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)

Poly(ADP-ribose) polymerase-1 (PARP-1) is a member of the PARP enzyme family consisting of PARP-1 and several recently identified novel poly(ADP-ribosylating) enzymes. PARP-1 is an abundant nuclear protein functioning as a DNA nick-sensor enzyme. Upon binding to DNA breaks, activated PARP cleaves NAD(+) into nicotinamide and ADP-ribose and polymerizes the latter onto nuclear acceptor proteins including histones, transcription factors, and PARP itself. Poly(ADP-ribosylation) contributes to DNA repair and to the maintenance of genomic stability. On the other hand, oxidative stress-induced overactivation of PARP consumes NAD(+) and consequently ATP, culminating in cell dysfunction or necrosis. This cellular suicide mechanism has been implicated in the pathomechanism of stroke, myocardial ischemia, diabetes, diabetes-associated cardiovascular dysfunction, shock, traumatic central nervous system injury, arthritis, colitis, allergic encephalomyelitis, and various other forms of inflammation. PARP has also been shown to associate with and regulate the function of several transcription factors. Of special interest is the enhancement by PARP of nuclear factor kappa B-mediated transcription, which plays a central role in the expression of inflammatory cytokines, chemokines, adhesion molecules, and inflammatory mediators. Herein we review the double-edged sword roles of PARP in DNA damage signaling and cell death and summarize the underlying mechanisms of the anti-inflammatory effects of PARP inhibitors. Moreover, we discuss the potential use of PARP inhibitors as anticancer agents, radiosensitizers, and antiviral agents.
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PMID:The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. 1222 30

The NO/superoxide (O2-) balance is a key regulator of endothelial function. O2- levels are elevated in many forms of cardiovascular disease; therefore, decreasing O2- should improve endothelial function. To explore this hypothesis, internal mammary arteries and saphenous veins, obtained from patients undergoing coronary artery revascularization, and aortic and carotid arteries from Wistar-Kyoto and spontaneously hypertensive stroke-prone rats were incubated with O2- dismutase or NAD(P)H oxidase inhibitors. O2- levels were measured using lucigenin chemiluminescence; NO bioavailability was assessed in organ chambers; and mRNA expression of NAD(P)H oxidase components was quantified by use of a Light Cycler. In rat arteries, phenylarsine oxide, 4-(2-aminoethyl)-benzenesulfanyl fluoride, and apocynin all decreased NADH-stimulated O2- production, but only apocynin increased NO bioavailability. In human internal mammary arteries and saphenous veins, apocynin decreased NAD(P)H-stimulated O2- generation and caused vasorelaxation that was endothelium dependent and reversed on addition of the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester. In addition, it increased NO production from cultured human endothelial saphenous vein cells. Polyethylene-glycolated O2- dismutase also increased NO bioavailability in rat carotid arteries and human blood vessels, but the effects were smaller than those observed with apocynin. NADH-generated O2- and mRNA expression of p22(phox), gp91(phox), and nox-1 were comparable between the 2 strains of rat. This is the first study to demonstrate pharmacological effects of apocynin in human blood vessels. The increases in NO bioavailability shown here suggest that the NAD(P)H oxidase pathway may be a novel target for drug intervention in cardiovascular disease.
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PMID:NAD(P)H oxidase inhibition improves endothelial function in rat and human blood vessels. 1241 73

Poly(ADP-ribose) polymerase-1 (PARP-1) is the principal member of the PARP enzyme family consisting of PARP-1 and several recently identified novel poly(ADP-ribosyl)ating enzymes. PARP-1 functions as a DNA damage sensor and signalling molecule. Upon binding to DNA breaks, activated PARP cleaves NAD(+) into nicotinamide and ADP-ribose and polymerizes the latter onto nuclear acceptor proteins including histones, transcription factors and PARP itself. This Poly(ADP-ribosyl)ation contributes to inflammatory signal transduction processes. In addition, oxidative stress-induced overactivation of PARP consumes NAD(+) and consequently ATP, culminating in cell dysfunction or necrosis. Activation of PARP has been implicated in the pathogenesis of stroke, myocardial ischemia, diabetes, diabetes-associated cardiovascular dysfunction, shock, traumatic central nervous system injury, arthritis, colitis, allergic encephalomyelitis and various other forms of inflammation. Therefore, inhibition of PARP by pharmacological agents may prove useful for the therapy of these diseases, as has been shown in preclinical animal models. Moreover, PARP inhibitors may have additional, potential utility as anticancer agents, radiosensitizers and antiviral agents. In the present article we overview the structures and pharmacological actions of various pharmacological classes of compounds which inhibit the catalytic activity of PARP.
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PMID:Poly(ADP-ribose) polymerase inhibitors. 1257 Jul 5

Peroxynitrite is formed in biological systems when superoxide and nitric oxide are produced at near equimolar ratio. Although not a free radical by chemical nature (as it has no unpaired electron), peroxynitrite is a powerful oxidant exhibiting a wide array of tissue damaging effects ranging from lipid peroxidation, inactivation of enzymes and ion channels via protein oxidation and nitration to inhibition of mitochondrial respiration. Low concentrations of peroxynitrite trigger apoptotic death, whereas higher concentrations induce necrosis with cellular energetics (ATP and NAD) serving as switch between the two modes of cell death. Peroxynitrite also damages DNA and thus triggers the activation of DNA repair systems. A DNA nick sensor enzyme, poly(ADP-ribose) polymerase-1 (PARP-1) also becomes activated upon sensing DNA breakage. Activated PARP-1 cleaves NAD(+) into nicotinamide and ADP-ribose and polymerizes the latter on nuclear acceptor proteins. Peroxynitrite-induced overactivation of PARP consumes NAD(+) and consequently ATP culminating in cell dysfunction, apoptosis or necrosis. This cellular suicide mechanism has been implicated among others in the pathomechanism of stroke, myocardial ischemia, diabetes and diabetes-associated cardiovascular dysfunction. Here, we review the cytotoxic effects (apoptosis and necrosis) of peroxynitrite focusing on the role of accelerated ADP-ribose turnover. Regulatory mechanisms of peroxynitrite-induced cytotoxicity such as antioxidant status, calcium signalling, NFkappaB activation, protein phosphorylation, cellular adaptation are also discussed.
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PMID:Peroxynitrite-induced cytotoxicity: mechanism and opportunities for intervention. 1267 57

Elevated production of hydrogen peroxide (H2O2) in the central nervous system has been implicated in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, ischemic reperfusion, stroke, and Alzheimer's disease. Pyruvic acid has a critical role in energy metabolism and a capability to nonenzymatically decarboxylate H2O2 into H2O. This study examined the effects of glycolytic regulation of pyruvic acid on H2O2 toxicity in murine neuroblastoma cells. Glycolytic energy substrates including D-(+)-glucose, D-(-) fructose and the adenosine transport blocker dipyridamole, were not effective in providing protection against H2O2 toxicity, negating energy as a factor. On the other hand, pyruvic acid completely prevented H2O2 toxicity, restoring the loss of ATP and cell viability. H2O2 toxicity was also attenuated by D-fructose 1,6 diphosphate (FBP), phospho (enol) pyruvate (PEP), niacinamide, beta-nicotinamide adenine dinucleotide (beta-NAD+), and reduced form (beta-NADH). Both FBP and PEP exerted positive kinetic effects on pyruvate kinase (PK) activity. Interestingly, only pyruvic acid and beta-NADH exhibited powerful stoichiometric H2O2 antioxidant properties. Further, beta-NADH may exert positive effects on PK activity. Subsequent pyruvic acid accumulation can lead to the recycling of beta-NAD+ through lactate dehydrogenase and beta-NADH through glyceraldehyde-3-phosphate dehydrogenase. It was concluded from these studies that intracellular pyruvic acid and beta-NADH appear to act in concert through glycolysis, to enhance H2O2 intracellular antioxidant capacity in neuroblastoma cells. Future research will be required to examine whether similar effects are observed in primary neuronal culture or intact tissue.
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PMID:Cytoprotection of pyruvic acid and reduced beta-nicotinamide adenine dinucleotide against hydrogen peroxide toxicity in neuroblastoma cells. 1271 24

This review summarizes the numerous reports that have documented the neuroprotective actions of melatonin in experimental models of ischemia/reperfusion injury (stroke). In these investigations, which have used three species (rat, gerbil, and cat), melatonin was universally found to reduce brain damage that normally occurs as a consequence of the temporary interruption of blood flow followed by the reflow of oxygenated blood to the brain. The exogenous administration of melatonin in these experimental stroke models reduced infarct volume, lowered the frequency of apoptosis, increased the number of surviving neurons, reduced reactive gliosis, lowered the oxidation of neural lipids and oxidatively damaged DNA, induced bcl-2 gene expression (the activity of which improves cell survival), upregulated excision repair cross-complementing factor 6 (an essential gene for preferential DNA excision repair), restrained poly(ADP ribose) synthetase (which depletes cellular NAD resulting in the loss of ATP) activity, and improved neurophysiologic outcomes. Under no circumstances did melatonin exacerbate the damage associated with ischemia/reperfusion injury. As well as the beneficial pharmacologic actions of melatonin, several studies show that a relative deficiency of endogenous melatonin exaggerates neural damage due to stroke; this suggests that even physiologic concentrations of melatonin normally serve to protect the brain against damage. The primary action to explain melatonin's protective effects may relate to its ubiquitous direct and indirect antioxidative actions, although other beneficial functions of melatonin are not precluded.
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PMID:Melatonin ameliorates neurologic damage and neurophysiologic deficits in experimental models of stroke. 1285 93

Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear enzyme that is activated primarily by DNA damage. Upon activation, the enzyme hydrolyzes NAD(+) to nicotinamide and transfers ADP ribose units to a variety of nuclear proteins, including histones and PARP-1 itself. This process is important in facilitating DNA repair. However, excessive activation of PARP-1 can lead to significant decrements in NAD(+), and ATP depletion, and cell death (suicide hypothesis). In response to cellular damage by oxygen radicals or excitotoxicity, a rapid and strong activation of PARP-1 occurs in neurons. Excessive PARP-1 activation is implicated in a variety of insults, including cerebral and cardiac ischemia, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism, traumatic spinal cord injury, and streptozotocin-induced diabetes. The use of PARP inhibitors has, therefore, been proposed as a protective therapy in decreasing excitotoxic neuronal cell death, as well as ischemic and other tissue damage. Excitotoxic brain lesions initially result in the primary destruction of brain parenchyma and subsequently in secondary damage of neighboring neurons hours after the insult. This secondary damage of initially surviving neurons accounts for most of the volume of the infarcted area and the loss of brain function after a stroke. One major component of secondary neuronal damage is the migration of macrophages and microglial cells toward the sites of injury, where they produce large quantities of toxic cytokines and oxygen radicals. Recent evidence indicates that this microglial migration is strongly controlled in living brain tissue by expression of the integrin CD11a, which is regulated in turn by PARP-1, proposing that PARP-1 downregulation may, therefore, be a promising strategy in protecting neurons from this secondary damage, as well. Studies demonstrating an important role for PARP-1 in the regulation of gene transcription have further increased the intricacy of poly(ADP-ribosyl)ation in the control of cell homeostasis and challenge the notion that energy collapse is the sole mechanism by which poly(ADP-ribose) formation contributes to cell death. The hypothesis that PARPs might regulate cell fate as essential modulators of death and survival transcriptional programs is discussed with relation to nuclear factor kappaB and p53.
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PMID:Poly(ADP-Ribose) polymerase-1 in acute neuronal death and inflammation: a strategy for neuroprotection. 1285 16

The purpose of the current study was to investigate aspects of improved bioenergetic function using nicotinamide during stroke. Using a global ischemia-reperfusion mouse model, ATP was depleted by 50% in the brain. The use of nicotinamide to provide a large reserve of brain NAD+ restored ATP levels to 61% of control levels. Alternatively, using nicotinamide as a PARP inhibitor restored ATP levels up to 72%. However, using a large reserve of NAD+ in the brain together with PARP inhibition proved to be additive, restoring ATP to 85% of control levels during the first critical 5 min of reperfusion. NAD+ and ATP levels correlated almost exactly. Brain mitochondrial function was also examined after cerebral ischemia-reperfusion. State 3 respiration of complex I was found to be abolished. However, this was a non-permanent inhibition of activity in vitro, since (NADH ubiquinone oxideroductase) complex I activity in these mitochondria was restored upon the addition of NADH. In vivo, the use of increased brain NAD+ and PARP inhibition was able to partially restore mitochondrial respiration. Taken together, the results show that nicotinamide offers a substantial protective role in terms of preservation of cellular ATP and mitochondrial NAD-linked respiration.
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PMID:Nicotinamide offers multiple protective mechanisms in stroke as a precursor for NAD+, as a PARP inhibitor and by partial restoration of mitochondrial function. 1451 2

Poly(ADP-ribose) polymerase 1 (PARP-1) protects the genome by functioning in the DNA damage surveillance network. In response to stresses that are toxic to the genome, PARP-1 activity increases substantially, an event that appears crucial for maintaining genomic integrity. Massive PARP-1 activation, however, can deplete the cell of NAD(+) and ATP, ultimately leading to energy failure and cell death. The discovery that cell death may be suppressed by PARP inhibitors or by deletion of the parp-1 gene has prompted a great deal of interest in the process of poly(ADP-ribosyl)ation. Suppression of PARP-1 is capable of protecting against cerebral and cardiac ischemia, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism, traumatic spinal cord injury, and streptozotocin-induced diabetes. The secondary damage of initially surviving neurons in brain stroke accounts for most of the volume of the infarcted area and the subsequent loss of brain function. Microglial migration is strongly controlled in living brain tissue by expression of the integrin CD11a, which is regulated in turn by PARP-1, proposing that PARP-1 downregulation may therefore be a promising strategy in protecting neurons from this secondary damage, as well. As PARP-1 is now recognised as playing a role also in the regulation of gene transcription, this further increases the intricacy of poly(ADP-ribosyl)ation in the control of cell homeostasis and challenges the notion that energy collapse is the sole mechanism by which poly(ADP-ribose) formation contributes to cell death. PARP(s) might regulate cell fate as essential modulators of death and survival transcriptional programs with relation to NF-kappaB and p53, proposing that inhibitors of poly(ADP-ribosyl)ation could therefore prevent the deleterious consequences of neuroinflammation by reducing NF-kappaB activity.
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PMID:Poly(ADP-ribosyl)ation enzyme-1 as a target for neuroprotection in acute central nervous system injury. 1452 60

Methylenetetrahydrofolate reductase (MTHFR) deficiency is the most common genetic cause of hyperhomocysteinemia, which is associated with increased risk for cardiovascular disease, stroke and possibly other neurological disorders. Microarray analysis of brain RNA from day 14 Mthfr(-/-) mice revealed several genes with altered expression. Expression changes in inositol 1,4,5-triphosphate receptor, type 1 (Itpr1), proteolipid protein (Plp), neurogenic differentiation factor 1 (Neurod1), S100 calcium binding protein A8 (S100a8), and methylenetetrahydrofolate dehydrogenase (NAD+ dependent), methenyltetrahydrofolate cyclohydrolase (Mthfd2) were confirmed by RT-PCR. We propose that neuronal damage by hyperhomocysteinemia may involve disruption of intracellular calcium.
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PMID:Microarray analysis of brain RNA in mice with methylenetetrahydrofolate reductase deficiency and hyperhomocysteinemia. 1501 4


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