Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The functional changes of astrocytes are deeply involved in neurodegenerating processes of various CNS diseases. ATP is released during various neuronal damages such as brain ischemia and may control astrocyte functions. We examined the effect of ATP on the production of nitric oxide in the cultured astrocytes from rat embryo. The astrocytes were stimulated by lipopolysaccharide instead of pathological activation in vivo. Nitric oxide production was evaluated by the fluorometric assay of nitrite accumulated in the medium. The expression of inducible nitric oxide synthase was analyzed by Western blotting. Nitric oxide production induced by 1 ng/ml lipopolysaccharide was enhanced by ATP with maximal enhancement of three- to four-fold; a half-effective concentration was about 0.3 mM. In the absence of ATP, half-effective concentration of lipopolysaccharide on nitric oxide production was about 3 ng/ml; however, half-effective concentration shifted to 0.3 ng/ml in the presence of 1.5-mM ATP. Several other P2 receptor agonists (uridine triphosphate, ADP, adenosine monophosphate, 2'- and 3'-O - (4-benzoylbenzoyl)-ATP, and 2-methylthioATP) showed a similar enhancing effect, and an antagonist, ATP-2',3'-dialdehyde, showed an inhibiting effect. Western blotting analysis revealed that the extent of lipopolysaccharide-induced expression of nitric oxide synthase increased several-fold by the addition of ATP; half-effective concentration was about 0.5 mM. These results suggest that the extracellular ATP plays an important role as a transmitter and regulates astrocyte functions via a certain P2 receptor and that such a change in astrocyte function is involved in either protection or aggravation in neurodegenerative processes.
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PMID:Potentiation by ATP of lipopolysaccharide-stimulated nitric oxide production in cultured astrocytes. 1260 90

The relationship between caspase-3 activation and delayed neuronal death after ischemia was examined. Expression of caspase-3 was evaluated by colorimetric assay, immunoblotting and by immunohistochemistry. Apoptosis was characterised by terminal desoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end-labelling. Immunohistochemistry showed caspase-3 activation in the whole hippocampus as early as 30 min after ischemia with exclusive localisation in fiber systems, especially in the perforant path and mossy fibers, Schaffer-collaterals, as well as apical and basal dendrites of pyramidal cells. One day post-ischemia, the 18 kDa cleavage product of caspase-3 (p18) was seen in all cell compartments (nucleus, cytosol and dendrites) throughout the entire subfields and the dentate gyrus with high distribution in mossy fibers. Two days post-ischemia, p18 kDa was only seen in the nuclei and cytosol of hippocampal cells without specific regional differences among hippocampal subfields. A significant number of apoptotic cells appeared only in the CA1 pyramidal cells at 2-3 days post-ischemia. Our data provides the first evidence that caspase-3 activation was detectable in the trisynaptic pathway fiber bundles which probably correspond to perforant path, alvear path and collaterals of Schaffer, and that activation of caspase-3 led to execution of apoptotic cell death program in selectively vulnerable areas, but not in the resistant area of the hippocampus.
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PMID:Post-ischemic activation of caspase-3 in the rat hippocampus: evidence of an axonal and dendritic localisation. 1268 1

Oxidative stress plays a pivotal role in ischemic-reperfusion cell injury. Oxygen-derived free radicals trigger DNA strand damage, which is responsible for the activation of poly(ADP-ribose) polymerase (PARP). Recent studies have shown that peroxynitrite is the primary mediator of DNA damage and, hence, PARP activation after ischemia. PARP activation depletes NAD and ATP pools, ultimately resulting in necrotic cell death by loss of energy stores. Our study shows that PARP is upregulated as early as 15 min after 1 h of transient focal cerebral ischemia and remains for 8 h. We also examined the role of superoxide in PARP induction using copper/zinc-superoxide dismutase transgenic mice. Immunohistochemical and Western blotting data showed that there was no increased induction in PARP expression in these mice, suggesting that one of the mechanisms by which ischemic injury is attenuated in these mice might be by the inhibition of PARP induction. Furthermore, double staining of ischemic tissue with a PARP antibody and terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end labeling (TUNEL) indicated that most cells that are positive for TUNEL do not stain for the PARP antibody, confirming recent reports that PARP activation is involved in necrotic cell death rather than apoptosis during ischemic-reperfusion injury.
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PMID:Role of superoxide in poly(ADP-ribose) polymerase upregulation after transient cerebral ischemia. 1275 3

The present study was aimed at characterizing alterations of the nucleotide content and morphological state of rat corticoencephalic cell cultures subjected to metabolic damage and treatment with modulators of mitochondrial ATP-dependent potassium channels (mitoK(ATP)). In a first series of experiments, in vitro ischemic changes of the contents of purine and pyrimidine nucleoside diphosphates and triphosphates were measured by high performance liquid chromatography (HPLC) and the corresponding histological alterations were determined by celestine blue/acid fuchsin staining. As an ischemic stimulus, incubation with a glucose-free medium saturated with argon was used. Ischemia decreased the levels of adenosine, guanine and uridine triphosphate (ATP, GTP, UTP) and increased the levels of the respective dinucleotides ADP and UDP, whereas the GDP content was not changed. Both 5-hydroxydecanoate (5-HD) and diazoxide failed to alter the contents of nucleoside diphosphates and triphosphates, when applied under normoxic conditions. 5-HD (30 microM) prevented the ischemia-induced changes of nucleotide and nucleoside levels. Diazoxide (300 microM), either alone or in combination with 5-hydroxydecanoate (30 microM) was ineffective. Pyruvate (5 mM) partially reversed the effects of ischemia or ischemia plus 2-deoxyglucose (20mM) in the incubation medium. Diazoxide (300 microM) and 5-HD (30 microM) had no effect in the presence of pyruvate (5mM) and 2-deoxyglucose (20mM). Staining the cells with celestine blue/acid fuchsin in order to classify them as intact, reversibly or profoundly injured, revealed a protective effect of 5-HD. When compared with 5-HD, diazoxide, pyruvate and 2-deoxyglucose had similar but less pronounced effects. In conclusion, these results suggest a protective role of 5-hydroxydecanoate on early corticoencephalic nucleotide and cell viability alterations during ischemia.
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PMID:Early biochemical and histological alterations in rat corticoencephalic cell cultures following metabolic damage and treatment with modulators of mitochondrial ATP-sensitive potassium channels. 1282 Sep 85

Spinal cord injury leads to acute local ischemia, which may contribute to secondary degeneration. Hypoxia stimulates angiogenesis through a cascade of events, involving angiogenesis stimulatory substances, such as vascular endothelial growth factor (VEGF). To test the importance of angiogenesis for functional outcome and wound healing in spinal cord injury VEGF165 (proangiogenic), Ringer's (control) or angiostatin (antiangiogenic) were delivered locally immediately after a contusion injury produced using the NYU impactor and a 25 mm weight-drop. Rats treated with VEGF showed significantly improved behavior up to 6 weeks after injury compared with control animals, while angiostatin treatment lead to no statistically significant changes in behavior outcome. Furthermore, VEGF-treated animals had an increased amount of spared tissue in the lesion center and a higher blood vessel density in parts of the wound area compared with controls. These effects were unlikely to be due to increased cell proliferation as determined by bromo-deoxy-uridine-labeling. Moreover, VEGF treatment led to decreased levels of apoptosis, as revealed by TUNEL assays. In situ hybridization demonstrated presence of mRNA for VEGF receptors Flt-1, fetal liver kinase-1, neuropilin-1 and -2 in several important cellular compartments of the spinal cord. The different experiments indicate that beneficial effects seen by acute VEGF delivery was attributable to protection/repair of blood vessels, decreased apoptosis and possibly also by other additional effects on glial cells or certain neuron populations.
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PMID:Vascular endothelial growth factor improves functional outcome and decreases secondary degeneration in experimental spinal cord contusion injury. 1292 1

Effects of idebenone on RNA and DNA contents as well as on synthesis rates of total and poly(A)(+) RNA in the brain were measured in two animal models: (1) Normal young and old, male C57BL/6J mice (6 and 32 months). Idebenone suspended in 5% gum arabic was applied in 50 mg/kg/day dose to old mice for 1 month through a gastric tube. (2) Adult female CFY rats (14-18 months) in which experimental partial cerebral ischemia was induced by bilateral common carotid artery occlusion. Idebenone was administered intraperitoneally in two dose (10mg/kg and 100 mg/kg body weight) 30 min before the interruption of carotid blood flow. DNA content remained invariate during aging in the brain; idebenone treatment did not exert any influence on this parameter. RNA content as well as total and poly(A)(+) RNA synthesis rates, which were measured by incorporation of tritiated uridine into RNA, decreased significantly with age in brain. Idebenone treatment did not cause any essential change of the metabolism of RNA under the given conditions. The RNA and DNA contents of brain were influenced neither by experimental partial cerebral ischemia nor by treatment with idebenone during the ischemia. Partial cerebral ischemia decreased the rate of total and poly(A)(+) RNA synthesis in the brain about 15-45% depending on the methods and basis of expression. This decline could totally be prevented by intraperitoneal application of 10 mg/kg idebenone 30 min before the onset of the partial ischemia. The dose of 100 mg/kg idebenone also elevated the rate of RNA synthesis; however, this increase remained statistically insignificant.
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PMID:The effects of idebenone on DNA and RNA contents as well as synthesis rates of total and poly(A)+ RNA in brain of normal, old C57BL/6J mice and in experimental partial cerebral ischemia of rats. 1537 78

Ischemia-reperfusion injury is often responsible for delayed graft function after transplantation. Trimetazidine (TMZ) is an antioxidant agent used to protect grafts from ischemia-reperfusion injury. The aim of the study was to examine the effect of TMZ on nucleotide profile in rat kidney with ischemia-reperfusion injury. The study was carried out on Wistar rats divided into two groups: animals treated with TMZ and control group receiving placebo. TMZ 10mg/kg/day was administrated for 30 days. Concentrations of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), adenosine (Ado), guanosine triphosphate (GTP), guanosine diphosphate (GDP), guanosine monophosphate (GMP), guanosine (Guo), inosine monophosphate (IMP), inosine (Ino), hypoxanthine (Hyp), xanthine (Xan), uric acid (UA), uridine (Urd), nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) were determined in kidney tissues after ischemia-reperfusion using HPLC. The total adenine nucleotide concentration (TAN) and adenylate energy charge (AEC) were also determined. Moreover the kidneys were evaluated histologically. Tissue concentrations of ATP, ADP, AMP, TAN and AEC were significantly increased in kidneys from rats treated with TMZ in comparison with rats receiving placebo. Concentrations of products of nucleotide degradation: inosine (Ino), guanosine (Guo) and uridine (Urd), as well as oxypurines: Hyp and Xan, were significantly decreased in rats treated with trimetazidine. Moreover, significantly less pronounced acute tubular necrosis was observed in kidneys of rats treated with TMZ. These results suggest that trimetazidine protects against dephosphorylation of nucleotides and ischemic damage.
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PMID:Effect of trimetazidine on the nucleotide profile in rat kidney with ischemia-reperfusion injury. 1638 83

The activity of mitochondrial ATP-dependent potassium channel (mitoKATP) of rat heart and liver mitochondria was shown to decrease during aging. This partially explains the increase of risk of ischemia at a mature age since mitoKATP activation provides cardioprotection. We demonstrated that uridine-5'-diphosphate (UDP) possesses the property to activate mitoKATP. At a concentration of 30 microM, it reactivated mitoKATP in mitochondria, and 5-hydroxydecanoate (5-HD) eliminated this effect. In experimental animals, UDP precursors uridine and uridine-5'-monophosphate (UMP) (both 30 mg/kg, administered intravenously 5 min before coronary occlusion) decreased the myocardium ischemic alteration index (1.9 and 3.5 times, respectively) and the T-wave amplitude within 60 min after occlusion. Both effects were inhibited by Glibenclamide (Glib) and 5-HD. UMP and uridine decreased the number of premature ventricular beats 5.6 and 1.9 times and the duration of ventricular tachycardia 9.4 and 4.1 times, respectively. Glib and 5-HD inhibited the anti-arrhythmic parameters, 5-HD being less effective. Uridine and UMP decreased the duration of fibrillation 10.8 and 3.6 times, respectively, and this effect was not abolished by Glib and 5-HD. Thus, uridine and UMP, which are the precursors of UDP in the cell, possess cardioprotective properties. MitoKATP prevents mainly ischemic injuries and partially rhythm disorders.
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PMID:The cardioprotective effect of uridine and uridine-5'-monophosphate: the role of the mitochondrial ATP-dependent potassium channel. 1662 91

Cerebral ischemic preconditioning protects against stroke, but is clinically feasible only when the occurrence of stroke is predictable. Reperfusion plays a critical role in cerebral injury after stroke; we tested the hypothesis that interrupting reperfusion lessens ischemic injury. We found for the first time that such postconditioning with a series of mechanical interruptions of reperfusion significantly reduces ischemic damage. Focal ischemia was generated by permanent distal middle cerebral artery (MCA) occlusion plus transient bilateral common carotid artery (CCA) occlusion. After 30 secs of CCA reperfusion, ischemic postconditioning was performed by occluding CCAs for 10 secs, and then allowing for another two cycles of 30 secs of reperfusion and 10 secs of CCA occlusion. Infarct size was measured 2 days later. Cerebral blood flow (CBF) was measured in animals subjected to permanent MCA occlusion plus 15 mins of bilateral CCA occlusion, which demonstrates that postconditioning disturbed the early hyperemia immediately after reperfusion. Postconditioning dose dependently reduced infarct size in animals subjected to permanent MCA occlusion combined with 15, 30, and 60 mins of bilateral CCA occlusion, by reducing infarct size approximately 80%, 51%, and 17%, respectively. In addition, postconditioning blocked terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end labeling-positive staining, a marker of apoptosis, in the penumbra 2 days after stroke. Furthermore, in situ superoxide detection using hydroethidine suggested that postconditioning attenuated superoxide products during early reperfusion after stroke. In conclusion, postconditioning reduced infarct size, most plausibly by blocking apoptosis and free radical generation. With further study it may eventually be clinically applicable for stroke treatment.
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PMID:Interrupting reperfusion as a stroke therapy: ischemic postconditioning reduces infarct size after focal ischemia in rats. 1673 38

Ischemia-reperfusion injury remains a major clinical problem in liver transplantation. One contributing factor is mitochondrial calcium (mCa(2+)) overload, which triggers apoptosis; calcium also regulates mitochondrial respiration and adenosine 5'-triphosphate (ATP) production. Recently, we reported the presence of purinergic P2Y(1)- and P2Y(2)-like receptor proteins in mitochondrial membranes. Herein, we present an evaluation of the functional characteristics of these receptors. In experiments with isolated mitochondria, specific P2Y(1) and P2Y(2) receptors ligands: 2-methylthio-adenosine 5'-diphosphate (2meSADP) and uridine 5'-triphosphate (UTP), respectively, were used, and mitochondrial calcium uptake was measured. 2meSADP and UTP had a maximum effect at concentrations in the range of the known P2Y(1) and P2Y(2) receptors. The P2Y inhibitor phosphate-6-azophenyl-2',4'-disulfonate (PPADS) blocked the effects of both ligands. The phospholipase C (PLC) antagonist U73122 inhibited the effect of both ligands while its inactive analog U73343 had no effect. These data strongly support the hypothesis that mitochondrial Ca(2+) uptake is regulated in part by adenine nucleotides via a P2Y-like receptor mechanism that involves mitochondrial PLC activation.
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PMID:Mitochondrial calcium transport is regulated by P2Y1- and P2Y2-like mitochondrial receptors. 1679 51


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