2009
DOI: 10.1038/jcbfm.2009.9
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Inhibition of Poly(ADP-Ribose) Polymerase Suppresses Inflammation and Promotes Recovery after Ischemic Injury

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-jB and required for NF-jB-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-… Show more

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Cited by 78 publications
(62 citation statements)
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“…Genetic inhibition of the canonical NF-κB pathway specifically in neurons has shown protective effect in focal ischemia models [37,38], and therefore, the neuroprotective effect seen in this study was likely due to direct modulation of cell death/survival pathways in neurons as suggested previously [23][24][25]. However, the inflammatory response can exacerbate neuronal death in the hippocampus [6][7][8][9]. Microglia undergoing the socalled M1-type pro-inflammatory activation can produce a number of cytotoxic mediators [39], and it has also been recently shown that microglia can phagocytose otherwise viable neurons and thus promote delayed neuronal death [10].…”
Section: Discussionmentioning
confidence: 53%
“…Genetic inhibition of the canonical NF-κB pathway specifically in neurons has shown protective effect in focal ischemia models [37,38], and therefore, the neuroprotective effect seen in this study was likely due to direct modulation of cell death/survival pathways in neurons as suggested previously [23][24][25]. However, the inflammatory response can exacerbate neuronal death in the hippocampus [6][7][8][9]. Microglia undergoing the socalled M1-type pro-inflammatory activation can produce a number of cytotoxic mediators [39], and it has also been recently shown that microglia can phagocytose otherwise viable neurons and thus promote delayed neuronal death [10].…”
Section: Discussionmentioning
confidence: 53%
“…221 Several studies using animal models have shown a reduction in poststroke microglial activation by acute administration of PARP inhibitors, 222,223 but this anti-inflammatory effect is difficult to interpret, given that acute administration of PARP inhibitors also has a neuroprotective effect 224 -226 that could independently reduce the subsequent inflammatory response. Nonetheless, PARP-1 inhibition begun 2 days after ischemia to selectively target the inflammatory response also reduced microglial activation and improved long-term outcomes, 227 suggesting a direct effect on poststroke inflammation in vivo.…”
Section: Other Factors That Influence Proinflammatory Gene Transcriptionmentioning
confidence: 95%
“…This type of cell death by PARP-1 activation, termed "parthanatos," (19) has been implicated as an important mediator of various central nervous system (CNS) disorders (20). Therefore, several studies have examined PARP-1 as a target for therapeutic intervention (21)(22)(23)(24), and PARP-1 inhibitors are currently the focus of several clinical trials (25).…”
mentioning
confidence: 99%