Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Poly(ADP-ribose) polymerase (PARP) activity is involved in DNA repair, replication, recombination, and transcription. Extensive activation of the most abundant PARP, PARP-1, during ischemia or inflammation can promote cell death. PARP inhibitors reduce this cell death and are currently under investigation for use as therapeutic agents. A recent study found that PARP activation was required for Hsp70 upregulation in heat-exposed Drosophila larvae. Here we sought to determine whether PARP activity is likewise required for Hsp70 upregulation in mammalian cells, since many of the settings in which PARP inhibitors are candidate therapeutic agents are also settings in which Hsp70 expression is an important component of the stress response. We examined this issue using murine astrocyte cultures, a mammalian preparation in which the Hsp70 response has been well characterized, and found that PARP inhibitors had no effect on heat shock-induced Hsp70 protein expression. PARP-1(-/-) astrocytes gave similar results. The present findings indicate that PARP activity, and specifically PARP-1, is not required for upregulation of Hsp70 expression in mammalian cells.Basel
 ...
PMID:Heat shock - induced Hsp70 expression in murine astrocytes does not require poly(ADP-ribose) polymerase activity. 1458 73

Poly(ADP-ribose) polymerase-1 (PARP-1) is the guardian of the genome acting as a sentinel for genomic damage. However, PARP-1 is also mediator of cell death after ischemia-reperfusion injury, glutamate excitotoxicity, and various inflammatory processes. The biochemistry underlying PARP-1-mediated cell death has remained elusive, although NAD(+) consumption and energy failure have been thought to be one of the possible molecular mechanisms. Recent observations link PARP-1 activation with translocation of apoptosis-inducing factor (AIF) to the nucleus and indicate that AIF is an essential downstream effector of PARP-1-mediated cell death. PARP-1 activation signals AIF release from the mitochondria, resulting in a novel, caspase-independent pathway of programmed cell death. These recent findings suggest that AIF maybe a target for development of future therapeutic treatment for many neurological disorders involving excitotoxicity.
 ...
PMID:Poly(ADP-ribose) polymerase-1 and apoptosis inducing factor in neurotoxicity. 1467 48

Poly(ADP-ribose) polymerase (PARP) was shown to be detrimental in cerebral ischemia but the mechanisms whereby PARP is deleterious have yet to be determined. They may include a role in neutrophil infiltration known to aggravate ischemic damage. In this context, we investigated the effect of 3-aminobenzamide (3-AB), a PARP inhibitor, on brain damage and neutrophil infiltration after transient focal cerebral ischemia in mice. Ischemia was induced in male Swiss mice, anaesthetized with chloral hydrate (400 mg/kg, i.p.), by a 15-min-occlusion of the left middle cerebral artery using an intraluminal suture. Treatments with 3-AB were first administered intraperitoneally 15 min before reperfusion and endpoints measured at 24 h. Among the range of dosages studied (20-320 mg/kg), 40 mg/kg gave the maximal neuroprotection with a 30% decrease in the infarct volume and tended to improve the neurological score evaluated by a grip test. The same dosage was, however, devoid of effect when injection was delayed 2 or 6 h after reperfusion. Myeloperoxidase (MPO) activity used as an index of neutrophil infiltration showed that infiltration peaked 48 h after reperfusion in our model. At this time point, 3-AB (40 mg/kg given 15 min before reperfusion) markedly reduced the neutrophil infiltration, as evidenced by a 72%-decrease in MPO activity, and was still neuroprotective. Our results confirm that 3-AB reduces brain damage. Moreover, for the first time, a quantitative study shows that 3-AB decreases neutrophil infiltration elicited by cerebral ischemia.
 ...
PMID:3-Aminobenzamide reduces brain infarction and neutrophil infiltration after transient focal cerebral ischemia in mice. 1476 90

Poly(ADP-ribose) polymerase (PARP) activation plays a key role in free radical-induced injury in the context of systemic inflammation and ischemia/reperfusion. In the present preclinical study, we investigated the effects of INO-1001, a novel PARP inhibitor, on cardiac and pulmonary function during reperfusion in an experimental model of cardioplegic arrest and extracorporal circulation. Twelve anesthetized dogs underwent hypothermic cardiopulmonary bypass. After 60 min of hypothermic cardiac arrest, reperfusion was started after application of either saline vehicle (control, n = 6), or INO-1001 (1 mg/kg), a potent PARP inhibitor (n = 6). Biventricular hemodynamic variables were measured by combined pressure-volume-conductance catheters. Coronary and pulmonary blood flow and vasodilative responses to acetylcholine and sodium nitroprusside as well as pulmonary gas exchange were also determined. The administration of INO-1001 led to a significantly better recovery of left and right ventricular systolic function (P < 0.05) after 60 min of reperfusion. Coronary blood flow was also significantly higher in the INO-1001 group (P < 0.05). Although the vasodilative response to sodium nitroprusside was similar in both groups, acetylcholine resulted in a significantly greater increase in coronary and pulmonary blood flow in the INO-1001 group (P < 0.05). Pulmonary function in terms of alveolar arterial oxygen difference was better preserved in the INO-1001-treated group (P < 0.05). Thus, PARP inhibition improves the recovery of myocardial and endothelial function after hypothermic cardiac arrest and reduces pulmonary injury associated with extracorporal circulation.
 ...
PMID:INO-1001 a novel poly(ADP-ribose) polymerase (PARP) inhibitor improves cardiac and pulmonary function after crystalloid cardioplegia and extracorporal circulation. 1508 18

Poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA, plays an important role in the tissue injury associated with ischemia-reperfusion and inflammation. Splanchnic artery occlusion and reperfusion causes an enhanced formation of reactive oxygen species which contribute to the pathophysiology of shock. The aim of the present study was to investigate the effects of 5-aminoisoquinolinone (5-AIQ), a potent water-soluble inhibitor of poly(ADP-ribose) polymerase (PARP), in the pathogenesis of splanchnic artery occlusion shock. Splanchnic artery occlusion shock was induced in rats by clamping both the superior mesenteric artery and the celiac artery for 45 min, followed thereafter by release of the clamp (reperfusion). At 60 min after reperfusion, all animals were sacrificed for histological examination and biochemical studies. Treatment of rats with 5-AIQ (3 mg/kg i.v.), attenuated the fall of mean arterial blood pressure caused by splanchnic artery occlusion shock. 5-AIQ also attenuated the ileum injury as well as the increase in the tissue levels of myeloperoxidase and malondialdehyde caused by splanchnic artery occlusion shock in the ileum. The immunohistochemical examination also demonstrated a marked increase in the immunoreactivity to PAR, nitrotyrosine, and intercellular adhesion molecule (ICAM-1) in the necrotic ileum from splanchnic artery occlusion-shocked rats. 5-AIQ treatment significantly reduced the increase of positive staining for PAR, nitrotyrosine and ICAM-I. In conclusion, these results show that 5-AIQ, a new water-soluble potent inhibitor of poly(ADP-ribose) polymerase, exerts multiple protective effects in splanchnic artery occlusion/reperfusion shock.
 ...
PMID:Beneficial effects of 5-aminoisoquinolinone, a novel, potent, water-soluble, inhibitor of poly (ADP-ribose) polymerase, in a rat model of splanchnic artery occlusion and reperfusion. 1517 66

Poly(ADP-ribose) polymerase-1 is over-activated in the adult brain in response to ischemia and contributes to neuronal death, but its role in perinatal brain injury remains uncertain. To address this issue, 7-day-old wild-type (wt) and PARP-1 gene deficient (parp+/- and parp-/-) Sv129/CD-1 hybrid mice were subjected to unilateral hypoxia-ischemia and histologic damage was assessed 10 days later by two evaluators. Poly(ADP-ribose) polymerase-1 knockout produced moderate but significant (p < 0.05) protection in the total group of animals, but analysis by sex revealed that males were strongly protected (p < 0.05) in contrast to females in which there was no significant effect. Separate experiments demonstrated that PARP-1 was activated over 1-24 h in both females and males after the insult in neonatal wt mice and rats using immnocytochemistry and western blotting for poly(ADP-ribose). Brain levels of NAD+ were also significantly reduced, but the decrease of NAD+ during the early post-hypoxia-ischemia (HI) phase was only seen in males. The results indicate that hypoxia-ischemia activates Poly(ADP-ribose) polymerase-1 in the neonatal brain and that the sex of the animal strongly influences its role in the pathogenesis of brain injury.
 ...
PMID:PARP-1 gene disruption in mice preferentially protects males from perinatal brain injury. 1531 62

Poly(ADP-ribose) polymerase-1 (PARP-1; EC 2.4.2.30), also termed as poly(ADP-ribose) synthetase, is a key enzyme in the recognition and repair of damaged DNA. Several conditions (e.g., ischemia-reperfusion or chemical-induced injury) have been shown to overactivate PARP-1, causing neurodegeneration and necrotic or apoptotic cell death from NAD+ and ATP depletion. In contrast, inhibitors of PARP-1 have been shown to have a neuroprotective effect by ameliorating this response. The purpose of this study was to determine the effects of three routinely used organic solvents (ethanol, methanol, and dimethyl sulfoxide (DMSO)) on the activity of purified PARP-1. A dose-response was examined with each of these solvents. A 112% and 82% increase in PARP-1 activity was observed with 15% ethanol and 20% methanol, respectively. In contrast, a near 20% decrease in the activity was observed with 4% DMSO. Kinetic analysis revealed that the maximal velocity remained unchanged with increasing concentrations of DMSO up to 20%, indicating that DMSO is a competitive inhibitor of PARP-1. Thus, PARP-1 inhibition by DMSO depends on NAD+ concentration and in some pathological processes might be significant even at low DMSO concentrations. Our findings suggest that the interpretation of data from dose-response studies obtained when using common organic solvents may be dramatically skewed, either exaggerating the inherent toxicity of the compound or masking its potential for damage.
 ...
PMID:The effects of organic solvents on poly(ADP-ribose) polymerase-1 activity: implications for neurotoxicity. 1558 63

Poly(ADP-ribose) polymerase (PARP EC 2.4.2.30) is a key enzyme in the DNA repair machinery, but its excessive stimulation during reperfusion after ischemia could play a critical role in cell death. Our previous study indicated that the PARP inhibitor 3-aminobenzamide (3-AB) significantly protected neuronal cells against death after a short ischemic insult. In this study we investigated the effect of 3-AB on the ischemia-evoked alterations in intracellular organelles. Gerbils were submitted to 3 min of transient forebrain ischemia followed by reinstitution of recirculation for 1-7 days. Electron microscopy showed only the signs of necrotic cell death after ischemia-reperfusion. The examination of specimens revealed a pronounced protective effect of 3-AB on the swelling of astrocytes and neurons 1 day after the ischemic insult. 3-AB also decreased the swelling of pericytes, but it had no effect on the accumulation of osmiophilic inclusions and fibril formation in astrocytes. 3-AB decreased the ischemia-induced swelling of mitochondria. The protective effects of 3-AB on cellular ultrastructure were also observed 7 days after reperfusion. These findings indicate that the inhibition of PARP may have a protective effect on cell swelling and on the state of intracellular organelles after a short-term ischemic episode.
 ...
PMID:Effects 3-aminobenzamide on ultrastructure of hippocampal CA1 layer after global ischemia in gerbils. 1561 4

Poly(ADP-ribose) polymerase (PARP) activation plays a role in the pathogenesis of various cardiovascular and inflammatory diseases. At the same time, PARP activation is also relevant for the ability of cells to repair injured DNA. Thus, depending on the circumstances, pharmacological inhibitors of PARP may be able to attenuate ischemic and inflammatory cell and organ injury or may be able to enhance the cytotoxicity of antitumor agents. Both aspects of the "double-edged sword" role of PARP can be exploited for the experimental therapy of disease. As several classes of PARP inhibitors move towards clinical development, or have already entered the stage of clinical trials, we expect that in the upcoming few years, clinical proof of PARP inhibitors' therapeutic effect will be obtained in human disease. In the current short overview, we summarize the pros and cons and challenges with respect to the clinical use of PARP inhibitors, the expected clinical outcomes and potential risks. It appears that on the cytoprotective aspect of PARP, acute, life-threatening diseases (myocardial infarction, cardiopulmonary bypass in high-risk patients, and other, severe forms of ischemia-reperfusion to other organs including stroke and thoracoabdominal aneurysm repair) may represent some of the prime development indications. In the context of inhibition of DNA repair, combination of PARP inhibitors with certain antitumor agents (for example temozolomide) in patients with tumors with extremely poor prognosis are expected to provide the initial clinical results. Development of PARP inhibitors for additional indications (e.g. chronic use for the therapy of neurodegeneration and neuroinflammation, or diabetic complications) may be more challenging because of the unknown potential long-term side effects of PARP inhibitors.
 ...
PMID:Clinical perspectives of PARP inhibitors. 1591 39

Poly(ADP-ribose) polymerase (PARP)-1 is a DNA nick sensor that transforms ADP-ribose from betaNAD+ in the form of polymer to over 40 nuclear proteins, particularly to histones, several transcription factors, and PARP itself, modulating their activities and functions. PARP-1 activated by DNA breaks facilitates transcription, replication, and DNA base excision repair. The last studies indicate that PARP-1 is the new nuclear target for fast signals evoked in cell membranes by depolarization and cholinergic and glutaminergic receptors stimulation. Excessive activation of PARP-1 by peroxynitrate-evoked DNA damage during oxidative stress can cause cell death by NAD+/ATP depletion after ischemia-reperfusion injury, inflammation, and diabetes mellitus. The PARP-1 through interaction with nuclear factor-kappaB, p53, and other transcription factors might significantly modulate cell survival and death and a type of death pathway. The pharmacological modulation of PARP-1 might offer a new effective approach for neuroprotection.
 ...
PMID:Poly(ADP-ribose) polymerase: the nuclear target in signal transduction and its role in brain ischemia-reperfusion injury. 1595 18


<< Previous 1 2 3 4 5 Next >>