Brain Ischemic Preconditioning Does Not Require PARP-1

Faraco, Giuseppe; Blasi, Francesco; Min, Wookee; Wang, Zhaoqi; Moroni, Flavio; Chiarugi, Alberto

doi:10.1161/strokeaha.109.567826

Cited by 8 publications

(8 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar results were obtained in an in vivo mouse model of brain ischemia and IPC. 24 Mice were exposed to diverse ischemic insults: (i) 5 min bilateral common carotid arteries were occluded (BCCAO) (preconditioning ischemia); (ii) 20 min MCAO; and (iii) IPC, that is, BCCAO followed by MCAO the next day. Ischemic areas (Figure 3a) and infarct volumes (Figure 3b) were evaluated 3 days later.…”

Section: Resultsmentioning

confidence: 99%

“…C57Bl/6 male mice (Harlan, Milan, Italy) were exposed to IPC and/or transient (20 min) MCAO as previously described. 24 For IPC, mice ( n =9) were anesthetized, and bilateral common carotid arteries were occluded (BCCAO) for 5 min with microclips. After 24 h, mice underwent 20 min MCAO as reported.…”

Section: Methodsmentioning

confidence: 99%

“…After 24 h, mice underwent 20 min MCAO as reported. 24 Parallel groups were subjected to BCCAO ( n =9) or MCAO ( n =9) alone. Infarcts were measured 3 days later to rule out transient neuroprotection.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

The acetylation of RelA in Lys310 dictates the NF-κB-dependent response in post-ischemic injury

et al. 2010

View full text Add to dashboard Cite

The activation of nuclear factor kappa B (NF-κB) p50/RelA is a key event in ischemic neuronal injury, as well as in brain ischemic tolerance. We tested whether epigenetic mechanisms affecting the acetylation state of RelA might discriminate between neuroprotective and neurotoxic activation of NF-κB during ischemia. NF-κB activation and RelA acetylation were investigated in cortices of mice subjected to preconditioning brain ischemia or lethal middle cerebral artery occlusion (MCAO) and primary cortical neurons exposed to preconditioning or lethal oxygen-glucose deprivation (OGD). In mice subjected to MCAO and in cortical neurons exposed to lethal OGD, activated RelA displayed a high level of Lys310 acetylation in spite of reduced total acetylation. Also, acetylated RelA on Lys310 interacted strongly with the CREB-binding protein (CBP). Conversely, RelA activated during preconditioning ischemia appeared deacetylated on Lys310. Overexpressing RelA increased Bim promoter activity and neuronal cell death both induced by lethal OGD, whereas overexpressing the acetylation-resistant RelA-K310R, carrying a mutation from Lys310 to arginine, prevented both responses. Pharmacological manipulation of Lys310 acetylation by the sirtuin 1 activator resveratrol repressed the activity of the Bim promoter and reduced the neuronal cell loss. We conclude that the acetylation of RelA in Lys310 dictates NF-κB-dependent pro-apoptotic responses and represents a suitable target to dissect pathological from neuroprotective NF-κB activation in brain ischemia.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

The acetylation of RelA in Lys310 dictates the NF-κB-dependent response in post-ischemic injury

et al. 2010

View full text Add to dashboard Cite

show abstract

“…30/09/2008) and the European Communities Council Directive (86/609/EEC). C57Bl/6 male mice (Harlan, Milan, Italy) were exposed to transient (20 min) MCAO as previously described [47]. Examination of infarct volume was performed in brains frozen in liquid nitrogen to avoid post-mortem changes.…”

Section: Methodsmentioning

confidence: 99%

1B/(−)IRE DMT1 Expression during Brain Ischemia Contributes to Cell Death Mediated by NF-κB/RelA Acetylation at Lys310

et al. 2012

Self Cite

View full text Add to dashboard Cite

The molecular mechanisms responsible for increasing iron and neurodegeneration in brain ischemia are an interesting area of research which could open new therapeutic approaches. Previous evidence has shown that activation of nuclear factor kappa B (NF-κB) through RelA acetylation on Lys310 is the prerequisite for p50/RelA-mediated apoptosis in cellular and animal models of brain ischemia. We hypothesized that the increase of iron through a NF-κB-regulated 1B isoform of the divalent metal transporter-1 (1B/DMT1) might contribute to post-ischemic neuronal damage. Both in mice subjected to transient middle cerebral artery occlusion (MCAO) and in neuronally differentiated SK-N-SH cells exposed to oxygen-glucose-deprivation (OGD), 1A/DMT1 was only barely expressed while the 1B/DMT1 without iron-response-element (−IRE) protein and mRNA were early up-regulated. Either OGD or over-expression of 1B/(−)IRE DMT1 isoform significantly increased iron uptake, as detected by total reflection X-ray fluorescence, and iron-dependent cell death. Iron chelation by deferoxamine treatment or (−)IRE DMT1 RNA silencing displayed significant neuroprotection against OGD which concomitantly decreased intracellular iron levels. We found evidence that 1B/(−)IRE DMT1 was a target gene for RelA activation and acetylation on Lys310 residue during ischemia. Chromatin immunoprecipitation analysis of the 1B/DMT1 promoter showed there was increased interaction with RelA and acetylation of H3 histone during OGD exposure of cortical neurons. Over-expression of wild-type RelA increased 1B/DMT1 promoter-luciferase activity, the (−)IRE DMT1 protein, as well as neuronal death. Expression of the acetylation-resistant RelA-K310R construct, which carried a mutation from lysine 310 to arginine, but not the acetyl-mimic mutant RelA-K310Q, down-regulated the 1B/DMT1 promoter, consequently offering neuroprotection. Our data showed that 1B/(−)IRE DMT1 expression and intracellular iron influx are early downstream responses to NF-κB/RelA activation and acetylation during brain ischemia and contribute to the pathogenesis of stroke-induced neuronal damage.

show abstract

“…This latter parameter is extremely important, because, most stroke patients arrive with an occluded blood vessel to the hospital, the testing of protective drugs is essential in post-treatment models, both in permanent and transient stroke experiments. The therapeutic window of intervention is substantial (up to 4-6 hours after the onset of ischemia in the middle cerebral artery ischemia-reperfusion models), as demonstrated by a variety of PARP inhibitors including nicotinamide, PJ-34, INO-1001, FR247304, DR2313, NU1025, MP-124, ONO-1294H, KCL-440 and various thienyl-isoquinolone derivatives (DAMYIQ and HYDAMTIQ) (Ducroq et al, 2000; Ayoub and Maynard, 2002; Abdelkarim et al, 2001; Ferraris et al, 2003; Komjati et al, 2004; Iwashita et al, 2004a; Iwashita et al, 2004b; Kamanaka et al, 2004; Ikeda et al, 2005; Nakajima et al, 2005; Haddad et al, 2006; Kaundal et al, 2006; Hamby et al, 2007; Haddad et al, 2008; Kauppinen et al, 2009; Faraco et al, 2010; Egi, 2011; Ikeda et al, 2011; Moroni et al, 2012; Haddad et al, 2012). The beneficial effect of PARP inhibition can be long lasting, i.e.…”

Section: Beyond Anticancer Therapy: Stroke Circulatory Shock Carmentioning

confidence: 99%

Therapeutic applications of PARP inhibitors: Anticancer therapy and beyond

Curtin

Szabó

2013

Molecular Aspects of Medicine

327

286

View full text Add to dashboard Cite

The aim of this article is to describe the current and potential clinical translation of pharmacological inhibitors of poly(ADP-ribose) polymerase (PARP) for the therapy of various diseases. The first section of the present review summarizes the available preclinical and clinical data with PARP inhibitors in various forms of cancer. In this context, the role of PARP in single-strand DNA break repair is relevant, leading to replication-associated lesions that cannot be repaired if homologous recombination (HRR) repair is defective, and the synthetic lethality of PARP inhibitors in HRR-defective cancer. HRR defects are classically associated with BRCA1 and 2 mutations associated with familial breast and ovarian cancer, but there may be many other causes of HRR defects. Thus, PARP inhibitors may be the drugs of choice for BRCA mutant breast and ovarian cancers, and extend beyond these tumors if appropriate biomarkers can be developed to identify HRR defects. Multiple lines of preclinical data demonstrate that PARP inhibition increases cytotoxicity and tumor growth delay in combination with temozolomide, topoisomerase inhibitors and ionizing radiation. Both single agent and combination clinical trials are underway. The final part of the first section of the present review summarizes the current status of the various PARP inhibitors that are in various stages of clinical development. The second section of the present review summarizes the role of PARP in selected non-oncologic indications. In a number of severe, acute diseases (such as stroke, neurotrauma, circulatory shock and acute myocardial infarction) the clinical translatability of PARP inhibition is supported by multiple lines of preclinical data, as well as observational data demonstrating PARP activation in human tissue samples. In these disease indications, PARP overactivation due to oxidative and nitrative stress drives cell necrosis and pro-inflammatory gene expression, which contributes to disease pathology. Accordingly, multiple lines of preclinical data indicate the efficacy of PARP inhibitors to preserve viable tissue and to down-regulate inflammatory responses. As the clinical trials with PARP inhibitors in various forms of cancer progress, it is hoped that a second line of clinical investigations, aimed at testing of PARP inhibitors for various non-oncologic indications, will be initiated, as well.

show abstract

Brain Ischemic Preconditioning Does Not Require PARP-1

Cited by 8 publications

References 13 publications

The acetylation of RelA in Lys310 dictates the NF-κB-dependent response in post-ischemic injury

The acetylation of RelA in Lys310 dictates the NF-κB-dependent response in post-ischemic injury

1B/(−)IRE DMT1 Expression during Brain Ischemia Contributes to Cell Death Mediated by NF-κB/RelA Acetylation at Lys310

Therapeutic applications of PARP inhibitors: Anticancer therapy and beyond

Contact Info

Product

Resources

About