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)

Ethyl pyruvate (EP), a simple aliphatic ester of pyruvic acid, has been shown to improve survival and ameliorate organ damage in animal models of sepsis, ischemia/reperfusion injury and hemorrhagic shock. Incubating IL3-dependent mouse hematopoietic progenitor cell 32Dcl3 cells before or after irradiation with 10 mM EP increased resistance to radiation as assessed by clonogenic radiation survival curves, decreased release of mitochondrial cytochrome C into the cytoplasm, and decreased apoptosis. EP inhibited radiation-induced caspase 3 activation and poly(ADP-ribose) polymerase (PARP) cleavage in 32Dcl3 cells in a concentration-dependent fashion. EP was given i.p. to C57BL/6NHsd mice irradiated with 9.75 Gy total-body irradiation (TBI). This treatment significantly improved survival. The survival benefit was apparent irrespective of whether treatment with EP was started 1 h before TBI and continued for 5 consecutive days after TBI or the compound was injected only 1 h before or only for 5 days after TBI. In all of the in vitro and in vivo experiments, ethyl lactate, an inactive analogue of EP, had no detectable radioprotective or mitigating effects. EP may be an effective radioprotector and mitigator of the hematopoietic syndrome induced by TBI.
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PMID:Ethyl pyruvate, a potentially effective mitigator of damage after total-body irradiation. 1797 49

Melatonin is a recognized antioxidant with high potential as a protective agent in many conditions related to oxidative stress such as neurodegenerative diseases, ischemia/reperfusion syndromes, sepsis and aging. These processes may be favorably affected by melatonin through its radical scavenging properties and/or antiapoptotic activity. Also, there is increasing evidence that these effects of melatonin could be relevant in keratinocytes, the main cell population of the skin where it would contribute to protection against damage induced by ultraviolet radiation (UVR). We therefore investigated the kinetics of UVR-induced apoptosis in cultured keratinocytes characterizing the morphological and mitochondrial changes, the caspases-dependent apoptotic pathways and involvement of poly(ADP-ribose) polymerase (PARP) activation as well as the protective effects of melatonin. When irradiated with UVB radiation (50 mJ/cm(2)), melatonin treated, cultured keratinocytes were more confluent, showed less cell blebbing, more uniform shape and less nuclear condensation as compared to irradiated, nonmelatonin-treated controls. Preincubation with melatonin also led to normalization of the decreased UVR-induced mitochondrial membrane potential. These melatonin effects were followed by suppression of the activation of mitochondrial pathway-related initiator caspase 9 (casp-9), but not of death receptor-dependent casp-8 between 24 and 48 hr after UVR exposure. Melatonin down-regulated effector caspases (casp-3/casp-7) at 24-48 hr post-UV irradiation and reduced PARP activation at 24 hr. Thus, melatonin is particularly active in UV-irradiated keratinocytes maintaining the mitochondrial membrane potential, inhibiting the consecutive activation of the intrinsic apoptotic pathway and reducing PARP activation. In conclusion, these data provide detailed evidence for specific antiapoptotic mechanisms of melatonin in UVR-induced damage of human keratinocytes.
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PMID:Melatonin maintains mitochondrial membrane potential and attenuates activation of initiator (casp-9) and effector caspases (casp-3/casp-7) and PARP in UVR-exposed HaCaT keratinocytes. 1808 47

The association of ADP-ribosylation with cell proliferation and ischemia-reperfusion injury suggests that it may be a suitable target for therapeutic control of revascularization-induced injury. The purpose of this study was to investigate the inhibitory actions of ADP-ribosylation inhibitors on restenosis. In organ culture, the poly(ADP-ribose) polymerase (PARP) inhibitor 3,4-dihydro-5-methylisoquinolinone (PD128763) was unable to prevent neointimal hyperplasia, whereas the arginine-dependent mono(ADP-ribosyl)transferase (ART) inhibitor meta-iodobenzylguanidine (MIBG) was highly effective (EC(50) 21 microM). Treatment with 3-aminobenzamide (3AB), a less potent ART inhibitor, also produced a significant reduction in neointimal hyperplasia. Single doses (25 mM) of MIBG and 3AB were also applied within a fibrin coagulum directly to the adventitial surface of the porcine femoral artery after balloon catheter injury in vivo. MIBG reduced the neointimal index, measured 14 days after angioplasty, by 82%, whereas 3AB was ineffective. However, when extended to 45 days, the neointimal index was not significantly decreased by MIBG treatment relative to control. Assessment of MIBG release from the fibrin glue showed that the bulk of the compound was eluted within 3 days, suggesting that the vehicle was not suitable for long-term delivery. On the other hand, direct infusion of MIBG into vessels was able to reduce neointimal hyperplasia over 14 days in organ culture. These data support the conclusion that the cellular retention characteristics of MIBG contribute significantly to the efficacy of this compound. Based on these results, ART, but not PARP, may be a credible target for therapeutic treatment of restenosis.
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PMID:Meta-iodobenzylguanidine, an inhibitor of arginine-dependent mono(ADP-ribosyl)ation, prevents neointimal hyperplasia. 1852 60

Blocking of poly(ADP-ribose) polymerase (PARP)-1 has been expected to protect the heart from ischemia-reperfusion injury. We have recently identified a novel and orally active PARP-1 inhibitor, KR-33889 [2-[methoxycarbonyl(4-methoxyphenyl)-methylsulfanyl]-1H-benzimidazole-4-carboxylic acid amide], and its major metabolite, KR-34285 [2-[carboxy(4-methoxyphenyl)methylsulfanyl]-1H-benzimidazole-4-carboxylic acid amide]. KR-33889 potently inhibited PARP-1 activity with an IC(50) value of 0.52 +/- 0.10 microM. In H9c2 myocardial cells, KR-33889 (0.03-30 microM) showed a resistance to hydrogen peroxide (2 mM)-mediated oxidative insult and significantly attenuated activation of intracellular PARP-1. In anesthetized rats subjected to 30 min of coronary occlusion and 3 h of reperfusion, KR-33889 (0.3-3 mg/kg i.v.) dose-dependently reduced myocardial infarct size. KR-34285, a major metabolite of KR-33889, exerted similar patterns to the parent compound with equi- or weaker potency in the same studies described above. In separate experiments for the therapeutic time window study, KR-33889 (3 mg/kg i.v.) given at preischemia, at reperfusion or in both, in rat models also significantly reduced the myocardial infarction compared with their respective vehicle-treated group. Furthermore, the oral administration of KR-33889 (1-10 mg/kg p.o.) at 1 h before occlusion significantly reduced myocardial injury. The ability of KR-33889 to inhibit PARP in the rat model of ischemic heart was confirmed by immunohistochemical detection of poly(ADP-ribose) activation. These results indicate that the novel PARP inhibitor KR-33889 exerts its cardioprotective effect in in vitro and in vivo studies of myocardial ischemia via potent PARP inhibition and also suggest that KR-33889 could be an attractive therapeutic candidate with oral activity for several cardiovascular disorders, including myocardial infarction.
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PMID:A novel and orally active poly(ADP-ribose) polymerase inhibitor, KR-33889 [2-[methoxycarbonyl(4-methoxyphenyl) methylsulfanyl]-1H-benzimidazole-4-carboxylic acid amide], attenuates injury in in vitro model of cell death and in vivo model of cardiac ischemia. 1883 68

Ischemic preconditioning (PC) of the brain is a phenomenon by which mild ischemic insults render neurons resistant to subsequent strong insults. Key steps in ischemic PC of the brain include caspase-3 activation and poly(ADP-ribose) polymerase-1 (PARP-1) cleavage, but upstream events have not been clearly elucidated. We have tested whether endogenous zinc is required for ischemic PC of the brain in rats. Mild, transient zinc accumulation was observed in certain neurons after ischemic PC. Moreover, intraventricular administration of CaEDTA during ischemic PC abrogated both zinc accumulation and the protective effect against subsequent full ischemia. To elucidate the mechanism of the zinc-triggered PC (Zn PC) effect, cortical cultures were exposed to sublethal levels of zinc, and 18 h later to lethal levels of zinc or NMDA. Zn PC exhibited the characteristic features of ischemic PC, including caspase-3 activation, PARP-1 cleavage, and HSP70 induction, all of which are crucial for subsequent neuroprotection against NMDA or zinc toxicity. HSP70 induction was necessary for protection, as it halted caspase-3 activation before apoptosis. Interestingly, in both Zn PC in vitro and ischemic PC in vivo, p75(NTR) was necessary for neuroprotection. These results suggest that caspase-3 activation during ischemic PC, a necessary event for subsequent neuroprotection, may result from mild zinc accumulation and the consequent p75(NTR) activation in neurons.
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PMID:Essential role for zinc-triggered p75NTR activation in preconditioning neuroprotection. 1894 99

We studied cardioprotective as well as Akt and extracellular signal-activated kinase (ERK) activating effect of a Ca(2+) antagonist and a beta-adrenergic receptor blocker during ischemia-reperfusion, and compared these properties of the substances with that of a poly(ADP-ribose) polymerase (PARP) inhibitor used as a positive control throughout the experiments. Langendorff-perfused isolated rat hearts were subjected to 25 min global ischemia followed by 45 min reperfusion, and recovery of energy metabolism as well as functional cardiac parameters were monitored. Although to varying extents, all substances improved recovery of creatine phosphate, ATP, intracellular pH, and reutilization of inorganic phosphate. These favorable changes were accompanied by improved recovery of heart function parameters and reduced infarct size. In addition and again to varying extents, all studied substances decreased oxidative damage (lipid peroxidation and protein oxidation), and activated Akt, glycogen synthase kinase (GSK)-3beta, and ERK1/2. Correlation between cardioprotective and kinase activating effectivity of the compounds proved to be statistically significant. Physiological significance of these kinase activations was established by demonstrating that inhibition of Akt by LY294002 and ERK1/2 by PD98059 compromised the cardioprotective effect of all the substances studied. In conclusion, we demonstrated for the first time that activation of phosphatidylinositol-3-kinase (PI-3K)-Akt and ERK2 pathways significantly contributed to cardioprotective effects of a Ca(2+) antagonist and a beta-adrenergic receptor blocker. Furthermore, we found a strong correlation between cardioprotective and kinase-activating potencies of the substances studied (Verapamil, Metoprolol and two PARP inhibitors), which indicated the potentiality of these kinases as drug-targets in the therapy of ischemic heart disease.
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PMID:Prevalent role of Akt and ERK activation in cardioprotective effect of Ca(2+) channel- and beta-adrenergic receptor blockers. 1897 57

After ischemic renal injury (IRI), selective damage occurs in the S(3) segments of the proximal tubules as a result of inhibition of glycolysis, but the mechanism of this inhibition is unknown. We previously reported that inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) activity protects against ischemia-induced necrosis in proximal tubules by preserving ATP levels. Here, we tested whether PARP-1 activation in proximal tubules after IRI leads to poly(ADP-ribosyl)ation of the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a modification that inhibits its activity. Using in vitro and in vivo models, under hypoxic conditions, we detected poly(ADP-ribosyl)ation and reduced activity of GAPDH; inhibition of PARP-1 activity restored GAPDH activity and ATP levels. Inhibition of GAPDH with iodoacetate exacerbated ATP depletion, cytotoxicity, and necrotic cell death of LLCPK(1) cells subjected to hypoxic conditions, whereas inhibition of PARP-1 activity was cytoprotective. In conclusion, these data indicate that poly(ADP-ribosyl)ation of GAPDH and the subsequent inhibition of anaerobic respiration exacerbate ATP depletion selectively in the proximal tubule after IRI.
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PMID:PARP-1 inhibits glycolysis in ischemic kidneys. 1905 68

During ischemia-reperfusion, reactive oxygen species are generated along the mitochondrial respiratory chain and induce lipid peroxidation, protein oxidation and DNA damage. Single-strand DNA breaks are the most potent activators of poly(ADP-ribose) polymerase (PARP); prolonged action of PARP culminates in intracellular oxidized nicotinamide adenine dinucleotide (NAD(+)) and ATP depletion. The integrity of cellular components and the myocardial energy metabolism can be preserved by using PARP inhibitors under conditions of ischemia and reperfusion. Oxidative stress is capable of activating the phosphoinositol-3-kinase-Akt/protein kinase B signalling pathway, which is further enhanced if treated with PARP inhibitors. Akt, in turn, promotes the survival of cardiomyocytes by inhibiting apoptotis, and causing metabolic adjustment and vasodilation in the jeopardized myocardium.
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PMID:Myocardial protection by selective poly(ADP-ribose) polymerase inhibitors. 1964 91

The ischemia/reperfusion (I/R) model in rats allows pharmacological investigation of protective renal effects of certain agents to thereby diminish the incidence of delayed graft function (DGF). The aim of this study was to determine the effects of preconditioning with triiodothyronine (T(3)) on renal function and oxidative status in renal I/R injury. Forty male Wistar rats were preconditioned with T(3) (100 microg/kg) or control (normal saline) at 24 hours prior to 45 minutes of renal ischemia, followed by a 4-hour (groups C-4h and T(3)-4h) or 24-hour (groups C-24h and T(3)-24h) reperfusion period. We determined renal function parameters (urea, creatinine, and proteinuria), oxidative stress biomarkers in plasma (malondialdehyde [MDA], glutathione [GSH], and superoxide dismutase [SOD]), urine (hydrogen peroxide [H(2)O(2)]), and renal tissue (GSH and MDA), and poly(ADP-ribose) polymerase (PARP-1) expression. Proteinuria was significantly lower in the T(3)-treated group (4.63 +/- 1.9 vs 9.27 +/- 0.72 mg/mL/100 g body weight). Pretreated rats showed lower levels of plasma and tissue MDA and urine H(2)O(2) (50.57 +/- 1.17 vs 71.16 +/- 1.14 micromol/100 g body weight). The T(3) treatment was associated with lower postischemia GSH concentrations (3.82 +/- 1.16 vs 4.89 +/- 0.68 nmol/mg protein) and higher SOD levels at 24 hours (11.27 +/- 0.86 vs 9.92 +/- 1.77 nmol/mg protein). Preconditioning with the hormone also reduced PARP-1 tissue expression by 18% (P <or= .05). These findings suggested that preconditioning with T(3) reduced proteinuria, improved lipid peroxidation biomarkers, and increased antioxidant enzyme levels in renal I/R injury.
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PMID:Effect of preconditioning with triiodothyronine on renal ischemia/reperfusion injury and poly(ADP-ribose) polymerase expression in rats. 1971 35

The pathogenesis of ischemic stroke is a complex sequence of events including inflammatory reaction, for which the microglia appears to be a major cellular contributor. However, whether post-ischemic activation of microglial cells has beneficial or detrimental effects remains to be elucidated, in particular on long term brain plasticity events. The objective of our study was to determine, through modulation of post-stroke inflammatory response, to what extent microglial cells are involved in some specific events of neuronal plasticity, neurite outgrowth and synaptogenesis. Since microglia is a source of neurotrophic factors, the identification of the brain-derived neurophic factor (BDNF) as possible molecular actor involved in these events was also attempted. As a means of down-regulating the microglial response induced by ischemia, 3-aminobenzamide (3-AB, 90 mg/kg, i.p.) was used to inhibit the poly(ADP-ribose) polymerase-1 (PARP-1). Indeed, PARP-1 contributes to the activation of the transcription factor NF-kB, which is essential to the upregulation of proinflammatory genes, in particular responsible for microglial activation/proliferation. Experiments were conducted in rats subjected to photothrombotic ischemia which leads to a strong and early microglial cells activation/proliferation followed by an infiltration of macrophages within the cortical lesion, events evaluated at serial time points up to 1 month post-ictus by immunostaining for OX-42 and ED-1. Our most striking finding was that the decrease in acute microglial activation induced by 3-AB was associated with a long term down-regulation of two neuronal plasticity proteins expression, synaptophysin (marker of synaptogenesis) and GAP-43 (marker of neuritogenesis) as well as to a significant decrease in tissue BDNF production. Thus, our data argue in favour of a supportive role for microglia in brain neuroplasticity stimulation possibly through BDNF production, suggesting that a targeted protection of microglial cells could represent an innovative approach to potentiate post-stroke neuroregeneration.
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PMID:Microglial involvement in neuroplastic changes following focal brain ischemia in rats. 1995 68


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