Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of cellular mediators that contribute to ischemia-induced neuronal degeneration on gamma-aminobutyric acid (GABAA)-receptor function were studied. In vitro, phospholipase A2 (PLA2) inhibited muscimol-induced 36Cl- uptake in cerebral cortical synaptoneurosomes. The major hydrolysis product of PLA2 activity, arachidonic acid, also inhibited GABA-mediated 36Cl- uptake. The unsaturated nature of arachidonic acid makes it (and its metabolites) highly susceptible to peroxidation by oxygen radicals. Incubation of synaptoneurosomes with the superoxide radical-generating system, xanthine and xanthine oxidase, decreased muscimol-induced 36Cl- uptake, suggesting that the peroxidation of arachidonic acid and/or its metabolites interferes with GABAA-receptor function. Another factor involved in ischemia-induced neuronal degeneration is an increase in intracellular Ca2+. Calcium also inhibited GABA-mediated 36Cl- flux, consistent with its ability to activate PLA2. In contrast, Mg2+, which blocks Ca2+ channels, enhanced muscimol-induced 36Cl- uptake, consistent with its neuroprotective effects. Each of these cellular processes is activated during cerebral ischemia and can lead to neuronal degeneration. We used a model of transient forebrain ischemia in gerbils to determine if GABAA-receptor regulation is altered in vivo at a time when CA1 hippocampal cells have degenerated. Four days after a 5 minute bilateral carotid artery occlusion, receptor autoradiography was performed to measure the binding of [35S]t-butylbicyclophosphorothionate (TBPS) to the GABA-gated chloride channel. Significant decreases in TBPS binding were observed only in the dendritic layers (stratum oriens and lacunosem moleculare) of the CA1 hippocampus. The results suggest that ischemia-induced cellular processes that contribute to cell death can decrease GABA-gated chloride channels on dendrites of CA1 pyramidal cells, and that GABAA receptors may also reside on neurons afferent to or intrinsic to the dendritic layers of CA1 hippocampus.
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PMID:Cellular regulation of the benzodiazepine/GABA receptor: arachidonic acid, calcium, and cerebral ischemia. 131 67

Oxypurinol, an inhibitor of the enzyme xanthine oxidase, reduced ischemic hippocampal damage and the associated hypermotility in Mongolian gerbils. Cerebral ischemia was induced in unanesthetized gerbils by a bilateral 5-min occlusion of the carotid arteries. Oxypurinol (40 mg/kg, IP), administered 20 min prior to carotid occlusion, prevented the increase in locomotor activity observed in saline-injected ischemic animals and significantly reduced the damage to, and loss of, CA1 hippocampal neurons observed 5 days postischemia. These findings suggest that oxypurinol may be useful for the prevention of cerebral ischemic damage.
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PMID:Oxypurinol attenuates ischemia-induced hippocampal damage in the gerbil. 261 88

Prostacyclin (PGI2) is a critical regulator of the cardiovascular system, via dilatation of vascular smooth muscle and inhibition of platelet aggregation (Moncada, S. 1982, Br. J. Pharmacol., 76, 3). Our previous studies demonstrated that a novel subtype of PGI2 receptor, which is clearly distinct from a peripheral subtype in terms of ligand specificity, is expressed in the rostral region of the brain, e.g. cerebral cortex, hippocampus, thalamus and striatum, and that (15R)-16-m-17,18,19,20-tetranorisocarbacyclin (15R-TIC) and 15-deoxy-16-m-17,18,19,20-tetranorisocarbacyclin (15-deoxy-TIC) specifically bind to the central nervous system (CNS)-specific PGI2 receptor. Here, we report that these CNS-specific PGI2 receptor ligands, including PGI2 itself, prevented the neuronal death. They prevented apoptotic cell death of hippocampal neurons induced by high (50%) oxygen atmosphere, xanthine + xanthine oxidase, and serum deprivation. IC50s for neuronal death were approximately 30 and 300 nM for 15-deoxy-TIC and 15R-TIC, respectively, which well correlated with the binding potency for the CNS-specific PGI2 receptor. 6-Keto-PGF1alpha (a stable metabolite of PGI2), peripheral nervous system-specific PGI2 ligands and other prostaglandins (PGs) than PGI2 did not show such neuroprotective effects. In vivo, 15R-TIC protected CA1 pyramidal neurons against ischaemic damage in gerbils. These results indicate that CNS-specific PGI2 ligands have neuronal survival-promoting activity both in vitro and in vivo, and may represent a new type of therapeutic drug for neurodegeneration.
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PMID:CNS-specific prostacyclin ligands as neuronal survival-promoting factors in the brain. 1051 Jan 75

Neuronal protein synthesis is inhibited in CA1 pyramidal neurons for many hours after ischemia, hypoxia or hypoglycemia. This inhibition precedes cell death, is a hallmark characteristic of necrotic damage and may play a key role in the death of vulnerable neurons after these insults. The sequence of events leading to this inhibition remains to be fully elucidated. The protein synthesis failure after 7.5 min anoxia/aglycemia in the rat hippocampal slice can be prevented by blocking N-methyl-D-aspartate receptors in a reduced calcium environment during the insult. In this study, we demonstrate that N-methyl-D-aspartate exposure directly causes a dose-dependent, receptor-mediated and prolonged protein synthesis inhibition in CA1 pyramidal neurons. The free radical scavenger Vitamin E significantly attenuates this damage due to low concentrations of N-methyl-D-aspartate (10 microM). Free radical generation by xanthine/xanthine oxidase (XOD) can directly damage protein synthesis in neurons of the slice. Vitamin E, ascorbic acid and N-acetylcysteine can each prevent the damage due to anoxia/aglycemia and to higher concentrations of N-methyl-D-aspartate (50 microM), provided calcium levels are reduced concomitantly. These findings indicate that both free radicals and calcium play a role in the sequence of events leading to protein synthesis failure after energetic stress like anoxia/aglycemia. They further suggest that the mechanism by which N-methyl-D-aspartate receptor activation damages protein synthesis involves free radical generation.
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PMID:Free radicals are involved in the damage to protein synthesis after anoxia/aglycemia and NMDA exposure. 1070 May 65

We have used an enzyme-based, twin-barrelled sensor to measure adenosine release during hypoxia in the CA1 region of rat hippocampal slices in conjunction with simultaneous extracellular field recordings of excitatory synaptic transmission. When loaded with a combination of adenosine deaminase, nucleoside phosphorylase and xanthine oxidase, the sensor responded linearly to exogenous adenosine over the concentration range 10 nM to 20 microM. Without enzymes, the sensor when placed on the surface of hippocampal slices recorded a very small net signal during hypoxia of 40 +/- 43 pA (mean +/- s.e.m.; n = 7). Only when one barrel was loaded with the complete sequence of enzymes and the other with the last two in the cascade did the sensor record a large net difference signal during hypoxia (1226 +/- 423 pA; n = 7). This signal increased progressively during the hypoxic episode, scaled with the hypoxic depression of the simultaneously recorded field excitatory postsynaptic potential and was greatly reduced (67 +/- 6.5 %; n = 9) by coformycin (0.5-2 microM), a selective inhibitor of adenosine deaminase, the first enzyme in the enzymic cascade within the sensor. For 5 min hypoxic episodes, the sensor recorded a peak concentration of adenosine of 5.6 +/- 1.2 microM (n = 16) with an IC(50) for the depression of transmission of approximately 3 microM. In slices pre-incubated for 3-6 h in nominally Ca(2+)-free artificial cerebrospinal fluid, 5 min of hypoxia resulted in an approximately 9-fold greater release of adenosine (48.9 +/- 17.7 microM; n = 6). High extracellular Ca(2+) (4 mM) both reduced the adenosine signal recorded by the sensor during hypoxia (3.5 +/- 0.6 microM; n = 4) and delayed the hypoxic depression of excitatory synaptic transmission.
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PMID:Direct measurement of adenosine release during hypoxia in the CA1 region of the rat hippocampal slice. 1087 7

Mitochondrial permeability transition (MPT) is a phenomenon which occurs under adverse conditions such as an increase in mitochondrial calcium content and oxidative stress. The MPT causes the opening of mitochondrial megachannels, loss of mitochondrial membrane potential, and uncoupling of mitochondrial respiration, leading to cellular energy failure. Recent experiments have suggested that the MPT also releases specific proteins from mitochondria and activates the cascades of programmed cell death. Although many investigators have reported that ischemia-reperfusion leads to apoptosis in the brain tissue, there are only a few studies on the roles of MPT in ischemia-reperfusion injury in the brain. The present study was aimed to assess the effects of calcium, pH, temperature and free radicals on permeability transition of brain mitochondria in vitro, by the use of spectrophotometry. The effect of cyclosporin A (CsA), which is known to be a potent suppressor of MPT in other organs such as liver and heart, was also evaluated. The author also studied the protective effects of CsA on delayed neuronal death in CA1 sector, using transient forebrain ischemia model of the gerbil. Non-synaptosomal (free) mitochondria isolated from the forebrain of the rat had well-coupled respiration. MPT was induced by more than 10 microM of calcium. However, oxygen free radicals derived from t-butyl hydroperoxide and xanthine/xanthine oxidase could not induce MPT. Acidosis and low temperature significantly suppressed calcium-induced MPT. CsA (0.1-10 microM) but not FK506 (0.1-1 microM) inhibited MPT. CsA (50 mg/kg, i.p.) dramatically protected CA1 neurons in the hippocampus for 7 days after 5-min forebrain ischemia in the gerbil. These results suggest that calcium is the major inducer of MPT of the brain mitochondria, and that CsA can potentially inhibit MPT and ameliorate the ischemic tissue injury of the brain.
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PMID:[The roles of mitochondrial permeability transition in brain ischemia]. 1097 4

Recent evidence suggests that reactive oxygen species (ROS), including superoxide, are not only neurotoxic but function as small messenger molecules in normal neuronal processes such as synaptic plasticity. Consistent with this idea, we show that brief incubation of hippocampal slices with the superoxide-generating system xanthine/xanthine oxidase (X/XO) produces a long-lasting potentiation of synaptic transmission in area CA1. We found that X/XO-induced potentiation was associated with a persistent superoxide-dependent increase in autonomous PKC activity that could be isolated via DEAE column chromatography. The X/XO-induced potentiation was blocked by the inhibition of PKC, indicating that the superoxide-dependent increase in autonomous PKC activity was necessary for the potentiation. We also found that X/XO-induced potentiation and long-term potentiation (LTP) occluded one another, suggesting that these forms of plasticity share similar cellular mechanisms. In further support of this idea, we found that a persistent, superoxide-dependent increase in autonomous PKC activity isolated via DEAE column chromatography also was associated with LTP. Taken together, our findings indicate that X/XO-induced potentiation and LTP share similar cellular mechanisms, including superoxide-dependent increases in autonomous PKC activity. Finally, our findings suggest that superoxide, in addition to its well known role as a neurotoxin, also can be considered a small messenger molecule critical for normal neuronal signaling.
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PMID:Potentiation of hippocampal synaptic transmission by superoxide requires the oxidative activation of protein kinase C. 1182 97

The accumulation of reactive oxygen species during cellular injury leads to oxidative stress. This can have profound effects on ionic homeostasis and neuronal transmission. Gamma-aminobutyric acid (GABA) neurotransmission is sensitive to reactive oxygen species, but most studies have indicated that this is due to alterations in GABA release. Here, we determined whether reactive oxygen species can alter GABA(A) receptor-gated Cl- channels in the adult hippocampus. First, we measured the effects of hydrogen peroxide on intracellular Cl- using UV laser scanning confocal microscopy and the Cl(-)-sensitive probe, 6-methoxy-N-ethylquinolium iodide (MEQ). Superfusion of adult rat hippocampal slices with hydrogen peroxide for 10 min decreased MEQ fluorescence (elevation in [Cl-]i) significantly in area CA1 pyramidal cell soma. Alterations in [Cl-]i were prevented by the vitamin E analog Trolox, an antioxidant that scavenges free radicals. After exposure of slices to hydrogen peroxide, the ability of the GABA agonist muscimol to increase [Cl-]i was attenuated. To determine if GABA(A) receptors were sensitive to oxidative insults, the effect of hydrogen peroxide on the binding of [35S]t-butylbicyclophosphorothionate (TBPS) to GABA-gated Cl- channels was measured using receptor autoradiography and homogenate binding assays. Hydrogen peroxide inhibited [35S]TBPS binding in a regionally selective manner, with the greatest inhibition in cerebral cortex, hippocampus and striatum, areas vulnerable to oxidative stress. Similarly, xanthine and xanthine oxidase, which generate superoxide radicals, reduced [35S]TBPS binding in these regions. The effect of hydrogen peroxide on [35S]TBPS binding was non-competitive and was prevented by Trolox and the iron chelator, deferoxamine. We conclude that reactive oxygen species may compromise GABA(A)-mediated neuronal inhibition via interaction with pre and postsynaptic sites. A reduction in GABA(A)-gated Cl- channel function during periods of oxidative stress may contribute to the development of neuronal damage.
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PMID:Modulation of the GABA(A)-gated chloride channel by reactive oxygen species. 1190 87

1. Quinolinic acid may be an important endogenous excitotoxin, but its concentrations in brain are low. We have therefore attempted to determine whether its neurotoxicity can be increased by the simultaneous presence of free radicals. 2. Quinolinic acid was injected into the hippocampus of anaesthetized rats at doses of 40 and 80 nmols which produced little neuronal loss, and 120 nmols which produced over 90% neuronal loss. 3. A mixture of xanthine and xanthine oxidase, a known source of free radical reactive oxygen species, also generated little damage alone, but killed over 80% of CA1 neurons when combined with 80 nmols of quinolinic acid. Similarly, the nitric oxide donor S-nitroso-N-acetylpenicillamine (SNAP) potentiated the damage produced by quinolinic acid. 4. The glutamate antagonist 5,7-dichlorokynurenic acid prevented the damage produced by 120 nmols of quinolinic acid, but not that produced by quinolinic acid plus xanthine/xanthine oxidase, indicating that damage was not simply the result of free radical enhancement of NMDA receptor activation. 5. Three chemically dissimilar antagonists at adenosine A(2A) receptors prevented the damage caused by quinolinic acid and xanthine/xanthine oxidase or by quinolinic acid plus SNAP. 6. It is concluded that reactive oxygen species can potentiate the neurotoxicity of quinolinic acid. The site of interaction is probably distal to the NMDA receptor. Blockade of adenosine A(2A) receptors can protect against this combined damage, suggesting potential value in the prevention of brain damage.
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PMID:Enhanced neuronal damage by co-administration of quinolinic acid and free radicals, and protection by adenosine A2A receptor antagonists. 1190 56

Reactive oxygen species-induced reperfusion injury of the brain is an important cause of neonatal morbidity and mortality following perinatal hypoxia-ischemia. Deferoxamine, allopurinol and oxypurinol have previously been shown to be neuroprotective in vivo during or directly after hypoxia-ischemia. To further characterize and more precisely elucidate whether the neuroprotective properties of these agents are mediated via neuronal and glial cells, or whether endothelial cells contribute to this effect, we tested their ability to protect CA1 neurons in organotypic hippocampal slices. Hippocampal slices obtained from 8-day-old rats were cultured for 7 days and exposed to oxygen/glucose deprivation for 50 min, or used as control slices. Cell damage was assessed at 48 h after oxygen/glucose deprivation using propidium iodide staining. At different time points following oxygen/glucose deprivation we administered dizocilpine, 6-cyano-7-nitroquinoxaline-2,3-dione, and alpha-phenyl-N-tert-butyl nitrone for validation purposes. Deferoxamine, allopurinol or oxypurinol were used as test substances. As expected, 89% and 98% protection was demonstrated with dizocilpine present during or during/after oxygen/glucose deprivation resp. alpha-Phenyl-N-tert-butyl nitrone administered during/after oxygen/glucose deprivation provided 44% protection. However, iron chelation with deferoxamine and inhibition of xanthine oxidase by allopurinol or oxypurinol did not confer neuroprotection. The neuroprotective effect of deferoxamine, allopurinol or oxypurinol, as seen in vivo, may be obtained via inhibition of the production of damaging factors by blood born substances or endothelial cells.
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PMID:Deferoxamine, allopurinol and oxypurinol are not neuroprotective after oxygen/glucose deprivation in an organotypic hippocampal model, lacking functional endothelial cells. 1256 Jan 12


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