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Selective PARP‐2 inhibitors increase apoptosis in hippocampal slices but protect cortical cells in models of post‐ischaemic brain damage
Author(s) -
Moroni F,
Formentini L,
Gerace E,
Camaioni E,
PellegriniGiampietro D E,
Chiarugi A,
Pellicciari R
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00232.x
Subject(s) - poly adp ribose polymerase , hippocampal formation , programmed cell death , apoptosis , necrosis , biology , dna damage , microbiology and biotechnology , neuroscience , biochemistry , genetics , polymerase , dna
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 µmol·L −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 µmol·L −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.