Inhibition of poly(ADP-ribose) polymerase suppresses inflammation and promotes recovery after ischemic injury.

Department of Neurology, University of California San Francisco, San Francisco, California 94121, USA.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism (Impact Factor: 5.46). 02/2009; 29(4):820-9. DOI:10.1038/jcbfm.2009.9
Source: PubMed

ABSTRACT The brain inflammatory response induced by stroke contributes to cell death and impairs neurogenesis. Poly(ADP-ribose) polymerase-1 (PARP-1) is a coactivator of the transcription factor NF-kappaB and required for NF-kappaB-mediated inflammatory responses. Here we evaluated PARP inhibition as a means of suppressing post-stroke inflammation and improving outcome after stroke. Rats were subjected to bilateral carotid occlusion-reperfusion, and treatment with the PARP inhibitor N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide (PJ34) was begun 48 h later. PJ34 was found to rapidly suppress the ischemia-induced microglial activation and astrogliosis. Behavioral tests performed 6 to 8 weeks after ischemia showed deficits in spatial memory and learning that were lessened by the PJ34 treatment. Immunohistochemical evaluation of hippocampus at 8 weeks after ischemia showed increased neuronal density in CA1 layer of PJ34-treated animals relative to vehicle-treated animals. Bromodeoxyuridine labeling showed formation of new neurons in hippocampal CA1 area in PJ34-treated animals, but not in vehicle-treated animals. Together, these results suggest that treatment with a PARP inhibitor for several days after ischemia enhances long-term neuronal survival and neurogenesis by reducing inflammation.

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    ABSTRACT: BACKGROUND AND PURPOSE: Ischemic/reperfusion neuronal injury is characterized by accumulation of reactive oxygen species and oxidative DNA damage, which can trigger cell death by various signaling pathways. Two of these modes of death include poly(ADP-ribose) polymerase 1-mediated death or p53- and Bax-mediated apoptosis. The present study tested the hypothesis that peroxiredoxin 2 (PRX2) attenuates DNA damage-mediated prodeath signaling using in vitro and in vivo models of ischemic injury. The impact of this peroxide scavenger on p53- and poly(ADP-ribose) polymerase 1-mediated ischemic death is unknown. METHODS: Neuronal PRX2 overexpression in primary cortical cultures and transgenic mice was combined with the poly(ADP-ribose) polymerase 1 inhibitor AG14361. AG14361 was also applied to p53 and Bax knockout cultures and mice and combined with the JNK inhibitor SP600125. DCF fluorescence, apurinic/apyrimidinic sites, single-strand breaks, Comet tail-length, nicotinamide adenine dinucleotide depletion, and viability were assessed in response to oxygen-glucose deprivation in cultures or transient focal cerebral ischemia in mice. RESULTS: PRX2 attenuated reactive oxygen species, DNA damage, nicotinamide adenine dinucleotide depletion, and cell death. PRX2 knockdown exacerbated neuronal death after oxygen and glucose deprivation. PRX2 ameliorated poly(ADP-ribose) polymerase 1, p53, Bax, and caspase activation after ischemia. AG14361 reduced ischemic cell death in wild-type and p53 or Bax knockout cultures and animals but had no additional effect in PRX2-overexpressing mice. AG14361 and p53 knockout elicited additive effects with SP600125 on viability in vitro. Our findings support the existence of multiple parallel prodeath pathways with some crosstalk. CONCLUSIONS: The promising therapeutic candidate PRX2 can clamp upstream DNA damage and efficiently inhibit multiple prodeath cascades operating in both parallel and interactive fashions.
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