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

Poly (ADP-ribose) polymerase (PARP) is involved in various cellular functions, including DNA repair, the cell cycle and cell death. While PARP activation could play a critical role in repairing ischemic brain damage, PARP inactivation caused by caspase 3-cleavage may also be important for apoptotic execution. In this study we investigated the effects of transient global ischemia and kainic acid (KA) neurotoxicity, in gerbil and rat brains, respectively, on PARP gene expression and protein cleavage. PARP mRNA increased in the dentate gyrus of gerbil brains 4 h after 10 min of global ischemia, which returned to basal levels 8 h after ischemia. KA injection (10 mg/kg) also induced a marked elevation in PARP mRNA level selectively in the dentate gyrus of rat brains 1 h following the injection, which returned to basal levels 4 h after the injection. These observations provide the first evidence of altered PARP gene expression in brains subjected to ischemic and excitotoxic insults. Using both monoclonal and polyclonal antibodies to PARP cleavage products, little evidence of significant PARP cleavage was found in gerbil brains within the first 3 days after 10 min of global ischemia. In addition, there was little evidence of significant PARP cleavage in rat brains within 2 days after kainate (KA) injection. Though these findings show that caspase induced PARP cleavage is not substantially activated by global ischemia and excitotoxicity in whole brain, the PARP mRNA induction could suggest a role for PARP in repairing DNA following brain injury.
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PMID:Effects of transient global ischemia and kainate on poly(ADP-ribose) polymerase (PARP) gene expression and proteolytic cleavage in gerbil and rat brains. 1103 24

Poly (ADP-ribose) polymerase (PARP) is a ubiquitous nuclear enzyme that, when activated by free-radical induced DNA damage, contributes to energy failure and cell death in models of central nervous system ischemia and reperfusion. PARP contributes to neuronal cell death in vivo after cerebral ischemia/reperfusion, however, the role of PARP in the pathogenesis of traumatic brain injury (TBI) is unknown. We hypothesized that, compared to wild type mice (+/+), mice deficient in PARP (-/-) would have reduced motor and cognitive deficits after TBI. Mice underwent controlled cortical impact (CCI) (6 m/s, 1.2 mm depth) and were tested for motor (d 1-5) and cognitive (d 14-18) function after CCI. PARP -/- mice demonstrated improved motor performance and improved cognitive function after CCI (both p < 0.05 compared to +/+). This is the first study to evaluate a role for PARP in functional outcome after TBI. The results suggest a detrimental role for PARP in the pathogenesis of TBI.
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PMID:Traumatic brain injury in mice deficient in poly-ADP(ribose) polymerase: a preliminary report. 1145 92

Poly(adenosine 5'-diphosphate) ribose polymerase is a nuclear enzyme activated in response to genotoxic stress induced by a variety of DNA damaging agents. Several oxygen and nitrogen-centered free radicals, notably peroxynitrite, are strong inducers of DNA damage and poly(adenosine 5'-diphosphate) ribose polymerase activation in vitro and in vivo. Activation of this nuclear enzyme depletes the intracellular stores of its substrate nicotinamide adenine dinucleotide, slowing the rate of glycolysis, mitochondrial electron transport and adenosine triphosphate formation. This process triggers a severe energetic crisis within the cell, leading to acute cell dysfunction and cell necrosis. Poly(adenosine 5'-diphosphate) ribose polymerase also plays an important role in the regulation of inflammatory cascades, through a functional association with various transcription factors and transcription co-activators. Recent works identified this enzyme as a critical mediator of cellular metabolic dysfunction, inflammatory injury, and organ damage in conditions associated with overwhelming oxidative stress, including systemic inflammation, circulatory shock, and ischemia-reperfusion. Accordingly, pharmacological inhibitors of poly(adenosine 5'-diphosphate) ribose polymerase protect against cell death and tissue injury in such conditions, and may therefore represent novel therapeutic tools to limit multiple organ damage and dysfunction in critically ill patients.
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PMID:Poly(adenosine 5'-diphosphate) ribose polymerase activation as a cause of metabolic dysfunction in critical illness. 1184 85

Housekeeping genes like glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and beta-actin are often used as internal standards for quantitative RNA analysis. In our study we analyzed the relative expression level of GAPDH and beta-actin as well as of the 18S rRNA and the Poly (A)+ RNA in growing collateral arteries in a rabbit model of arteriogenesis which is not associated with ischemia. Relative quantitation of the housekeeping genes displayed a significant upregulation of the beta-actin- and GAPDH mRNA during the first 24 h of vessel growth. For day 3 our results revealed an even stronger upregulation of the beta-actin mRNA (140%) but a significant downregulation of the GAPDH mRNA (50% of control). The 18S rRNA, however, showed for the same periods only minor alterations compared to the Poly (A)+ RNA. From these results we conclude that the 18S rRNA, but not the GAPDH- or beta-actin mRNA is an appropriate internal control for relative quantitation of gene expression under conditions of cell proliferation in growing vessels.
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PMID:Differential expression of GAPDH and beta3-actin in growing collateral arteries. 1219 Jan 13

To study the effect of extracellular acidosis on apoptosis and necrosis during ischemia and reoxygenation, we exposed human post-mitotic NT2-N neurones to oxygen and glucose deprivation (OGD) followed by reoxygenation. In some experiments, pH of the cell medium was lowered to 5.9 during either OGD or reoxygenation or both. Staurosporine, used as a positive control for apoptosis, caused Poly(ADP-ribose)-polymerase (PARP) cleavage and nuclear fragmentation, but no PARP cleavage and little fragmentation were seen after OGD. Low molecular weight DNA fragments were found after staurosporine treatment, but not after OGD. No protective effect of caspase inhibitors was seen after 3 h of OGD and 21 h of reoxygenation, but after 45 h of reoxygenation caspase inhibition induced a modest improvement in 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) cleavage. While acidosis during OGD accompanied by neutral medium during reoxygenation protected the neurones (MTT: 228 +/- 117% of neutral medium, p < 0.001), acidosis during reoxygenation only was detrimental (MTT: 38 +/- 25%, p < 0.01). We conclude that apoptotic mechanisms play a minor role after OGD in NT2-N neurones. The effect of acidosis on neuronal survival depends on the timing of acidosis, as acidosis was protective during OGD and detrimental during reoxygenation.
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PMID:Acidosis has opposite effects on neuronal survival during hypoxia and reoxygenation. 1260 26

Poly(ADP-ribose) is synthesized from nicotinamide adenine dinucleotide (NAD(+)) by poly(ADP-ribose) polymerase (PARP) and degraded by poly(ADP-ribose) glycohydrolase (PARG). Overactivation of the poly(ADP-ribose) pathway increases nicotinamide and decreases cellular NAD(+)/ATP, which leads to cell death. Blocking poly(ADP-ribose) metabolism by inactivating PARP has been shown to reduce ischemia injury. We investigated whether disrupting the poly(ADP-ribose) cycle by PARG inhibition could achieve similar protection. We demonstrate that either pre- or post-ischemia treatment with 40 mg/kg of N-bis-(3-phenyl-propyl)9-oxo-fluorene-2,7-diamide, a novel PARG inhibitor, significantly reduces brain infarct volumes by 40-53% in a rat model of focal cerebral ischemia. Our result provides the first evidence that PARG inhibitors can ameliorate ischemic brain damage in vivo, in support of PARG as a new therapeutic target for treating ischemia injury.
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PMID:Post-treatment with a novel PARG inhibitor reduces infarct in cerebral ischemia in the rat. 1283 3

Myocardial ischemia-reperfusion can lead to increased oxidative stress both locally and in circulating leukocytes. Oxidant-mediated DNA single strand breaks are known to activate the nuclear enzyme poly(ADP-ribose) polymerase (PARP) in various forms of shock, inflammation, and ischemia-reperfusion injury. The aim of the current study was to investigate whether a local insult such as myocardial ischemia-reperfusion is sufficient to lead to activation of PARP in circulating leukocytes. In anesthetized rats myocardial ischemia-reperfusion was induced by transient ligation of the left anterior descending coronary artery. There was a marked increase in poly(ADP-ribosyl)ation of proteins in homogenates of leukocytes isolated from rats at the end of the reperfusion period. Poly(ADP-ribosyl)ation was inhibited by administration of the pharmacologic PARP inhibitor INO-1001 (30 mg/kg) to the rats. We conclude that local insults, such as myocardial reperfusion injury, are sufficient to activate PARP in circulating leukocytes. PARP activation in circulating cells may mediate certain systemic effects of local ischemia-reperfusion injury such as inflammatory mediator production and remote organ injury.
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PMID:Activation of poly(ADP-ribose) polymerase in circulating leukocytes during myocardial infarction. 1477 35

Following ischemia/reperfusion the death of retinal ganglion cells in adult Wistar rat retina continues for weeks. Using new, more stable caspase inhibitor, Q-VD-OPH we studied its neuroprotective effect on identifiable retinal ganglion cells after 75 min ischemia followed by reperfusion. Q-VD-OPH was injected intravitreally 48 h after ischemia/reperfusion. Retinal ganglion cells were labeled by intratectal injection of Fluorogold and cells were counted on flat mounted retinas. Retinal ganglion cells survival increased after 2 and 3 weeks of ischemia/reperfusion in Q-VD-OPH injected eyes. We studied apoptotic cell death by immunocytochemically labeling retina with cleaved Poly (ADP-ribose) polymerase (PARP). Labeling for cleaved PARP remained elevated in the ganglion cell layer and inner nuclear layer after 1,2and 3 weeks of ischemia/reperfusion. Administration of Q-VD-OPH significantly reduced the labeling for cleaved PARP in the retina and increased the survival of retinal ganglion cells.
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PMID:Broad spectrum caspase inhibitor rescues retinal ganglion cells after ischemia. 1507 19

Modulation of ischemic cell death can be accomplished via a multitude of mechanisms, such as quenching radical species, providing alternative energy sources, or altering glutamate excitation. Transient cerebral ischemia will induce apoptotic cell death selectively to hippocampal cornus ammon's field 1 of the hippocampus (CA1) pyramidal cells, while neighboring CA3 and dentate neurons are spared. Poly MVA is a dietary supplement based on the nontoxic chemotherapeutic lipoic acid-palladium complex (LAPd). LAPd is a liquid crystal that works in cancer cells by transferring excess electrons from membrane fatty acids to DNA via the mitochondria. Therefore, by its structural nature and action as a redox shuttle, it can both quench radicals as well as provide energy to the mitochondria. To understand the role of LAPd in regulating ischemic cell death, we studied Poly MVA. Male Mongolian gerbils were subjected to 5 min of bilateral carotid artery occlusion under a controlled temperature environment (37.0-38.0 degrees C). Animals were injected with physiological saline or either 30, 50, or 70 mg/kg of Poly MVA every 24 h beginning immediately after the occlusion until being sacrificed on experimental day 4. Damage was evaluated by analyzing nesting behavior and conducting blinded measures of viable CA1 lengths. All Poly MVA treatment dosages significantly (p < 0.05) reduced hippocampal CA1 damage by 72 h. Nesting scores were significantly improved after 30 and 50 mg/kg treatment but not 70 mg/kg. While nesting is usually a very accurate indicator of morphological damage, the 70 mg/kg-treated animals demonstrated excessive energy, thus ignoring the nesting material. While numerous routes offer varying degrees of CA1 neuronal survival after transient global ischemia, only the LAPd complex, which quenches radicals and provides energy to stabilize the mitochondria, offers such significant protection. Thus, the administration of Poly MVA may be a potent neuroprotective agent for victims of transient ischemic attack (TIA), cardiac arrest, anesthetic accidents, or drowning.
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PMID:Regulation of ischemic cell death by the lipoic acid-palladium complex, Poly MVA, in gerbils. 1529 31

Poly(ADP-ribosyl)ation is rapidly formed in cells following DNA damage and is regulated by poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 is known to be involved in various cellular processes, such as DNA repair, genomic stability, transcription, and cell death. During apoptosis, PARP-1 is cleaved by caspases to generate 89-kDa and 24-kDa fragments, a hallmark of apoptosis. This cleavage is thought to be a regulatory event for cellular death. In order to understand the biological significance of PARP-1 cleavage, we generated a PARP-1 knockin (PARP-1(KI/KI)) mouse model, in which the caspase cleavage site of PARP-1, DEVD(214), was mutated to render the protein resistant to caspases during apoptosis. While PARP-1(KI/KI) mice developed normally, they were highly resistant to endotoxic shock and to intestinal and renal ischemia-reperfusions, which were associated with reduced inflammatory responses in the target tissues and cells due to the compromised production of specific inflammatory mediators. Despite normal binding of NF-kappaB to DNA, NF-kappaB-mediated transcription activity was impaired in the presence of caspase-resistant PARP-1. This study provides a novel insight into the function of PARP-1 in inflammation and ischemia-related pathophysiologies.
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PMID:Noncleavable poly(ADP-ribose) polymerase-1 regulates the inflammation response in mice. 1548 54


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