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


METHODS
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.


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.


CONCLUSIONS
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.
Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy.
F
F
Moroni
L
L
Formentini
E
E
Gerace
E
E
Camaioni
D E
DE
Pellegrini-Giampietro
A
A
Chiarugi
R
R
Pellicciari
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D015687:Cell Hypoxia; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D005947:Glucose / Q000172:deficiency; D006367:HeLa Cells; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D009336:Necrosis; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000633:toxicity; D010100:Oxygen / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D046509:Tissue Culture Techniques
D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; C487881:poly(ADP-ribose)polymerase-2, rat; C459820:Parp2 protein, mouse; D005947:Glucose; D010100:Oxygen