Differential Effect of PARP-2 Deletion on Brain Injury after Focal and Global Cerebral Ischemia

Abstract

Poly(ADP-ribose) polymerase-2 (PARP-2) is a member of the PARP enzyme family, and, similarly to PARP-1, catalyzes the formation of ADP-ribose polymers in response to DNA damage. While PARP-1 overactivation contributes to ischemic cell death, no information is available regarding the role of PARP-2. In this study, we evaluated the impact of PARP-2 deletion on histopathological outcome from two different experimental models of cerebral ischemia. Male PARP-2 À/À mice and wild-type (WT) littermates were subjected to either 2 h of middle cerebral artery occlusion (MCAO) followed by 22 h reperfusion, or underwent 10 mins of KCl-induced cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR) and 3-day survival. After MCAO, infarct volume was reduced in PARP-2 À/À mice (38%712% of contralateral hemisphere) compared with WT (64%716%). After CA/CPR, PARP-2 deletion significantly increased neuronal cell loss in the hippocampal CA1 field (65%736% ischemic neurons) when compared with WT mice (31%733%), with no effect in either striatum or cortex. We conclude that PARP-2 is a novel executioner of cell death pathways in focal cerebral ischemia, but might be a necessary survival factor after global ischemia to mitigate hippocampal delayed cell death.

Transcriptome profiling of the newborn mouse brain after hypoxia–reoxygenation: hyperoxic reoxygenation induces inflammatory and energy failure responsive genes

“…It is highly important to customize therapy after a hypoxia situation at birth followed by resuscitation in regard to insult severity and timing, which can be monitored both by imaging and biomarkers. The alteration of cell death pathways and response to neuroprotective strategies seem to have different effects on focal vs. global hypoxia (20), with the latter being independently able to induce oxidative injury in the cerebral cortex (21). Nevertheless, the hypoxia-reoxygenation model is a milder oxidative insult than HI, and there is evidence that this hypoxia-provoked oxidative stress can be counteracted by central nervous system protective mechanisms (22).…”

Poly(ADP-ribose) polymerase-2: emerging transcriptional roles of a DNA-repair protein

“…Depletion of PARP-2 also resulted in a protective phenotype against diseases associated with increased oxidative stress. Genetic deletion or silencing of PARP-2 has provided protection in models of focal and global cerebral ischaemia [99,100], colitis [59] and doxorubicin-induced vascular smooth muscle damage [33]. Since PARP-2 accounts for a small fraction of total cellular PARP activity [8,32,33], it is unlikely that the ablation of PARP-2 could protect against the loss of cellular NAD + and ATP suggesting different mechanisms of cell death as compared to the case of PARP-1 ablation.…”

Nuclear ADP-Ribosylation Reactions in Mammalian Cells: Where Are We Today and Where Are We Going?

“…These nonactively growing cells are therefore more sensitive to inhibition of the mitochondrial respiratory chain. The decision between cell death and survival after exposure to necrosis-inducing agents is regulated mainly by the availability of metabolic substrates and the expression levels or enzymatic activities of PARP-1 and, in part, PARP-2 (47,205,468). Thus, there is clear evidence that poly-ADP-ribosylation reactions play a central role in "programmed necrosis" pathways (47,113,449,468).…”

“…Recent studies demonstrated that the cellular metabolic status is a key factor in determining how ATP levels are affected by overstimulation of poly-ADP-ribosylation reactions (449,468). The massive generation of poly-ADP-ribose in the nucleus by overactivation of PARP-1 and, to a lesser extent, PARP-2 was suggested to preferentially deplete the nuclear and cytosolic pools of NAD ϩ but not the mitochondrial pools, thereby inhibiting glycolysis but not oxidative phosphorylation (205,468). Actively proliferating cells use glucose almost exclusively through aerobic glycolysis for the production of ATP and die from NAD ϩ and ATP depletion resulting from overactivation of poly-ADP-ribosylation.…”