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: 5.41). 02/2009; 29(4):820-9. DOI: 10.1038/jcbfm.2009.9
Source: PubMed


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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Available from: Aaron Hamby, Oct 28, 2015
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    • "The cytotoxic properties of inflammation after brain ischemia have been well documented; we and other groups have shown that Hsp70 can protect by inhibiting various inflammatory mediators (Zheng et al., 2008; Wang et al., 2009; Kauppinen et al., 2009). Earlier studies from our lab indicate that overexpression of Hsp70 decreases infarct sizes in a middle cerebral artery Fig. 1. "
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    ABSTRACT: Inflammation is an important event in ischemic injury. These immune responses begin with the expression of pro-inflammatory genes modulating transcription factors, such as nuclear factor-κB (NF-κB), activator protein-1 (AP-1), and signal transducers and activator of transcription-1 (STAT-1). The 70-kDa heat shock protein (Hsp70) can both induce and arrest inflammatory reactions and lead to improved neurological outcome in experimental brain injury and ischemia. Since Hsp70 are induced under heat stress, we investigated the link between Hsp70 neuroprotection and phosphorylation of inhibitor of κB (IκB), c-Jun N-terminal kinases (JNK) and p38 through co-immunoprecipitation and ELISA assay. Transcription factors and pro-inflammatory genes were quantified by immunoblotting, EMSA and RT-PCR assays. The results showed that heat stress led to Hsp70 overexpression which rendered neuroprotection after ischemia-like injury. Overexpression Hsp70 also interrupts the phosphorylation of IκB, JNK and p38 and blunts DNA binding of their transcription factors (NF-κB, AP-1 and STAT-1), effectively downregulating the expression of pro-inflammatory genes in heat-pretreated astrocytes. Taken together, these results suggest that overexpression of Hsp70 may protect against brain ischemia via an anti-inflammatory mechanism by interrupting the phosphorylation of upstream of transcription factors. Copyright © 2014. Published by Elsevier Ltd.
    Neuroscience 12/2014; 286. DOI:10.1016/j.neuroscience.2014.11.057 · 3.36 Impact Factor
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    • "Such early ROS generation could be sufficient to boost AQP4 expression via unspecified oxidative transcription factors, while also initiating nuclear DNA fragmentation and thus enhancing upregulation of PARP-1. Repetitive binges would greatly augment these events, leading to astroglial swelling-related activation/expression of cPLA2 and sPLA2, which evoke excessive AA mobilization, loss of endogenous DHA turnover due to decreased iPLA2, and greater increases in neuron-damaging ROS levels, concomitant with PAR-mediated glial activation [54] and associated parthanatos. "
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    ABSTRACT: Evidence that brain edema and aquaporin-4 (AQP4) water channels have roles in experimental binge ethanol-induced neurodegeneration has stimulated interest in swelling/edema-linked neuroinflammatory pathways leading to oxidative stress. We report here that neurotoxic binge ethanol exposure produces comparable significant effects in vivo and in vitro on adult rat brain levels of AQP4 as well as neuroinflammation-linked enzymes: key phospholipase A2 (PLA2) family members and poly (ADP-ribose) polymerase-1 (PARP-1). In adult male rats, repetitive ethanol intoxication (3 gavages/d for 4 d, ∼9 g/kg/d, achieving blood ethanol levels ∼375 mg/dl; "Majchrowicz" model) significantly increased AQP4, Ca+2-dependent PLA2 GIVA (cPLA2), phospho-cPLA2 GIVA (p-cPLA2), secretory PLA2 GIIA (sPLA2) and PARP-1 in regions incurring extensive neurodegeneration in this model-hippocampus, entorhinal cortex, and olfactory bulb-but not in two regions typically lacking neurodamage, frontal cortex and cerebellum. Also, ethanol reduced hippocampal Ca+2-independent PLA2 GVIA (iPLA2) levels and increased brain "oxidative stress footprints" (4-hydroxynonenal-adducted proteins). For in vitro studies, organotypic cultures of rat hippocampal-entorhinocortical slices of adult age (∼60 d) were ethanol-binged (100 mM or ∼450 mg/dl) for 4 d, which augments AQP4 and causes neurodegeneration (Collins et al. 2013). Reproducing the in vivo results, cPLA2, p-cPLA2, sPLA2 and PARP-1 were significantly elevated while iPLA2 was decreased. Furthermore, supplementation with docosahexaenoic acid (DHA; 22:6n-3), known to quell AQP4 and neurodegeneration in ethanol-treated slices, blocked PARP-1 and PLA2 changes while counteracting endogenous DHA reduction and increases in oxidative stress footprints (3-nitrotyrosinated proteins). Notably, the PARP-1 inhibitor PJ-34 suppressed binge ethanol-dependent neurodegeneration, indicating PARP upstream involvement. The results with corresponding models support involvement of AQP4- and PLA2-associated neuroinflammatory pro-oxidative pathways in the neurodamage, with potential regulation by PARP-1 as well. Furthermore, DHA emerges as an effective inhibitor of these binge ethanol-dependent neuroinflammatory pathways as well as associated neurodegeneration in adult-age brain.
    PLoS ONE 07/2014; 9(7):e101223. DOI:10.1371/journal.pone.0101223 · 3.23 Impact Factor
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    • "In addition, recent studies have clearly demonstrated the role of PARP activation in various forms of local inflammation [36-38]. Information about the role of PARP3 in CP is sparse; however, it has been shown that other members of the PARP family, such as PARP1, coactivate the transcription factor nuclear factor κB (NF-κB) and is required for NF-κB-mediated inflammatory responses [39]. CP is characterized by pancreatic inflammation, thus PARP3 might potentially play a role in its inflammatory processes. "
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    ABSTRACT: Background Diagnosis at an early stage of chronic pancreatitis (CP) is challenging. It has been reported that microRNAs (miRNAs) are increasingly found and applied as targets for the diagnosis and treatment of various cancers. However, to the best of our knowledge, few published papers have described the role of miRNAs in the diagnosis of CP. Method We downloaded gene expression profile data from the Gene Expression Omnibus and identified differentially expressed genes (DEGs) between CP and normal samples of Harlan mice and Jackson Laboratory mice. Common DEGs were filtered out, and the semantic similarities of gene classes were calculated using the GOSemSim software package. The gene class with the highest functional consistency was selected, and then the Lists2Networks web-based system was used to analyse regulatory relationships between miRNAs and gene classes. The functional enrichment of the gene classes was assessed based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway annotation terms. Results A total of 405 common upregulated DEGs and 7 common downregulated DEGs were extracted from the two kinds of mice. Gene cluster D was selected from the common upregulated DEGs because it had the highest semantic similarity. miRNA 124a (miR-124a) was found to have a significant regulatory relationship with cluster D, and DEGs such as CHSY1 and ABCC4 were found to be regulated by miR-124a. The GO term of response to DNA damage stimulus and the pathway of Escherichia coli infection were significantly enriched in cluster D. Conclusion DNA damage and E. coli infection might play important roles in CP pathogenesis. In addition, miR-124a might be a potential target for the diagnosis and treatment of CP.
    European journal of medical research 05/2014; 19(1):31. DOI:10.1186/2047-783X-19-31 · 1.50 Impact Factor
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