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Selective PARP-2 Inhibitors Increase Apoptosis in Hippocampal Slices but Protect Cortical Cells in Models of Post-Ischaemic Brain Damage

Selective PARP-2 Inhibitors Increase Apoptosis in Hippocampal Slices but Protect Cortical Cells in Models of Post-Ischaemic Brain Damage

F Moroni, L Formentini, E Gerace, E Camaioni, D E Pellegrini-Giampietro, A Chiarugi, R Pellicciari

Br J Pharmacol. 2009 Jul;157(5):854-62.

PMID: 19422384

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4242025	UPF-1069			Price

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