis Inducing Factor / metabolism
  • Cell Line, Transformed
  • Enzyme Inhibitors / pharmacology
  • Glutamic Acid / metabolism*
  • Glutamic Acid / toxicity
  • Imidazoles / pharmacology
  • Indoles / pharmacology
  • Methylnitronitrosoguanidine / pharmacology
  • Mice
  • Necrosis
  • Nerve Degeneration / metabolism*
  • Nerve Degeneration / pathology*
  • Neurotoxins / metabolism
  • Neurotoxins / toxicity
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology*
  • Phenanthrenes / pharmacology
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Poly(ADP-ribose) Polymerases / physiology

Substances

  • Apoptosis Inducing Factor
  • Enzyme Inhibitors
  • Imidazoles
  • Indoles
  • N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
  • Neurotoxins
  • Phenanthrenes
  • Poly(ADP-ribose) Polymerase Inhibitors
  • necrostatin-1
  • Methylnitronitrosoguanidine
  • Glutamic Acid
  • Parp1 protein, mouse
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases