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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptotic cell death has been implicated in Alzheimer's disease pathology and amyloid peptide induced neurotoxicity. We investigated the survival promoting effects of Propentofylline in two models of apoptotic cell death, nerve growth factor withdrawal and beta-amyloid mediated cell death in nerve growth factor differentiated rat pheochromocytoma cell lines. The increase in cell death as measured by lactate dehydrogenase release in response to nerve growth factor withdrawal was suppressed by nitric oxide donor S-nitroso-N-acetylpenicillamine (12.5 to 200 microM) and by 8-bromoguanosine-3',5'-cyclic monophosphate (1.25 to 10mM). Both agents decreased cell death mediated by 25 microM beta-amyloid, suggesting that the protective mechanism involves guanosine -3', 5'-cyclic monophosphate. In support of this hypothesis we can show that S-nitroso-N-acetylpenicillamine increases intracellular levels of guanosine -3',5'-cyclic monophosphate in pheochromocytoma cell lines 3 to 8 fold.Propentofylline, a phosphodiesterase inhibitor, has previously demonstrated neuroprotective activity in stroke models and is a potential candidate for therapeutic treatment in neurodegenerative diseases. The present findings support this claim by providing evidence that Propentofylline has protective effects in both nerve growth factor withdrawal and beta-amyloid mediated cell death. Lactate dehydrogenase release was significantly reduced and caspase-3-like activity was attenuated after cotreatment with Propentofylline. Furthermore Propentofylline dose responsively increases intracellular guanosine-3',5'-cyclic monophosphate levels over the same dose range that provided protection. We hypothesized that guanosine-3',5'-cyclic monophosphate is a key mediator of neuroprotection under these conditions.
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PMID:Guanosine 3',5'-cyclic monophosphate mediated inhibition of cell death induced by nerve growth factor withdrawal and beta-amyloid: protective effects of propentofylline. 1097 37

Lactate production and expressions of monocarboxylate transporter 1 (MCT1) and lactate dehydrogenase (LDH) mRNA after hypoxia and reoxygenation (H/R) were examined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) using astrocytes in culture isolated from stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar Kyoto rats (WKY). The basal production of lactate in SHRSP was the same as that observed in WKY. In contrast the lactate levels in SHRSP at 1 and 6 h of reoxygenation after hypoxia were significantly lower than those observed in WKY. In addition LDH and MCT1 mRNA expressions in SHRSP were significantly less strong compared with those in WKY during H/R. These findings indicate that decreased production and slow transport of lactate in SHRSP astrocytes are involved in neuronal energy depletion and possibly encourage neuronal damage, although hereditary weakness of cortical neurons is also related to cell death during H/R.
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PMID:Reduced production of lactate during hypoxia and reoxygenation in astrocytes isolated from stroke-prone spontaneously hypertensive rats. 1110 94

The aim of this study is to clarify whether the activation of a Na(+)/H(+) exchanger (NHE) is tightly concerned with neuronal and glial cell injury induced by ischemia using a selective NHE inhibitor, SM-20220 (N-(aminoiminomethyl)-1-methyl-1H-indole-2-carboxamide methanesulfonate). Two hours of hypoxia followed by 24 h of reoxygenation induced lactate dehydrogenase (LDH) release, a marker of cell membrane damage, in cultured neurons and glia derived from rats. SM-20220 significantly reduced LDH release in both cells in a concentration-dependent manner, and this effect was statistically significant at concentrations of more than 10(-8) mol/l for neurons and 10(-7) mol/l for glia. A standard NHE inhibitor, 5-(N-ethyl-N-isopropyl)-amiloride, also reduced LDH release in neurons at concentrations of more than 10(-7) mol/l. In a rat transient middle cerebral artery occlusion model, intravenous infusion of SM-20220 reduced cerebral infarction when the serum concentration of SM- 20220 was maintained at about 10(-7) mol/l. These results suggest that the activation of the NHE plays an important role in ischemic neuronal and glial cell injury, and NHE inhibitor may have good therapeutic value for the treatment of ischemic stroke.
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PMID:The Na(+)/H(+) exchanger SM-20220 attenuates ischemic injury in in vitro and in vivo models. 1149 Jan 99

DNA damage induced by low doses of ionizing radiation causes apoptosis, which is partially mediated via the generation of free radicals. Both free radicals and apoptosis are involved in the majority of brain diseases, including stroke, Alzheimer's disease and amyotrophic lateral sclerosis. Because previous studies have shown that tetracycline derivatives doxycycline and minocycline have anti-inflammatory effects and are protective against brain ischemia, we studied whether minocycline and doxycycline or ceftriaxone, a cephalosporin antibiotic with the potential to inhibit excitotoxicity, protect neurons against ionizing radiation in primary cortical cultures. A single dose of 1 Gy significantly increased lactate dehydrogenase release, induced DNA fragmentation in neurons and triggered microglial proliferation. Treatment with minocycline (20 nM), doxycycline (20 nM) and ceftriaxone (1 microM) significantly reduced irradiation-induced lactate dehydrogenase release and DNA fragmentation. The most efficient protection was achieved by minocycline treatment, which also inhibited the irradiation-induced increase in microglial cell number. Our results suggest that some tetracycline derivatives, such as doxycycline and minocycline, and ceftriaxone, a cephalosporin derivative, protect neurons against apoptotic death.
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PMID:Tetracycline derivatives and ceftriaxone, a cephalosporin antibiotic, protect neurons against apoptosis induced by ionizing radiation. 1157 49

Our clinical-biological study has been performed in patients with various clinical forms of arterial hypertension (AHT), as well as with sequelae-type complications from stroke that had occurred during the evolution of the disease. We performed biological determinations of the activity of four erythrocytic enzymes: glutathione-s-transferase (GST), catalase, gamma-glutamyltransferase (GGT), and lactate dehydrogenase (LDH). The results point to the existence of individual values and also of important differences depending on the presence of arterial hypertension complications. We found a moderate but significant increase of erythrocytic GGT in hypertensive patients compared to healthy controls. Erythrocytic GST and LDH were decreased in patients vs controls. The results of the enzymatic, erythrocyitc activities of GST, GGT, catalase and LDH can also be correlated with the parameters of erythrocyitc membrane permeability and with the thiolic groups, fibrinogen and ionic calcium concentration. The data described in this paper suggest the possible involvement of the disturbances mentioned above in the etiopathogeny of AHT.
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PMID:Activity of glutathione-s-transferase, gammaglutamiltransferase and catalase in the erythrocytic membrane in arterial hypertension. 1179 39

HIF-1 is composed of HIF-1alpha and HIF-1beta protein subunits. HIF-1 is induced by hypoxia and binds to promoter/enhancer elements and stimulates the transcription of hypoxia-inducible target genes. Because HIF-1 activation might promote cell survival in hypoxic tissues, we studied the effect of stroke on the expression of HIF-1alpha, HIF-1beta and several HIF-1 target genes in adult rat brain. After focal cerebral ischemia, mRNAs encoding HIF-1alpha, glucose transporter-1 and several glycolytic enzymes including lactate dehydrogenase were up-regulated in the areas around the infarction. HIF and its target genes were induced by 7.5 hours after the onset of ischemia and increased further at 19 and 24 hours. Since hypoxia induces HIF in other tissues, systemic hypoxia (6% O2 for 4.5 h) was also shown to increase HIF-1alpha protein expression in the adult rat brain. It is proposed that decreased blood flow to the penumbra decreases the supply of oxygen and that this induces HIF-1 and its target genes. Because HIF-1 activation may promote cell survival in hypoxic tissues, we studied the effect of hypoxic preconditioning on HIF-1 expression in neonatal rat brain. Hypoxic preconditioning (8% O2/3 hrs), a treatment known to protect the newborn rat brain against hypoxic-ischemic injury, markedly increased HIF-1alpha and HIF-1beta expression. We also studied the effect of two other known HIF-1 inducers, cobalt chloride (CoCl2) and desferrioxamine (DFX), on HIF-1 expression and neuroprotection in newborn brain. HIF-1alpha and HIF-1beta protein levels were markedly increased after i.p. injection of CoCl2 and DFX. Preconditioning with CoCl2 or DFX 24 hours before the stroke decreased infarction by 75% and 56% respectively, compared with vehicle-injected, littermate controls. Thus, HIF-1 activation could contribute to protective brain preconditioning.
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PMID:Hypoxia-inducible factor in brain. 1195 Jan 44

N-Methyl-D-aspartate (NMDA) receptor-mediated cell death is complex, probably involving elements of necrosis and apoptosis. The mechanisms underlying this phenomenon are incompletely understood but have been suggested to involve reactive oxygen species such as nitric oxide and superoxide anion (O(2)) and nuclear factor-kappaB (NF-kappaB) signaling. In this study, we used a selective nonpeptidyl superoxide dismutase mimetic (M40403) and SN50, a peptide inhibitor of NF-kappaB translocation, to investigate the role of O(2) and the potential downstream signaling molecules in cell death induced by activation of the NMDA receptor. Application of NMDA to a mixed neuronal/glial forebrain culture resulted in an early increase in the release of cytoplasmic lactate dehydrogenase (LDH), which peaked at 4 h. This was followed by a reduction in mitochondrial metabolism of the dye MTT [3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide] that continued to decrease throughout the 20-h exposure. A substantial increase in DNA fragmentation as measured by an enzyme-linked immunosorbent assay (ELISA) specific for DNA-associated histone proteins (nucleosomes) was observed at 7 and 20 h. M40403 and SN50 blocked NMDA-induced changes in LDH release at 2, 4, and 20 h, MTT metabolism at 4 and 20 h, and DNA fragmentation at 20 h as measured by the ELISA and by an increase in terminal dUTP-nick end labeling. M40403 also prevented NMDA-induced nuclear transport of NF-kappaB and increased expression of Bax relative to Bcl-X(L). SN50 was also able to block NMDA-induced cell death as well as the increased Bax/Bcl-X(L) ratio. Time course studies and experiments with SN50 and M40403 suggest that O(2) production and NF-kappaB translocation may be involved in necrosis and apoptosis, but the latter also requires an increased expression of Bax. The ability of M40403 to prevent NMDA-induced cell death relatively early in this cascade suggests its potential therapeutic utility in central nervous systems diseases such as stroke that are associated with increased NMDA receptor-mediated production of O(2).
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PMID:The role of superoxide and nuclear factor-kappaB signaling in N-methyl-D-aspartate-induced necrosis and apoptosis. 1196 Oct 46

Dexrazoxane is a cardioprotective antioxidant that is clinically used to reduce the cardiotoxicity of the chemotherapeutic drug doxorubicin. We examined the hypothesis that dexrazoxane also may be able to protect neonatal rat cardiac myocytes from hypoxia-reoxygenation damage. Hypoxia-reoxygenation damage is thought to involve oxidative stress on the heart muscle, possibly by the production of hydroxyl radicals mediated by iron. The results of this study showed that dexrazoxane was highly effective in protecting myocytes from hypoxia-reoxygenation-induced lactate dehydrogenase release. The metal chelating hydrolysis product of dexrazoxane, ADR-925, also protected myocytes from hypoxia-reoxygenation damage, although it was less effective than dexrazoxane. This study also showed that ADR-925 and dexrazoxane rapidly entered myocytes and displaced iron from a fluorescence-quenched trapped intracellular iron-calcein complex. These results suggest that dexrazoxane may protect myocytes against hypoxia-reoxygenation-induced damage by chelating free or loosely bound iron, thus preventing site-specific iron-based oxygen radical damage. Thus, dexrazoxane or its analogs may have some clinical utility in preventing tissue damage that occurs after a stroke or heart attack.
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PMID:Dexrazoxane (ICRF-187) protects cardiac myocytes against hypoxia-reoxygenation damage. 1227 Nov 54

Levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and creatine kinase (CK) were estimated in serum and cerebrospinal fluid of 25 patients of stroke, and were correlated with severity of disease. 21 (84%) patients had ischemic stroke and four (16%) had hemorrhagic stroke. Serum and CSF AST levels were significantly elevated in the study group. The rise in CSF AST was more in the hemorrhagic subtype than in the ischemic subtype. Serum ALT and CSF LDH levels were also significantly elevated in patients with ischemic stroke. None of the enzyme levels were related to the severity of disease as assessed by the Glasgow coma scale.
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PMID:Evaluation of enzymes in serum and cerebrospinal fluid in cases of stroke. 1257 13

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


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