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)

We have recently demonstrated in a rat model that traumatic brain injury induces perturbation of cellular calcium homeostasis with an overload of cytosolic calcium and excessive calcium adsorbed on the mitochondrial membrane, consequently the mitochondrial respiratory chain-linked oxidative phosphorylation was impaired. We report the effect of a selective N-type calcium channel blocker, SNX-111 on mitochondrial dysfunction induced by a controlled cortical impact. Intravenous administration of SNX-111 at varying times post injury was made. The concentration titration profile revealed SNX-111 at 4 mg kg-1 to be optimal, and the time window to be administration at 4 h post-injury, in line with that reported on the effect of SNX-111 in experimental stroke. Under optimal conditions, SNX-111 significantly improved the mitochondrial respiratory chain-linked functions, such as the electron transfer activities with both succinate and NAD-linked substrates, and the accompanied energy coupling capacities measured as respiratory control indices (RCI) and ATP synthesis (P/O ratio), and the energy linked Ca2+ transport. In order to assess the applicability of these data to the clinical setting, we have initiated studies with brain tissue which has to be resected during surgical treatment. Five patients suffered from brain trauma, one from intracranial hypertension due to stroke (noninfarcted tissue was taken), and one from epilepsy. Our data revealed that brain mitochondria derived from the patient with intracranial hypertension and the patient with epilepsy were tightly coupled with good respiratory rates with glutamate and malate as substrates, and high P/O ratios. The rates of respiration and ATP synthesis were severely impaired in the brain mitochondria isolated from traumatized patients. These results indicate that investigation of brain mitochondrial functions can be used as a measure for trauma-induced impairment of brain energy metabolism. The time window for the effect of SNX-111 in mitochondrial function and the (preliminary) similarity between mitochondrial dysfunction in experimental animals and humans make the drug appear to be well suited for clinical trials in severe head injury.
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PMID:Mitochondrial dysfunction after experimental and human brain injury and its possible reversal with a selective N-type calcium channel antagonist (SNX-111). 919 88

Peroxynitrite triggers DNA single-strand breakage, which activates the nuclear enzyme poly(ADP-ribose) synthetase (PARS). Activation of PARS depletes its substrate, NAD+, slowing the rate of glycolysis, electron transport, and ATP formation, resulting in cell necrosis. Here, we demonstrate that inhibition of PARS with the novel, potent PARS inhibitor 5-iodo-6-amino-1,2-benzopyrone (INH2BP) protects against peroxynitrite-induced cell death (as measured by measurement of mitochondrial respiration and release of lactate dehydrogenase) in C6 glioma cells in vitro, and in a murine stroke model in vivo. Inhibition of PARS with INH2BP may represent a novel approach for the experimental therapy of stroke.
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PMID:Protective effects of 5-iodo-6-amino-1,2-benzopyrone, an inhibitor of poly(ADP-ribose) synthetase against peroxynitrite-induced glial damage and stroke development. 972 Oct 31

Brain ischemia initiates a complex cascade of metabolic events, several of which involve the generation of nitrogen and oxygen free radicals. These free radicals and related reactive chemical species mediate much of damage that occurs after transient brain ischemia, and in the penumbral region of infarcts caused by permanent ischemia. Nitric oxide, a water- and lipid-soluble free radical, is generated by the action of nitric oxide synthases. Ischemia causes a surge in nitric oxide synthase 1 (NOS 1) activity in neurons and, possibly, glia, increased NOS 3 activity in vascular endothelium, and later an increase in NOS 2 activity in a range of cells including infiltrating neutrophils and macrophages, activated microglia and astrocytes. The effects of ischemia on the activity of NOS 1, a Ca2+-dependent enzyme, are thought to be secondary to reversal of glutamate reuptake at synapses, activation of NMDA receptors, and resulting elevation of intracellular Ca2+. The up-regulation of NOS 2 activity is mediated by transcriptional inducers. In the context of brain ischemia, the activity of NOS 1 and NOS 2 is broadly deleterious, and their inhibition or inactivation is neuroprotective. However, the production of nitric oxide in blood vessels by NOS 3, which, like NOS 1, is Ca2+-dependent, causes vasodilatation and improves blood flow in the penumbral region of brain infarcts. In addition to causing the synthesis of nitric oxide, brain ischemia leads to the generation of superoxide, through the action of nitric oxide synthases, xanthine oxidase, leakage from the mitochondrial electron transport chain, and other mechanisms. Nitric oxide and superoxide are themselves highly reactive but can also combine to form a highly toxic anion, peroxynitrite. The toxicity of the free radicals and peroxynitrite results from their modification of macromolecules, especially DNA, and from the resulting induction of apoptotic and necrotic pathways. The mode of cell death that prevails probably depends on the severity and precise nature of the ischemic injury. Recent studies have emphasized the role of peroxynitrite in causing single-strand breaks in DNA, which activate the DNA repair protein poly(ADP-ribose) polymerase (PARP). This catalyzes the cleavage and thereby the consumption of NAD+, the source of energy for many vital cellular processes. Over-activation of PARP, with resulting depletion of NAD+, has been shown to make a major contribution to brain damage after transient focal ischemia in experimental animals. Neuronal accumulation of poly(ADP-ribose), the end-product of PARP activity has been demonstrated after brain ischemia in man. Several therapeutic strategies have been used to try to prevent oxidative damage and its consequences after brain ischemia in man. Although some of the drugs used in early studies were ineffective or had unacceptable side effects, other trials with antioxidant drugs have proven highly encouraging. The findings in recent animal studies are likely to lead to a range of further pharmacological strategies to limit brain injury in stroke patients.
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PMID:Oxidative stress in brain ischemia. 998 55

Ischemia depletes ATP and initiates cascades leading to irreversible tissue injury. Nicotinamide is a precursor of nicotinamide adenine dinucleotide (NAD+) which increases neuronal ATP concentration and protects against malonate-induced neurotoxicity, trauma and nitric oxide toxicity. We therefore examined whether nicotinamide could protect against stroke, using a model of permanent middle cerebral artery occlusion (MCA) occlusion in Wistar rats. Nicotinamide reduced neuronal infarction in a dose-specific manner. Furthermore, nicotinamide (500 mg/kg) reduced infarcts when administered up to 2 h after the onset of permanent MCA occlusion. The mechanism of action underlying the neuroprotection observed with nicotinamide remains to be clarified. These results are potentially important since nicotinamide is already used clinically, though not in the treatment of stroke.
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PMID:Nicotinamide reduces infarction up to two hours after the onset of permanent focal cerebral ischemia in Wistar rats. 1002 46

In the present study, the effect of poly(ADP-ribose) polymerase (PARP) inhibition on rat cortical energy state was investigated at 24 h after global cerebral ischemia induced by permanent bilateral common carotid artery ligation plus transient hypotension. The specific PARP inhibitor 3-aminobenzamide was injected 10 min before induction of ischemia at a dosage of 5, 10, and 20 mg/kg intracerebroventricularly. Twenty-four hours after ischemia cortical PARP enzyme activity increased from 0.425+/-0.144 to 0.794+/-0.193 units/mg protein. Cerebral ischemia was associated by a decrease in adenosine triphosphate (ATP) and phosphocreatine concentrations to 72.5 and 76.8% of controls, respectively. In addition, an 1.9- and 2. 2-fold increase in adenosine monophosphate and adenosine was observed. Specific PARP inhibition with 10 mg/kg 3-aminobenzamide protected the rat energy state by preserving cortical phosphocreatine and NAD(+). Cortical ATP was not changed significantly after PARP inhibition. In conclusion, activation of the nuclear enzyme PARP plays an important role in cerebral energy metabolism during rat global ischemia. Therefore, specific PARP inhibition may offer new strategies in the therapy of vascular diseases such as stroke.
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PMID:The neuroprotective effect of cerebral poly(ADP-ribose)polymerase inhibition in a rat model of global ischemia. 1077 Nov 74

Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme, activated by DNA strand breaks to participate in DNA repair. Overactivation of PARP by cellular insults depletes its substrate NAD(+) and then ATP, leading to a major energy deficit and cell death. This mechanism appears to be prominent in vascular stroke and other neurodegenerative processes in which PARP gene deletion and PARP-inhibiting drugs provide major protection. Cell death associated with PARP-1 overactivation appears to be predominantly necrotic while apoptosis is associated with PARP-1 cleavage, which may conserve energy needed for the apoptotic process. Novel forms of PARP derived from distinct genes and lacking classic DNA-binding domains may have nonnuclear functions, perhaps linked to cellular energy dynamics.
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PMID:Poly(ADP-ribose) polymerase-1 in the nervous system. 1096 95

Elevated plasma levels of the sulfur-containing amino acid homocysteine increase the risk for atherosclerosis, stroke, and possibly Alzheimer's disease, but the underlying mechanisms are unknown. We now report that homocysteine induces apoptosis in rat hippocampal neurons. DNA strand breaks and associated activation of poly-ADP-ribose polymerase (PARP) and NAD depletion occur rapidly after exposure to homocysteine and precede mitochondrial dysfunction, oxidative stress, and caspase activation. The PARP inhibitor 3-aminobenzamide (3AB) protects neurons against homocysteine-induced NAD depletion, loss of mitochondrial transmembrane potential, and cell death, demonstrating a requirement for PARP activation and/or NAD depletion in homocysteine-induced apoptosis. Caspase inhibition accelerates the loss of mitochondrial potential and shifts the mode of cell death to necrosis; inhibition of PARP with 3AB attenuates this effect of caspase inhibition. Homocysteine markedly increases the vulnerability of hippocampal neurons to excitotoxic and oxidative injury in cell culture and in vivo, suggesting a mechanism by which homocysteine may contribute to the pathogenesis of neurodegenerative disorders.
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PMID:Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. 1099 36

O2 sensing is a fundamental biological process necessary for adaptation of living organisms to variable habitats and physiological situations. Cellular responses to hypoxia can be acute or chronic. Acute responses rely mainly on O2-regulated ion channels, which mediate adaptive changes in cell excitability, contractility, and secretory activity. Chronic responses depend on the modulation of hypoxia-inducible transcription factors, which determine the expression of numerous genes encoding enzymes, transporters and growth factors. O2-regulated ion channels and transcription factors are part of a widely operating signaling system that helps provide sufficient O2 to the tissues and protect the cells against damage due to O2 deficiency. Despite recent advances in the molecular characterization of O2-regulated ion channels and hypoxia-inducible factors, several unanswered questions remain regarding the nature of the O2 sensor molecules and the mechanisms of interaction between the sensors and the effectors. Current models of O2 sensing are based on either a heme protein capable of reversibly binding O2 or the production of oxygen reactive species by NAD(P)H oxidases and mitochondria. Complete molecular characterization of the hypoxia signaling pathways will help elucidate the differential sensitivity to hypoxia of the various cell types and the gradation of the cellular responses to variable levels of PO2. A deeper understanding of the cellular mechanisms of O2 sensing will facilitate the development of new pharmacological tools effective in the treatment of diseases such as stroke or myocardial ischemia caused by localized deficits of O2.
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PMID:Cellular mechanism of oxygen sensing. 1118 57

Alterations in the function and structure of the blood vessel wall account for most clinical events in the coronary and cerebrovascular circulation such as myocardial infarction and stroke. Cardiovascular drugs may exert beneficial effects on the vascular wall both at the level of the endothelium and vascular smooth muscle cells. Therefore, endothelial mediators, in particular nitric oxide (NO) and endothelin (ET), are of special interest. Drugs can modulate the expression and actions of NO, a vasodilator with antiproliferative and antithrombotic properties, and of ET, a potent vasoconstrictor and proliferative mitogenic agent. The most successful drugs in this context are statins and angiotensin-converting enzyme (ACE)-inhibitors. While statins increase the expression of NO synthase. ACE-inhibitors increase the release of NO via bradykinin-mediated mechanisms. Antioxidant properties of drugs are also important, as oxidative stress is crucial in atherosclerotic vascular disease. These properties may explain part of the effects of calcium antagonists and ACE-inhibitors. Indeed, angiotensin II stimulates NAD(P)H oxidases responsible for the formation of superoxide, which inactivates NO. ACE-Inhibitors thus increase the bioavailability of NO. Newer cardiovascular drugs such as nebivolol are able to directly stimulate NO release from the endothelium both in isolated arteries and in the human forearm circulation. ET receptor antagonists may exert beneficial effects in the vessel wall by preventing the effects of ET at its receptors and by reducing ET production. In summary, cardiovascular drugs have important effects on the vessel wall, which may be clinically relevant for the prevention and treatment of cardiovascular disease.
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PMID:Vascular effects of newer cardiovascular drugs: focus on nebivolol and ACE-inhibitors. 1181 90

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, that presently includes six members, is an abundant nuclear enzyme implicated in cellular responses to DNA injury provoked by genotoxic stress (oxygen radicals, ionizing radiations and monofunctional alkylating agents). Due to its involvement either in DNA repair or in cell death, PARP-1 is regarded as a double-edged regulator of cellular functions. In fact, when the DNA damage is moderate, PARP-1 participates in the DNA repair process. Conversely, in the case of massive DNA injury, elevated PARP-1 activation leads to rapid NAD(+)/ATP consumption and cell death by necrosis. Excessive PARP-1 activity has been implicated in the pathogenesis of numerous clinical conditions such as stroke, myocardial infarction, shock, diabetes and neurodegenerative disorders. PARP-1 could therefore be considered as a potential target for the development of pharmacological strategies to enhance the antitumor efficacy of radio- and chemotherapy or to treat a number of clinical conditions characterized by oxidative or NO-induced stress and consequent PARP-1 activation. Moreover, the discovery of novel functions for the multiple members of the PARP family might lead in the future to additional clinical indications for PARP inhibitors.
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PMID:Potential clinical applications of poly(ADP-ribose) polymerase (PARP) inhibitors. 1184 17


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