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)polymerase (PARP, EC 2.4.2.30), an abundant nuclear protein activated by DNA nicks, mediates cell death in vitro by nicotinamide adenine dinucleotide (NAD) depletion after exposure to nitric oxide. The authors examined whether genetic deletion of PARP (PARP null mice) or its pharmacologic inhibition by 3-aminobenzamide (3-AB) attenuates tissue injury after transient cerebral ischemia. Twenty-two hours after reperfusion following 2 hours of filamentous middle cerebral artery occlusion, ischemic injury was decreased in PARP-/- and PARP+/- mice compared with PARP+/+ litter mates, and also was attenuated in 129/SV wild-type mice after 3-AB treatment compared with controls. Infarct sparing was accompanied by functional recovery in PARP-/- and 3-AB-treated mice. Increased poly(ADP-ribose) immunostaining observed in ischemic cell nuclei 5 minutes after reperfusion was reduced by 3-AB treatment. Levels of NAD--the substrate of PARP--were reduced 2 hours after reperfusion and were 35% of contralateral levels at 24 hours. The decreases were attenuated in PARP-/- mice and in 3-AB-treated animals. Poly(ADP-ribose)polymerase cleavage by caspase-3 (CPP-32) has been proposed as an important step in apoptotic cell death. Markers of apoptosis, such as oligonucleosomal DNA damage, total DNA fragmentation, and the density of terminal deoxynucleotidyl transferase dUTP nick-end-labelled (TUNEL +) cells, however, did not differ in ischemic brain tissue of PARP-/- mice or in 3-AB-treated animals versus controls, although there were differences in the number of TUNEL-stained cells reflecting the decrease in infarct size. Thus, ischemic brain injury activates PARP and contributes to cell death most likely by NAD depletion and energy failure, although the authors have not excluded a role for PARP in apoptotic cell death at earlier or later stages in ischemic cell death. Inhibitors of PARP activation could provide a potential therapy in acute stroke.
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PMID:Ischemic brain injury is mediated by the activation of poly(ADP-ribose)polymerase. 939 Jun 45

We examined the timing of apoptosis and the expression of the DNA repair proteins poly(ADP-ribose) polymerase (PARP) and Ku80 in sections of frontal and temporal lobes from patients who had suffered severe brain ischaemia due to a cardiac arrent. In situ end-labelling (ISEL) was used to detect apoptotic cells, and immunohistochemistry to assess PARP and Ku80. ISEL of scattered neurons and glia was demonstrable predominantly during the first 24 h after ischaemia. PARP and Ku80 immunoreactivity increased markedly after cerebral ischaemia, PARP particularly in the regions of greatest susceptibility to hypoxic injury: the CA1 field of the hippocampus and the depths of neocortical sulci. The up-regulation of PARP is in keeping with experimental observations concerning the key role of this enzyme in mediating ischaemic cell death.
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PMID:Apoptosis and expression of DNA repair proteins in ischaemic brain injury in man. 960 49

Poly (ADP-ribose) polymerase (PARP) is a nuclear enzyme that is activated by DNA strand breaks to participate in DNA repair. Excessive activation of PARP, however, can deplete tissue stores of nicotinamide adenine dinucleotide (NAD), the PARP substrate which, with the resultant depletion of ATP, leads to cell death. In many cases of CNS damage, for example vascular stroke, nitric oxide release is a key stimulus to DNA damage and PARP activation. In conditions as diverse as focal cerebral ischaemia, myocardial infarction and toxin-induced diabetes, PARP inhibitors and PARP gene deletion afford dramatic protection from tissue damage. Accordingly, PARP inhibitors could provide novel therapeutic approaches in a wide range of clinical disorders.
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PMID:Poly (ADP-ribose) polymerase, nitric oxide and cell death. 1032 3

Poly(ADP-ribose) polymerase (PARP) is thought to play a physio-logical role in maintaining genomic integrity and in the repair of DNA strand breaks. However, the activation of PARP by free radical-damaged DNA plays a pivotal role in mediating ischemia-reperfusion injury. The excessive activation of PARP causes a rapid depletion of intracellular energy leading to cell death. The present study examined the effect of post-ischemic pharmacological inhibition of PARP in a rat focal cerebral ischemia model. In Long-Evans rats, focal cerebral ischemia was produced by cauterization of the right distal middle cerebral artery (MCA) with bilateral temporary common carotid artery (CCA) occlusion for 90 min. A PARP inhibitor, 3, 4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone (DPQ; IC50=1 microM/l) was injected i.p. 30 min after the onset of MCA occlusion (control: 10, 20, 40 and 80 mg/kg; n=7 each). Twenty-four hours later, the total infarct volume was measured. Regional blood flow in the right parietal cortex decreased to approximately 20% of the baseline following MCA occlusion in all groups. PARP inhibition lead to a significant decrease in damaged volume in all treated groups with the largest reduction in the 40 mg/kg group (111.5+/-24. 8 mm3, mean+/-SD, p<0.01), compared to the control group (193.5+/-28. 6 mm3). We also found there was a significant increase of poly(ADP-ribose) immunoreactivity in the ischemic region, as compared to the contralateral side, with DPQ treatment diminishing poly(ADP-ribose) production. These findings indicate that DPQ exerts its neuroprotective effects in vivo by PARP inhibition and that PARP inhibitors may be effective for treating ischemic stroke, even when the treatment is initiated after the onset of ischemia.
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PMID:Post-treatment with an inhibitor of poly(ADP-ribose) polymerase attenuates cerebral damage in focal ischemia. 1035 May 29

The activation of poly(ADP-ribose) polymerase (PARP) by free radical-damaged DNA plays a pivotal role in mediating ischemia-reperfusion injury. The purpose of the present study was to examine the neuroprotective effects of a PARP inhibitor, 3-aminobenzamide (3-ABA), which was administered either prior to or following reperfusion, to determine the importance of PARP inhibition prior to reperfusion. 3-ABA was injected i.p. either 15 min before or 15 min following reperfusion in a transient focal ischemia model in the rat. Treatment prior to the reperfusion led to a significant decrease in the volume of damaged tissue at 24 h (118.7 +/- 18.8 mm3, mean +/- s.d., p < 0.01), compared with the control (176.1 +/- 22.8 mm3). However, treatment after the reperfusion failed to produce a reduction in the damaged volume (171.9 +/- 27.6 mm3). These findings suggest that PARP activation sufficient to produce cellular damage occurs immediately after the reperfusion following cerebral ischemia.
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PMID:The effect of reperfusion on neuroprotection using an inhibitor of poly(ADP-ribose) polymerase. 1042 67

Nitric oxide (NO) and its reactant product, peroxynitrite, have been implied to mediate neuronal damage following cerebral ischemia. However, the cellular targets of these compounds remain unclear. Studies using poly(ADP-ribose) polymerase (PARP) inhibitors and PARP knock-out mice have recently demonstrated that excessive activation of this nuclear enzyme plays an important role in NO-induced neurotoxicity. To evaluate the relevance of this plausible candidate gene to human stroke, we undertook a case-control study in Japanese. Participants comprised 213 cerebral infarction cases and 374 age- and sex-matched controls. As a primary investigation, we screened polymorphic sites of the PARP gene, and newly identified a total of four polymorphisms in 1230-bp 5'-flanking sequence. None of them were, however, located on the known promoter components of the gene. Two bi-allelic polymorphisms selected and a CA-repeat polymorphism were subsequently characterized in the case-control study, but none were significantly associated with cerebral infarction in the present study. Our data thus suggest that the tested PARP polymorphisms do not principally contribute to cerebral infarction, although extensive searches would be required to clarify whether the PARP gene plays an important role in the pathogenesis of human stroke.
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PMID:Evaluation of the poly(ADP-ribose) polymerase gene in human stroke. 1065 71

In experimental models of cerebral ischemia, cells within the damaged territory die by necrosis and by apoptosis that contributes to the expansion of the insult. Apoptotic machinery mobilizes intracellular processes such as induction of Bcl-2 family members, activation of the proteolytic cascade including the caspases, and cleavage of caspase substrates, such as poly(ADP-ribose) polymerase or PARP. Mitochondria play a pivotal role in controlling apoptosis by releasing cytochrome c and modulating redox state, both under the regulation of manganese superoxide dismutase (Mn SOD) via superoxide anion detoxification. The implication and the kinetics of such events in apoptosis induced after focal permanent ischemia in mice remains to be studied. In a paradigm of ischemic insult induced by occlusion of the middle cerebral artery (MCAO) in mice, we showed by immunohistochemistry a constitutive expression of caspase-3 that is enhanced after MCAO in neurons localized within the infarcted zone. As a function of time intervals after MCAO, the cytochrome c amount increased in the cytosolic fraction of ischemic cortical extracts. The kinetics of the release was in concordance with the expression of caspase-3 and the subsequent cleavage of PARP appearing before the internucleosomal fragmentation of DNA, the ultimate step of apoptosis. When the apoptotic markers progressively appeared, no changes of Mn SOD activity or Mn SOD expression were detected after MCAO. We can therefore speculate that the recruitment of Mn SOD did not participate per se in the release of cytochrome c elicited after permanent focal ischemia.
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PMID:Early and sequential recruitment of apoptotic effectors after focal permanent ischemia in mice. 1067 15

In the present study, the effect of poly(ADP-ribose) polymerase (PARP) inhibition on rat cortical energy state was investigated at 24 h after global cerebral ischemia induced by permanent bilateral common carotid artery ligation plus transient hypotension. The specific PARP inhibitor 3-aminobenzamide was injected 10 min before induction of ischemia at a dosage of 5, 10, and 20 mg/kg intracerebroventricularly. Twenty-four hours after ischemia cortical PARP enzyme activity increased from 0.425+/-0.144 to 0.794+/-0.193 units/mg protein. Cerebral ischemia was associated by a decrease in adenosine triphosphate (ATP) and phosphocreatine concentrations to 72.5 and 76.8% of controls, respectively. In addition, an 1.9- and 2. 2-fold increase in adenosine monophosphate and adenosine was observed. Specific PARP inhibition with 10 mg/kg 3-aminobenzamide protected the rat energy state by preserving cortical phosphocreatine and NAD(+). Cortical ATP was not changed significantly after PARP inhibition. In conclusion, activation of the nuclear enzyme PARP plays an important role in cerebral energy metabolism during rat global ischemia. Therefore, specific PARP inhibition may offer new strategies in the therapy of vascular diseases such as stroke.
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PMID:The neuroprotective effect of cerebral poly(ADP-ribose)polymerase inhibition in a rat model of global ischemia. 1077 Nov 74

Experimental evidence suggests that the massive release of glutamate during experimental brain ischemia both directly and indirectly regulates downstream mechanisms of cell suicide. Cerebral ischemia was produced by distal, permanent occlusion of the middle cerebral artery (MCAO) in the rat. Sets of three animals and one sham-operated for each time-point were kept alive for 0-30 min, 1, 4, 12, 24, and 48 h, and 4 days. Additional animals were treated by local administration of a 10 microM (in 10 microl) cocktail of caspase inhibitors (YVAD-cmk, DEVD-fmk, IETD). Immunohistochemistry was performed on free-floating tissue sections with goat polyclonal antibodies to procaspase-1, -2, -3, -6, and -8. Some sections were processed for double-labeling procaspase immunohistochemistry and in situ end-labeling of nuclear DNA fragmentation (TUNEL method). Both immunohistochemistry and double-labeling procaspase immunohistochemistry and TUNEL method were carried out on formalin-fixed sections. For gel electrophoresis and Western blotting, we used antibodies to poly (ADP-ribose) polymerase (PARP), lamin B, and PKC-delta, as specific cleavage substrates of caspases. There was increased immunoreactivity ipsilaterally in the areas corresponding to the infarct and surrounding penumbra with the peak of immunoreactivity between 12 and 24 h for most of the procaspases. Procaspases were present early in the infarcted tissue neurones and their dendrites and axons. Additional procaspase expression occurred in astrocytes and microglial cells at different times following ischemia. Cells with positive in situ end-labeling of nuclear DNA fragmentation appeared in high number predominantly in the infarcted areas and at the edge of the infarction and colocalized with enhanced procaspase expression. These findings suggest increased procaspase expression in dying cells at the edge of the infarction. A major product of PARP degradation of about 89 kDa was found in the samples taken from the infarcted and penumbra areas. There was no difference in the intensity of the bands corresponding to lamin B or PKC-delta. Injection of procaspase inhibitors reduced the levels of major PARP products of 89 kDa and decreased the number of TUNEL-positive cells at 12 h post-MCAO. In conclusion, these results give support to further research on the use of caspase inhibitors as add-on therapeutic agents for the treatment of ischemia.
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PMID:Expression of caspases and their substrates in the rat model of focal cerebral ischemia. 1096 5

Poly(ADP-ribose) polymerase (PARP-1), a nuclear enzyme that facilitates DNA repair, may be instrumental in acute neuronal cell death in a variety of insults including, cerebral ischemia, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism, and CNS trauma. Excitotoxicity is thought to underlie these and other toxic models of neuronal death. Different glutamate agonists may trigger different downstream pathways toward neurotoxicity. We examine the role of PARP-1 in NMDA- and non-NMDA-mediated excitotoxicity. NMDA and non-NMDA agonists were stereotactically delivered into the striatum of mice lacking PARP-1 and control mice in acute (48 hr) and chronic (3 week) toxicity paradigms. Mice lacking PARP-1 are highly resistant to the excitoxicity induced by NMDA but are as equally susceptible to AMPA excitotoxicity as wild-type mice. Restoring PARP-1 protein in mice lacking PARP-1 by viral transfection restored susceptibility to NMDA, supporting the requirement of PARP-1 in NMDA neurotoxicity. Furthermore, Western blot analyses demonstrate that PARP-1 is activated after NMDA delivery but not after AMPA administration. Consistent with the theory that nitric oxide (NO) and peroxynitrite are prominent in NMDA-induced neurotoxicity, PARP-1 was not activated in mice lacking the gene for neuronal NO synthase after NMDA administration. These results suggest a selective role of PARP-1 in glutamate excitoxicity, and strategies of inhibiting PARP-1 in NMDA-mediated neurotoxicity may offer substantial acute and chronic neuroprotection.
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PMID:NMDA but not non-NMDA excitotoxicity is mediated by Poly(ADP-ribose) polymerase. 1105 Jan 21


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