Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.4.2.30 (PARP)
13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Poly(ADP-ribose) polymerases (PARPs) are members of a family of enzymes that utilize nicotinamide adenine dinucleotide (NAD(+)) as substrate to form large ADP-ribose polymers (PAR) in the nucleus. PAR has a very short half-life due to its rapid degradation by poly(ADP-ribose) glycohydrolase (PARG). PARP-1 mediates acute neuronal cell death induced by a variety of insults including cerebral ischemia, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism, and CNS trauma. While PARP-1 is localized to the nucleus, PARG resides in both the nucleus and cytoplasm. Surprisingly, there appears to be only one gene encoding PARG activity, which has been characterized in vitro to generate different splice variants, in contrast to the growing family of PARPs. Little is known regarding the spatial and functional relationships of PARG and PARP-1. Here we evaluate PARG expression in the brain and its cellular and subcellular distribution in relation to PARP-1. Anti-PARG (alpha-PARG) antibodies raised in rabbits using a purified 30 kDa C-terminal fragment of murine PARG recognize a single band at 111 kDa in the brain. Western blot analysis also shows that PARG and PARP-1 are evenly distributed throughout the brain. Immunohistochemical studies using alpha-PARG antibodies reveal punctate cytosolic staining, whereas anti-PARP-1 (alpha-PARP-1) antibodies demonstrate nuclear staining. PARG is enriched in the mitochondrial fraction together with manganese superoxide dismutase (MnSOD) and cytochrome C (Cyt C) following whole brain subcellular fractionation and Western blot analysis. Confocal microscopy confirms the co-localization of PARG and Cyt C. Finally, PARG translocation to the nucleus is triggered by NMDA-induced PARP-1 activation. Therefore, the subcellular segregation of PARG in the mitochondria and PARP-1 in the nucleus suggests that PARG translocation is necessary for their functional interaction. This translocation is PARP-1 dependent, further demonstrating a functional interaction of PARP-1 and PARG in the brain.
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PMID:Spatial and functional relationship between poly(ADP-ribose) polymerase-1 and poly(ADP-ribose) glycohydrolase in the brain. 1764 Aug 16

Hemorrhagic transformation is an aggravating event that occurs in 15 to 43% of patients suffering from ischemic stroke. This phenomenon due to blood-brain barrier breakdown appears to be mediated in part by matrix metalloproteinases (MMPs) among which MMP-2 and MMP-9 could be particularly involved. Recent experimental studies demonstrated that post-ischemic MMP-9 overexpression is regulated by poly(ADP-ribose)polymerase (PARP). In this context, our study aimed to evaluate the effect of PJ34 (N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-2-(N,N-dimethylamino)acetamide), a potent PARP inhibitor, on MMP-2 and MMP-9 levels and on hemorrhagic transformations in a model of permanent focal cerebral ischemia in mice. PJ34 (6.25-12.5 mg/kg, i.p.) was given at the time of ischemia onset and 4 h later. Hemorrhagic transformations, divided into microscopic and macroscopic hemorrhages, were counted 48 h after ischemia on 12 coronal brain slices. Microscopic and macroscopic hemorrhages were respectively reduced by 38% and 69% with 6.25 mg/kg PJ34. The anti-hemorrhagic effect of PJ34 was associated with a 57% decrease in MMP-9 overexpression assessed by gelatin zymography. No increase in MMP-2 activity was observed after ischemia in our model. The vascular protection achieved by PJ34 was associated with a reduction in the motor deficit (P<0.05) and in infarct volume (-31%, P<0.01). In conclusion, our study demonstrates for the first time that PJ34 reduces hemorrhagic transformations after cerebral ischemia. Thus this PARP inhibitor exhibits both anti-hemorrhagic and neuroprotective effects that may be of valuable interest for the treatment of stroke.
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PMID:Reduction of hemorrhagic transformation by PJ34, a poly(ADP-ribose)polymerase inhibitor, after permanent focal cerebral ischemia in mice. 1846 97

Pinocembrin is one of the flavonoids at the highest concentration in propolis. In this study, we investigated the neuroprotective effect of pinocembrin on ischemia/reperfusion and ischemia/reperfusion-like insults. Protection by pinocembrin was studied at the in vivo level using a model of middle cerebral artery occlusion and reperfusion in rats. Pinocembrin was administrated at the start of reperfusion. Pinocembrin markedly increased rat viability, reduced infarct volumes and neurological deficit scores in all treatment groups. Primary cortical neuronal cultures were subjected to oxygen-glucose deprivation/reoxygenation, a model of ischemia/reperfusion-like injury, and treated with pinocembrin at the start of reoxygenation. Neuronal survival rates were increased, LDH release was decreased and both neurite length and apoptosis were alleviated when pinocembrin was present during reoxygenation, and this protection was associated with the reduction of reactive oxygen species, nitric oxide and neuronal nitric oxide synthase (nNOS) and inducible NOS (iNOS), and an increase of glutathione. Moreover, DNA laddering was decreased in treatment groups of pinocembrin. Caspase-3 protein was down-regulated and PARP degradation was alleviated after pinocembrin treatments. Our results suggest that pinocembrin may be a novel therapeutic strategy to reduce cerebral ischemia/reperfusion injury, and may act by the anti-oxidative and anti-apoptotic effects.
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PMID:Pinocembrin protects rat brain against oxidation and apoptosis induced by ischemia-reperfusion both in vivo and in vitro. 1849 93

The present study is aimed at evaluating the functional and neuroprotective effect of benzamide, a poly-(ADP-ribose) polymerase (PARP) inhibitor on delayed neuronal death (DND) in hippocampus CA1 region and memory impairment following global cerebral ischemia (GCI) in a mouse model. GCI was induced by bilateral common carotid artery occlusion (BCAo) for 20 min followed by reperfusion for 9 days. Postischemic continuous treatment with benzamide (160 mg/kg b w i.p. for 9 days) significantly reversed the GCI-induced anterograde memory impairment in passive avoidance step through and elevated plus maze tasks. The observed memory impairment in vehicle treated ischemia group was found to be well correlated with DND and downregulation of cholinergic muscarinic receptor-1 expression, which was possibly mediated by inflammation and apoptosis, as revealed from inducible nitric oxide synthase (iNOS) expression and number of TUNEL positive neurons in hippocampus CA1 region. It is clear from the present experiment that benzamide treatment significantly decreases the iNOS expression and number of apoptotic neurons and thereby improves the neuronal survival and memory during GCI. Our present findings provide compelling evidence that multiple doses of benzamide treatment is a promising therapeutic approach for cerebrovascular and neurodegenerative diseases, which deserves further clinical evaluation.
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PMID:Benzamide protects delayed neuronal death and behavioural impairment in a mouse model of global cerebral ischemia. 1850 76

Microglia are resident immune cells of the CNS. When stimulated by infection, tissue injury, or other signals, microglia assume an activated, "ameboid" morphology and release matrix metalloproteinases, reactive oxygen species, and other proinflammatory factors. This innate immune response augments host defenses, but it can also contribute to neuronal death. Zinc is released by neurons under several conditions in which microglial activation occurs, and zinc chelators can reduce neuronal death in animal models of cerebral ischemia and neurodegenerative disorders. Here, we show that zinc directly triggers microglial activation. Microglia transfected with a nuclear factor-kappaB (NF-kappaB) reporter gene showed a severalfold increase in NF-kappaB activity in response to 30 microm zinc. Cultured mouse microglia exposed to 15-30 microm zinc increased nitric oxide production, increased F4/80 expression, altered cytokine expression, and assumed the activated morphology. Zinc-induced microglial activation was blocked by inhibiting NADPH oxidase, poly(ADP-ribose) polymerase-1 (PARP-1), or NF-kappaB activation. Zinc injected directly into mouse brain induced microglial activation in wild-type mice, but not in mice genetically lacking PARP-1 or NADPH oxidase activity. Endogenous zinc release, induced by cerebral ischemia-reperfusion, likewise induced a robust microglial reaction, and this reaction was suppressed by the zinc chelator CaEDTA. Together, these results suggest that extracellular zinc triggers microglial activation through the sequential activation of NADPH oxidase, PARP-1, and NF-kappaB. These findings identify a novel trigger for microglial activation and a previously unrecognized mechanism by which zinc may contribute to neurological disorders.
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PMID:Zinc triggers microglial activation. 1850 44

In cerebral ischemia survival of neurons, astrocytes, oligodendrocytes and endothelial cells is threatened during energy deprivation and/or following re-supply of oxygen and glucose. After a brief summary of characteristics of different cells types, emphasizing the dependence of all on oxidative metabolism, the bioenergetics of focal and global ischemia is discussed, distinguishing between events during energy deprivation and subsequent recovery attempt after re-circulation. Gray and white matter ischemia are described separately, and distinctions are made between mature and immature brains. Next comes a description of bioenergetics in individual cell types in culture during oxygen/glucose deprivation or exposure to metabolic inhibitors and following re-establishment of normal aerated conditions. Due to their expression of NMDA and non-NMDA receptors neurons and oligodendrocytes are exquisitely sensitive to excitotoxicity by glutamate, which reaches high extracellular concentrations in ischemic brain for several reasons, including failing astrocytic uptake. Excitotoxicity kills brain cells by energetic exhaustion (due to Na(+) extrusion after channel-mediated entry) combined with mitochondrial Ca(2+)-mediated injury and formation of reactive oxygen species. Many (but not all) astrocytes survive energy deprivation for extended periods, but after return to aerated conditions they are vulnerable to mitochondrial damage by cytoplasmic/mitochondrial Ca(2+) overload and to NAD(+) deficiency. Ca(2+) overload is established by reversal of Na(+)/Ca(2+) exchangers following Na(+) accumulation during Na(+)-K(+)-Cl(-) cotransporter stimulation or pH regulation, compensating for excessive acid production. NAD(+) deficiency inhibits glycolysis and eventually oxidative metabolism, secondary to poly(ADP-ribose)polymerase (PARP) activity following DNA damage. Hyperglycemia can be beneficial for neurons but increases astrocytic death due to enhanced acidosis.
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PMID:Bioenergetics of cerebral ischemia: a cellular perspective. 1863 6

Apoptosis Inducing Factor is a mitochondrial protein which upon translocation to nucleus causes large scale DNA fragmentation. The stimulus for the cytosolic release and nuclear translocation for this protein still remains to be understood. The role of calpains, cathepsin-b, Poly ADP (ribose) Polymerase and granzyme-b in the nuclear translocation of AIF has been investigated in the pathology of cerebral ischemia. Calpains, cathepsin-b and PARP-1 which were mostly confined to cytosol, lysosomes and nucleus respectively were found to be elevated in the mitochondrial fraction interacting with AIF in the western blot analysis and double immunofluorescence analysis. Western blot and immunohistochemical analysis revealed elevated levels of granzyme-b secreted by cytotoxic T lymphocytes and natural killer cells in the infarct of ischemic mouse brain. Co-immunoprecipitation revealed and western blot analysis the interaction and break down of Heat Shock Protein-70 an endogenous inhibitor of AIF into signature fragments by granzyme-b facilitating the nuclear translocation of AIF. Break down of HSP-70 correlated with the nuclear translocation of AIF observed in western and immunohistochemical analysis. These results indicate that multiple proteases were involved in the nuclear translocation of AIF during the pathology of cerebral ischemia.
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PMID:Multiple apoptogenic proteins are involved in the nuclear translocation of Apoptosis Inducing Factor during transient focal cerebral ischemia in rat. 1893 46

Scutellarin (Scu) is the major active principle (flavonoid) extracted from Erigeron breviscapus (Vant.) Hand-Mazz, a Chinese herbal medicine. In this paper, we investigated the effects of Scu on brain injury through the inhibition of AIF-mediated apoptosis induced by transient focal brain ischemia in rats. Rats were treated with Scu for 7 d and then subjected to cerebral ischemia/reperfusion (I/R) injury induced by a middle cerebral artery occlusion (MCAO). After 2 h of ischemia and 22 h of reperfusion, the infarct volume and the neurological deficit were determined by TTC staining and Longa's score. IN SITU end-labeling of nuclear DNA fragments (TUNEL) was employed to determine the degree of DNA fragmentation. NAD content and PARP activity in brain homogenate were determined. The expression of AIF in the nucleus was analyzed by Western blot. The present study showed that Scu significantly reduced the infarct volume and ameliorated the neurological deficit. An increase in the number of TUNEL-positive cells and a decrease in the NAD level were also observed after 2 h of ischemia and 22 h of reperfusion. At the same time, Scu (50 and 75 mg kg (-1), i. g.) treatment reversed brain NAD depletion and reduced DNA fragmentation. Scu also inhibited PARP overactivation and AIF translocation from the mitochondria to the nucleus following cerebral I/R. These findings suggested that the neuroprotective effects of Scu on brain ischemic injury-induced apoptosis might be associated with inhibition of PARP-dependent mitochondrial dysfunction and subsequent translocation of AIF.
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PMID:Protective effects of scutellarin against cerebral ischemia in rats: evidence for inhibition of the apoptosis-inducing factor pathway. 1903 63

Stimulation of neutrophils by different factors increases their oxidative activity and the free radicals produced can report on the degree of activation. Poly(adenosine 5'-diphosphate ribose)polymerase-1 (PARP-1), a nuclear enzyme activated by strand breaks in DNA, plays an important role in the tissue injury associated with ischaemia-reperfusion injury and inflammation. 5-aminoisoquinolin-1-one (5-AIQ) is a potent inhibitor of PARP-1 activity in vitro and in vivo in rats. Acute (80 min) and prolonged (24h) focal cerebral ischaemia was induced in rats by obstruction of the median cerebral artery, with or without reperfusion, with or without administration of 5-AIQ. The oxidative activity of neutrophils was measured by chemiluminescence. Administration of 5-AIQ.HCl (3.0 mg kg(-1) b.w. - i.v.) caused a significant decrease in the oxidative activity of neutrophils in the group which had experienced chronic ischaemia for 24h but had no significant effect in the group which had received 80 min ischaemia, when compared to the control group. Increase of the oxidative activity of neutrophils was confirmed in rats with prolonged cerebral ischaemia, followed by reperfusion. 5-AIQ probably may decrease this activity through inhibition of PARP-1 in focus of local ischaemia as well as hence lowering the expression of inflammatory mediators by activated neutrophils.
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PMID:Influence of 5-aminoisoquinolin-1-one (5-AIQ) on neutrophil chemiluminescence in rats with transient and prolonged focal cerebral ischemia and after reperfusion. 1921 13

It is increasingly recognized that histological and functional outcomes after stroke are shaped by biologic sex. Emerging data suggests that ischemic cell death pathways are sexually dimorphic (Hurn, P., Vannucci, S., Hagberg, H. (2005) Adult or perinatal brain injury: does sex matter?. Stroke 36, 193-195 ; Lang, J.T., McCullough, L.D. (2008) Pathways to ischemic neuronal cell death: are sex differences relevant?. J. Transl. Med. 6). Reducing neuronal nitric oxide (NO) or poly-ADP-ribose polymerase (PARP1) activation protects only the male brain (Hagberg, H., et al. PARP-1 gene disruption in mice preferentially protects males from perinatal brain injury. J. Neurochem. 90, 1068-1075 (2004)), and paradoxically enhances ischemic injury in females (McCullough, L.D., et al. Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. J. Cereb. Blood Flow Metab. 25, 502-512 (2005)). In this study, we examined downstream mediators of NO/PARP activation to investigate possible mediators of ischemic sexual dimorphism. Nuclear translocation of Apoptosis Inducing Factor (AIF) was equivalent in wild type males and females after stroke and was unaffected by estrogen exposure. Deletion of PARP1 led to a dramatic reduction in stroke-induced poly (ADP-ribose) polymerase (PAR) formation and AIF translocation in both sexes, yet ischemic damage was reduced only in males. Subsequent examination of AIF-deficient Harlequin mice demonstrated that male Harlequin mice had less PAR formation, reduced AIF translocation and less ischemic damage than male wild type mice. In contrast, female Harlequin mice had no neuroprotective effect of gene deletion despite robust reductions in PAR formation and AIF translocation. Although equivalent activation of this cell death pathway occurs in both sexes after ischemia, detrimental effects are only present in males. AIF translocation and PAR formation do not mediate ischemic injury in the female brain, therefore agents designed to reduce PARP1 activation are unlikely to benefit females.
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PMID:Sex differences in the response to activation of the poly (ADP-ribose) polymerase pathway after experimental stroke. 1926 68


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