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

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

Author information

1
Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy.

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.

PMID:
19422384
PMCID:
PMC2721269
DOI:
10.1111/j.1476-5381.2009.00232.x
[Indexed for MEDLINE]
Free PMC Article

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