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 four additional, recently identified poly(ADP-ribosylating) enzymes. PARP-1 is one of the most abundant nuclear proteins and functions 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. On one hand, PARP is viewed as a guardian angel of genomic integrity, and inhibition of PARP has been used to facilitate the death of tumor cells alone, or in combination with antitumor agents. On the other hand, overactivation of PARP in response to oxidant- and free radical-mediated excessive DNA single strand breaks promotes cell dysfunction and necrotic type cell death in a variety of pathophysiological conditions. Pharmacological inhibition of PARP, consequently, exerts cytoprotective effects in a variety of diseases including stroke, myocardial infarction, heart failure and diabetes mellitus. The research into the role of PARP in diabetic cardiovascular injury is now supported by novel tools such as new classes of potent inhibitors of PARP as well as genetically engineered animals lacking the gene for PARP. In addition, potent PARP inhibitors have entered the stage of clinical testing. The current review provides an update on the most recent developments in the area of PARP.
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PMID:Poly(ADP-ribose) polymerase as a drug target for cardiovascular disease and cancer: an update. 1752 94

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

There is accumulating evidence that caspase-independent programs play a significant role in delayed neuronal death following ischemic stroke. Previous research has implicated mitochondrial proteins, such as apoptosis-inducing factor (AIF) and Bcl-2/adenovirus E1B 19 kDa-interacting protein (BNIP3), as players involved in this pathway. More recent work has begun to hone in on the specific interactions between these molecules and the mediators that might function upstream [e.g., poly(ADP-ribose) polymerase-1 (PARP-1)] and downstream [e.g., endonuclease G (EndoG)] of them. As the study of caspase-independent programs has expanded, it has become increasingly apparent that this pathway is not simply an alternative to apoptosis when caspases are unavailable, but a unique process, distinct from both apoptosis and necrosis. Similar caspase-independent pathways as the ones mentioned apply to organ systems outside of the central nervous system. Put together, the data suggest that caspase-independent programmed cell death is a complex and resilient death program that will likely need to be considered and countered in devising an effective drug therapy for the treatment of ischemic stroke.
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PMID:Caspase-independent programmed cell death following ischemic stroke. 1856 35

Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear protein best known to facilitate DNA base excision repair. Recent work has expanded the physiologic functions of PARP-1, and it is clear that the full range of biologic actions of this important protein are not yet fully understood. Regulation of the product of PARP-1, poly(ADP-ribose) (PAR), is a dynamic process with PAR glycohydrolase playing the major role in the degradation of the polymer. Under pathophysiologic situations overactivation of PARP-1 results in unregulated PAR synthesis and widespread neuronal cell death. Once thought to be necrotic cell death resulting from energy failure, we have found that PARP-1-dependent cell death is dependent on the generation of PAR, which triggers the nuclear translocation of apoptosis-inducing factor resulting in caspase-independent cell death. This form of cell death is distinct from apoptosis, necrosis, or autophagy and is termed parthanatos. PARP-1-dependent cell death has been implicated in tissues throughout the body and in diseases afflicting hundreds of millions worldwide, including stroke, Parkinson's disease, heart attack, diabetes, and ischemia reperfusion injury in numerous tissues. The breadth of indications for PARP-1 injury make parthanatos a clinically important form of cell death to understand and control.
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PMID:Mitochondrial and nuclear cross talk in cell death: parthanatos. 1907 45

Stroke is the third leading cause of death in industrialized countries but efficacious stroke treatment is still an unmet need. Preclinical research indicates that different molecules afford protection from ischemic neurodegeneration, but all clinical trials conducted so far have inexorably failed. Critical re-evaluation of experimental data shows that all the components of the neurovascular unit, such as neurons, glia, endothelia and basal membranes, must be protected during the ischemic insult to obtain substantial and long-lasting neuroprotection. Here, we propose the nuclear enzyme poly(ADP-ribose) polymerase (PARP-1) as a key effector of cell death in the various elements of the neurovascular units, and assert that drugs inhibiting PARP-1 may therefore represent valuable tools for pharmacological treatment of stroke patients.
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PMID:Post-ischemic brain damage: targeting PARP-1 within the ischemic neurovascular units as a realistic avenue to stroke treatment. 1908 98

The brain inflammatory response induced by stroke contributes to cell death and impairs neurogenesis. Poly(ADP-ribose) polymerase-1 (PARP-1) is a coactivator of the transcription factor NF-kappaB and required for NF-kappaB-mediated inflammatory responses. Here we evaluated PARP inhibition as a means of suppressing post-stroke inflammation and improving outcome after stroke. Rats were subjected to bilateral carotid occlusion-reperfusion, and treatment with the PARP inhibitor N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide (PJ34) was begun 48 h later. PJ34 was found to rapidly suppress the ischemia-induced microglial activation and astrogliosis. Behavioral tests performed 6 to 8 weeks after ischemia showed deficits in spatial memory and learning that were lessened by the PJ34 treatment. Immunohistochemical evaluation of hippocampus at 8 weeks after ischemia showed increased neuronal density in CA1 layer of PJ34-treated animals relative to vehicle-treated animals. Bromodeoxyuridine labeling showed formation of new neurons in hippocampal CA1 area in PJ34-treated animals, but not in vehicle-treated animals. Together, these results suggest that treatment with a PARP inhibitor for several days after ischemia enhances long-term neuronal survival and neurogenesis by reducing inflammation.
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PMID:Inhibition of poly(ADP-ribose) polymerase suppresses inflammation and promotes recovery after ischemic injury. 1919 Jun 53

It is increasingly recognized that histological and functional outcomes after stroke are shaped by biologic sex. Emerging data suggests that ischemic cell death pathways are sexually dimorphic (Hurn, P., Vannucci, S., Hagberg, H. (2005) Adult or perinatal brain injury: does sex matter?. Stroke 36, 193-195 ; Lang, J.T., McCullough, L.D. (2008) Pathways to ischemic neuronal cell death: are sex differences relevant?. J. Transl. Med. 6). Reducing neuronal nitric oxide (NO) or poly-ADP-ribose polymerase (PARP1) activation protects only the male brain (Hagberg, H., et al. PARP-1 gene disruption in mice preferentially protects males from perinatal brain injury. J. Neurochem. 90, 1068-1075 (2004)), and paradoxically enhances ischemic injury in females (McCullough, L.D., et al. Ischemic nitric oxide and poly (ADP-ribose) polymerase-1 in cerebral ischemia: male toxicity, female protection. J. Cereb. Blood Flow Metab. 25, 502-512 (2005)). In this study, we examined downstream mediators of NO/PARP activation to investigate possible mediators of ischemic sexual dimorphism. Nuclear translocation of Apoptosis Inducing Factor (AIF) was equivalent in wild type males and females after stroke and was unaffected by estrogen exposure. Deletion of PARP1 led to a dramatic reduction in stroke-induced poly (ADP-ribose) polymerase (PAR) formation and AIF translocation in both sexes, yet ischemic damage was reduced only in males. Subsequent examination of AIF-deficient Harlequin mice demonstrated that male Harlequin mice had less PAR formation, reduced AIF translocation and less ischemic damage than male wild type mice. In contrast, female Harlequin mice had no neuroprotective effect of gene deletion despite robust reductions in PAR formation and AIF translocation. Although equivalent activation of this cell death pathway occurs in both sexes after ischemia, detrimental effects are only present in males. AIF translocation and PAR formation do not mediate ischemic injury in the female brain, therefore agents designed to reduce PARP1 activation are unlikely to benefit females.
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PMID:Sex differences in the response to activation of the poly (ADP-ribose) polymerase pathway after experimental stroke. 1926 68

Poly (ADP-robose) glycohydrolase (PARG) is a catabolic enzyme that cleaves ADP-ribose polymers synthesized by members of the poly (ADP-ribose) polymerase (PARP) family of enzymes. The growing evidence supports the importance of a tight control of poly (ADP-ribose) metabolism by the two major enzymes, PARP-1 and PARG. Recent studies have advanced the understanding of PARPs' and PARG's functions in various cellular and physiological processes. In the last 10 years, homeostasis of poly (ADP-ribosyl)ation has been a target of pharmaceutical interventions for various pathologies. Although the polymer synthesizing enzyme PARP-1 has been well studied, the function of PARG remains largely unknown. However, a great effort has been made in recent years to delineate biological functions of PARG and to explore the therapeutical potentials of PARG inhibition in pathophysiological conditions such as inflammation, ischemia, stroke, and cancer chemotherapy.
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PMID:Poly (ADP-ribose) glycohydrolase (PARG) and its therapeutic potential. 1927 51

Neurons require large amounts of energy to support their survival and function, and are therefore susceptible to excitotoxicity, a form of cell death involving bioenergetic stress that may occur in several neurological disorders including stroke and Alzheimer's disease. Here we studied the roles of NAD(+) bioenergetic state, and the NAD(+)-dependent enzymes SIRT1 and PARP-1, in excitotoxic neuronal death in cultured neurons and in a mouse model of focal ischemic stroke. Excitotoxic activation of NMDA receptors induced a rapid decrease of cellular NAD(P)H levels and mitochondrial membrane potential. Decreased NAD(+) levels and poly (ADP-ribose) polymer (PAR) accumulation in nuclei were relatively early events (<4 h) that preceded the appearance of propidium iodide- and TUNEL-positive cells (markers of necrotic cell death and DNA strand breakage, respectively) which became evident by 6 h. Nicotinamide, an NAD(+) precursor and an inhibitor of SIRT1 and PARP1, inhibited SIRT1 deacetylase activity without affecting SIRT1 protein levels. NAD(+) levels were preserved and PAR accumulation and neuronal death induced by excitotoxic insults were attenuated in nicotinamide-treated cells. Treatment of neurons with the SIRT1 activator resveratrol did not protect them from glutamate/NMDA-induced NAD(+) depletion and death. In a mouse model of focal cerebral ischemic stroke, NAD(+) levels were decreased in both the contralateral and ipsilateral cortex 6 h after the onset of ischemia. Stroke resulted in dynamic changes of SIRT1 protein and activity levels which varied among brain regions. Administration of nicotinamide (200 mg/kg, i.p.) up to 1 h after the onset of ischemia elevated brain NAD(+) levels and reduced ischemic infarct size. Our findings demonstrate that the NAD(+) bioenergetic state is critical in determining whether neurons live or die in excitotoxic and ischemic conditions, and suggest a potential therapeutic benefit in stroke of agents that preserve cellular NAD(+) levels. Our data further suggest that, SIRT1 is linked to bioenergetic state and stress responses in neurons, and that under conditions of reduced cellular energy levels SIRT1 enzyme activity may consume sufficient NAD(+) to nullify any cell survival-promoting effects of its deacetylase action on protein substrates.
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PMID:Nicotinamide prevents NAD+ depletion and protects neurons against excitotoxicity and cerebral ischemia: NAD+ consumption by SIRT1 may endanger energetically compromised neurons. 1928 25

Poly(ADP-ribose) polymerases (PARPs) are defined as cell signaling enzymes that catalyze the transfer of ADP-ribose units from NAD(+) to a number of acceptor proteins. PARP-1, the best characterized member of the PARP family, which currently comprises 18 members, is an abundant nuclear enzyme implicated in cellular responses to DNA injury provoked by genotoxic stress. PARP is involved in DNA repair and transcriptional regulation and is now recognized as a key regulator of cell survival and cell death as well as a master component of a number of transcription factors involved in tumor development and inflammation. PARP-1 is essential to the repair of DNA single-strand breaks via the base excision repair pathway. Inhibitors of PARP-1 have been shown to enhance the cytotoxic effects of ionizing radiation and DNA-damaging chemotherapy agents, such as the methylating agents and topoisomerase I inhibitors. There are currently at least five PARP inhibitors in clinical trial development. Recent in vitro and in vivo evidence suggests that PARP inhibitors could be used not only as chemo/radiotherapy sensitizers, but also as single agents to selectively kill cancers defective in DNA repair, specifically cancers with mutations in the breast cancer-associated genes (BRCA1 and BRCA2). PARP becomes activated in response to oxidative DNA damage and depletes cellular energy pools, thus leading to cellular dysfunction in various tissues. The activation of PARP may also induce various cell death processes and promotes an inflammatory response associated with multiple organ failure. Inhibition of PARP activity is protective in a wide range of inflammatory and ischemia-reperfusion-associated diseases, including cardiovascular diseases, diabetes, rheumatoid arthritis, endotoxic shock, and stroke. The aim of this review is to overview the emerging data in the literature showing the role of PARP in the pathogenesis of cancer and inflammatory diseases and unravel the solid body of literature that supports the view that PARP is an important target for therapeutic intervention in critical illness.
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PMID:PARP inhibitors: new partners in the therapy of cancer and inflammatory diseases. 1936 86


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