Selective PARP-2 inhibitors increase apoptosis in hippocampal slices but protect cortical cells in models of post-ischaemic brain damage

Br J Pharmacol. 2009 Jul;157(5):854-62. doi: 10.1111/j.1476-5381.2009.00232.x. Epub 2009 May 5.

Abstract

Background and purpose: Poly(ADP-ribose) polymerases (PARP)-1 and PARP-2 play complementary tasks in the maintenance of genomic integrity, but their role in cell death or survival processes is rather different. A recently described series of selective PARP-2 inhibitors (UPF-1035, UPF-1069) were used to study the role of PARP-1 and PARP-2 in post-ischaemic brain damage.

Experimental approach: We evaluated post-ischaemic brain damage in two different in vitro models: rat organotypic hippocampal slices exposed to oxygen-glucose deprivation (OGD) for 20-30 min, a model characterized by apoptosis-like cell death and mouse mixed cortical cell cultures exposed to 60 min OGD, a model in which cells die with mostly necrosis-like features.

Key results: In organotypic hippocampal slices, PARP-2 inhibition with UPF-1069 (0.01-1 micromolxL(-1)) caused a concentration-dependent exacerbation (up to 155%) of OGD-induced CA1 pyramidal cell death. Higher concentrations, acting on both PARP-1 and PARP-2, had no effect on OGD injury. In mouse mixed cortical cells exposed to OGD, on the contrary, UPF-1069 (1-10 micromolxL(-1)) significantly reduced post-ischaemic damage.

Conclusion and implications: Selective PARP-2 inhibitors increased post-OGD cell death in a model characterized by loss of neurons through a caspase-dependent, apoptosis-like process (hippocampal slice cultures), but they reduced post-OGD damage and increased cell survival in a model characterized by a necrosis-like process (cortical neurons). UPF-1069 may be a valuable tool to explore the function of PARP-2 in biological systems and to examine the different roles of PARP isoenzymes in the mechanisms of cell death and survival.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / enzymology
  • Brain Ischemia / pathology
  • Cell Hypoxia
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / enzymology
  • Cerebral Cortex / pathology
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / toxicity
  • Glucose / deficiency
  • HeLa Cells
  • Hippocampus / drug effects*
  • Hippocampus / enzymology
  • Hippocampus / pathology
  • Humans
  • Male
  • Mice
  • Mitosis / drug effects
  • Necrosis
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / toxicity
  • Oxygen / metabolism
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / enzymology
  • Pyramidal Cells / pathology
  • Rats
  • Rats, Wistar
  • Time Factors
  • Tissue Culture Techniques

Substances

  • Enzyme Inhibitors
  • Neuroprotective Agents
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Poly(ADP-ribose) Polymerases
  • poly(ADP-ribose)polymerase-2, rat
  • Parp2 protein, mouse
  • Glucose
  • Oxygen