Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The poly(ADP-ribose)polymerases (PARPs) catalyse the transfer of ADP-ribose units from the substrate NAD(+) to acceptor proteins, biosynthesising polyanionic poly(ADP-ribose) polymers. A major isoform, PARP-1, has been the target for design of inhibitors for over twenty-five years. Inhibitors of the activity of PARP-1 have been claimed to have applications in the treatment of many disease states, including cancer, haemorrhagic shock, cardiac infarct, stroke, diabetes, inflammation and retroviral infection, but only recently have PARP-1 inhibitors entered clinical trial. Most PARP-1 inhibitors mimic the nicotinamide of NAD(+) and the structure-activity relationships are understood in terms of the structure of the catalytic site. However, five questions remain if PARP-1 inhibitors are to realise their potential in treating human diseases. Firstly, the consensus pharmacophore is a benzamide with N-H conformationally constrained anti to the carbonyl-arene bond but this is also a "pharmacophore" for insolubility in water; can water-solubility be designed into inhibitors without loss of potency? Secondly, some potential clinical applications require tissue-selective PARP-1 inhibition; is this possible through pro-drug approaches? Thirdly, different diseases may require therapeutic PARP-1 inhibition to be either short-term or chronic; are there potential problems associated with chronic inhibition of this DNA-repair process? Fourthly, PARP-1 is one of at least eighteen isoforms; is isoform-selectivity essential, desirable or even possible? Fifthly, PARP activity can be inhibited in cells by inhibition of poly(ADP-ribose)-glycohydrolase (PARG); will this be a viable strategy for future drug design? The answers to these questions will determine the future of disease therapy through inhibition of PARP.
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PMID:Poly(ADP-ribose)polymerase inhibition - where now? 1618 Nov 38

Poly(ADP-ribose) polymerase (PARP) plays a pivotal role in the repair of DNA strand breaks. However, excessive activation of PARP causes a rapid depletion of intracellular energy, leading to cell death. PARP inhibitors may have potential therapeutic benefit in the treatment of myocardial ischemia, stroke, and neurodegenerative disease. With these emerging medicinal interests, various screening programs have identified small molecules that inhibit PARP with reasonable potencies. However, the increasing numbers of diverse small molecules generated through combinatorial chemistry necessitate the use of robust assays with good sensitivity and specificity for use as a high-throughput screening (HTS) program. Here, we report the development and the validation of a nonisotopic PARP-1 assay suitable for HTS by converting a biotinylated NAD-based colorimetric assay to a miniaturized 384-well plate format. Comparing with the conventional methods, this miniaturized PARP-1 inhibition assay was equally sensitive with excellent reproducibility and cost-effectiveness. Because nonisotopic PARP-1 inhibition assays are widely used, the methodology described in this article can expand the feasibility of this assay as a high-throughput assay for screening of PARP-1 inhibitors from a random chemical library.
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PMID:Development of a miniaturized assay for the high-throughput screening program for poly(ADP-ribose) polymerase-1. 1635 45

Mild hypothermia, applied either during or soon after cerebral ischemia, has been shown to confer robust neuroprotection against brain injury in experimental stroke and in patients recovering from cardiac arrest. However, the mechanism underlying hypothermic neuroprotection is not completely understood. In this study, the effect of mild hypothermia on the induction of oxidative DNA damage, an early harmful event during post-ischemic reperfusion that triggers both necrotic and apoptotic cell death in the brain, was studied using the rat model of middle cerebral artery occlusion (MCAO) and reperfusion. Rats were subjected to 2-hr MCAO and reperfusion of various durations up to 3 days. Selective brain hypothermia (33 degrees C) was induced at the onset of ischemia and terminated at the beginning of reperfusion, and this significantly decreased infarct volume 72 hr later. Correlated with this protective effect, intraischemic mild hypothermia markedly attenuated the nuclear accumulations of several oxidative DNA lesions, including 8-oxodG, AP sites, and DNA single-strand breaks, after 2-hr MCAO. Consequently, harmful DNA damage-dependent signaling events, including NAD depletion, p53 activation, and mitochondrial translocation of PUMA and NOXA, were reduced during post-ischemic reperfusion in hypothermia-treated brains. These results suggest that the attenuation of oxidative DNA damage and DNA damage-triggered pro-death signaling events may be an important mechanism underlying the neuroprotective effect of mild hypothermia against ischemic brain injury.
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PMID:Mild hypothermia diminishes oxidative DNA damage and pro-death signaling events after cerebral ischemia: a mechanism for neuroprotection. 1712 18

Although vascular cells express multiple members of the Nox family of nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase, including gp91phox, Nox1, and Nox4, the reasons for the different expressions and specific roles of these members in vascular injury in chronic hypertension have remained unclear. Thus, we quantified the mRNA expressions of these NAD(P)H oxidase components by real-time polymerase chain reaction and evaluated superoxide production and morphological changes in the aortas of 32-week-old stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched Wistar Kyoto rats (WKY). The aortic media of SHRSP had an approximately 2.5-fold greater level of Nox4 mRNA and an approximately 10-fold greater level of Nox1 mRNA than WKY. The mRNA expressions of gp91phox and p22phox in SHRSP and WKY were comparable. SHRSP were treated from 24 weeks of age for 8 weeks with either high or low doses of candesartan (4 mg/kg/day or 0.2 mg/kg/day), or a combination of hydralazine (30 mg/kg/day) and hydrochlorothiazide (4.5 mg/kg/day). The high-dose candesartan or the hydralazine plus hydrochlorothiazide decreased the blood pressure of SHRSP to that of WKY, whereas the low-dose candesartan exerted no significant antihypertensive action. Media thickening and fibrosis, as well as the increased production of superoxide in SHRSP, were nearly normalized with high-dose candesartan and partially corrected with low-dose candesartan or hydralazine plus hydrochlorothiazide. These changes by antihypertensive treatment paralleled the decrease in mRNA expression of Nox4 and Nox1. These results suggest that blood pressure and angiotensin II type 1 receptor activation are involved in the up-regulation of Nox1 and Nox4 expression, which could contribute to vascular injury during chronic hypertension.
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PMID:Increased expression of gp91phox homologues of NAD(P)H oxidase in the aortic media during chronic hypertension: involvement of the renin-angiotensin system. 1728 59

Increased mortality after stroke is associated with development of brain edema. The aim of the present study was to examine the contribution of endothelial myosin light chain (MLC) phosphorylation to hypoxia-induced blood-brain barrier (BBB) opening. Measurements of trans-endothelial electrical resistance (TEER) were performed to analyse BBB integrity in an in vitro co-culture model (bovine brain microvascular endothelial cells (BEC) and rat astrocytes). Brain fluid content was analysed in rats after stroke induction using a two-vein occlusion model. Dihydroethidium was used to monitor intracellular generation of reactive oxygen species (ROS) in BEC. MLC phosphorylation was detected using immunohistochemistry and immunoblot analysis. Hypoxia caused a decrease of TEER values by more than 40%, which was prevented by inhibition of the MLC-kinase (ML-7, 10 micromol/L). In addition, ML-7 significantly reduced the brain fluid content in vivo after stroke. The NAD(P)H-oxidase inhibitor apocynin (500 micromol/L) prevented the hypoxia-induced TEER decrease. Hypoxia-dependent ROS generation was completely abolished by apocynin. Furthermore, ML-7 and apocynin blocked hypoxia-dependent phosphorylation of MLC. Our data demonstrate that hypoxia causes a breakdown of the BBB in vitro and in vivo involving ROS and the contractile machinery.
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PMID:Inhibition of the myosin light chain kinase prevents hypoxia-induced blood-brain barrier disruption. 1741 8

Poly(ADP-ribose) polymerase (PARP) comprise of a family of enzymes which catalyses poly(ADP-ribosyl)ation of DNA-binding proteins. To date, seven isoforms have been identified: PARP-1, PARP-2, PARP-3, PARP-4 (Vault-PARP), PARP-5 (Tankyrases), PARP-7 and PARP-10 with structural domains and different functions. PARP-1, the best characterised member, works as a DNA damage nick-sensor protein that uses beta-NAD(+) to form polymers of ADP-ribose and has been implicated in DNA repair, maintenance of genomic integrity and mammalian longevity. The generation of free radicals, reactive oxygen species, and peroxynitrite causes overactivation of PARP resulting in the depletion of NAD(+) and ATP and consequently in necrotic cell death and organ dysfunction. PARP has also been involved in the up-regulation of numerous pro-inflammatory genes through the activation of several transcription nuclear factors. Thus, PARP plays an important role in the pathogenesis of several diseases, such as, stroke, myocardial infarction, circulatory shock, diabetes, neurodegenerative disorders, including Parkinson and Alzheimer diseases, allergy, colitis and other inflammatory disorders. Pharmacological modulation of PARP activity may constitute a suitable target to enhance the cytotoxicity of certain DNA-damaging anticancer drugs. Also, PARP inhibition may be a viable strategy to control viral infections. This review is intended to provide an appreciation of new pharmacological perspectives of these remarkable drugs, summarize novel underlying mechanisms and discuss their potential clinical implications.
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PMID:Poly(ADP-ribose) polymerase inhibitors: new pharmacological functions and potential clinical implications. 1743 Jan 91

Reactive oxygen species are believed to participate in the pathogenesis of traumatic brain injury (TBI). To evaluate the role of cellular glutathione peroxidase (Gpx1), a selenium-containing enzyme functioning in reduction of hydrogen peroxide and alkyl hyperoxides, in protecting animals against TBI, a line of Gpx1 transgenic mice was generated. Overexpression of Gpx1 was found in many organs including the brain of the transgenic mice. This line of transgenic mice and knockout mice deficient in Gpx1 were used in a model of controlled cortical impact injury and the efficiency of oxidative phosphorylation in brain mitochondria was determined. Although a 2-mm depth of mechanical impact caused a drastic decrease in NAD-linked electron transfer activities and energy-coupling capacities in brain mitochondria of nontransgenic mice, the decrease in mitochondrial function was completely prevented by overexpression of Gpx1 in Gpx1 transgenic mice. In addition, a 1-mm deformation depth hardly affected brain mitochondrial function in wild-type (Gpx1+/+) mice, yet resulted in a significant decrease in mitochondrial bioenergetic capacity in brains of homozygous Gpx1 knockout (Gpx1-/-) mice. Further experiments showed that inclusion of calcium chelator egtazic acid in measurement of mitochondrial respiration could completely restore the efficiency of mitochondrial respiration in injured brains of nontransgenic mice and Gpx1-/- mice, suggesting that the observed mitochondrial dysfunction is a direct result of increase in mitochondrion-associated calcium, which is secondary to the increased oxidative stress. These studies not only establish the role of Gpx1 in preventing mitochondrial dysfunction in mouse brain after TBI, but also suggest the species of reactive oxygen responsible for this event.
J Stroke Cerebrovasc Dis
PMID:The protective role of cellular glutathione peroxidase against trauma-induced mitochondrial dysfunction in the mouse brain. 1790 64

Poly(ADP-ribose)polymerases (PARPs) are enzymes that are able to catalyze the transfer of ADP-ribose units from NAD to substrate proteins and are particularly abundant in cell nuclei where they play key roles in the maintenance of genomic integrity, control of cell cycle and gene expression. Brain ischemia overactivates PARPs and PARP-deficient mice or animal treated with PARP inhibitors have a drastically reduced brain damage in various stroke models. PARP 'overactivation' occurs not only in neurons but also in astrocytes, microglial cells, endothelia, and infiltrating leukocytes. The ensuing cell death occurs through various molecular mechanisms: a) excessive ATP use for NAD synthesis and inhibition of mitochondrial function with subsequent energy failure (particularly important in neurons); b) apoptosis-inducing factor (AIF) translocation from the mitochondria to the nucleus (present in neurons, endothelial, and other cells); c) excessive expression of inflammatory mediators (well demonstrated in glial cells) or d) reduced expression of prosurvival factors. Thus PARPs seem to play key roles in postischemic brain damage and are now considered interesting targets for therapies aimed at reducing stroke pathology.
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PMID:Poly(ADP-ribose)polymerase 1 (PARP-1) and postischemic brain damage. 1803 9

Several recent findings point to an important role for redox regulation of platelet responses to collagen involving the receptor, glycoprotein (GP)VI. First, the antioxidant dietary compound, quercetin, was shown to inhibit GPVI-dependent platelet activation and signaling responses to collagen. Second, collagen increased platelet production of the oxygen radical, superoxide anion (O2-), mediated by the multi-subunit enzyme nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidase. In that case, O2- was implicated in regulating not initial aggregation, but collagen-induced thrombus stabilization involving release of ADP. Third, our laboratory showed that an unpaired thiol in the GPVI cytoplasmic tail undergoes rapid oxidation to form GPVI homodimers following ligand binding, preceding GPVI signaling and ectodomain metalloproteolysis, and indicating formation of an oxidative submembranous environment in activated platelets. This review examines receptor/redox regulation in other cells, and relevance to the pathophysiological function of GPVI and other platelet receptors initiating thrombus formation in haemostasis or thrombotic diseases such as heart attack and stroke.
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PMID:Platelet receptor redox regulation. 1823 33

Throughout the last 2 decades, experimental evidence from in vitro studies and preclinical models of disease has demonstrated that reactive oxygen and nitrogen species, including the reactive oxidant peroxynitrite, are generated in parenchymal, endothelial, and infiltrating inflammatory cells during stroke, myocardial and other forms of reperfusion injury, myocardial hypertrophy and heart failure, cardiomyopathies, circulatory shock, cardiovascular aging, atherosclerosis and vascular remodeling after injury, diabetic complications, and neurodegenerative disorders. Peroxynitrite and other reactive species induce oxidative DNA damage and consequent activation of the nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP-1), the most abundant isoform of the PARP enzyme family. PARP overactivation depletes its substrate NAD(+), slowing the rate of glycolysis, electron transport, and ATP formation, eventually leading to functional impairment or death of cells, as well as up-regulation of various proinflammatory pathways. In related animal models of disease, peroxynitrite neutralization or pharmacological inhibition of PARP provides significant therapeutic benefits. Therefore, novel antioxidants and PARP inhibitors have entered clinical development for the experimental therapy of various cardiovascular and other diseases. This review focuses on the human data available on the pathophysiological relevance of the peroxynitrite-PARP pathway in a wide range of disparate diseases, ranging from myocardial ischemia/reperfusion injury, myocarditis, heart failure, circulatory shock, and diabetic complications to atherosclerosis, arthritis, colitis, and neurodegenerative disorders.
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PMID:Role of the peroxynitrite-poly(ADP-ribose) polymerase pathway in human disease. 1853 82


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