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

The effects of arachidonic acid and its metabolites on gamma-aminobutyric acid (GABAA) receptor function were determined in rat cerebral cortical synaptoneurosomes. Incubation of synaptoneurosomes with phospholipase A2 decreased muscimol-induced 36Cl- uptake. Arachidonic acid, the major unsaturated fatty acid released by phospholipase A2, also inhibited muscimol-induced 36Cl uptake. Similar inhibition was obtained with other unsaturated fatty acids (docosahexaenoic, oleic) but not with saturated fatty acids (stearic, palmitic). The effect of arachidonic acid on muscimol responses was inhibited by bovine serum albumin (BSA), and BSA enhanced muscimol responses directly, indicating the generation of endogenous arachidonic acid in the synaptoneurosome preparation. The generation of endogenous arachidonic acid was also indicated by the ability of 2 inhibitors of arachidonic acid metabolism, indomethacin and nordihydroguaiaretic acid (NDGA), to inhibit muscimol-induced 36Cl uptake. We conclude that arachidonic acid probably has both direct and indirect actions on muscimol responses since both enzyme inhibitors inhibited muscimol responses but did not prevent the effect of exogenously added arachidonic acid. In additional experiments, arachidonic acid metabolites generated by cyclooxygenase, prostaglandins D2, E2 and F2 alpha, each decreased muscimol responses; prostaglandins F2 alpha was the most potent inhibitor. Since the unsaturated fatty acids and their metabolites are most susceptible to peroxidation, a generating system of superoxide radicals was tested on muscimol responses. A combination of xanthine and xanthine oxidase inhibited muscimol-induced 36Cl uptake in a concentration-dependent manner. We propose that the inhibition of GABAA neurotransmission by arachidonic acid and its metabolites can lead to increased neuronal excitability. This mechanism may play an important role in the development of neuronal damage following seizures or cerebral ischemia.
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PMID:Inhibition of GABA-gated chloride channel function by arachidonic acid. 132 73

The role of xanthine dehydrogenase and oxidase as a source of free radicals contributing to focal cerebral ischemic injury was evaluated in Long-Evans rats after the middle cerebral artery was permanently occluded and both carotid arteries were clamped for 90 min. The fraction of xanthine dehydrogenase present as the free radical producing oxidase increased slightly from 22% in control cortex to 30% in the ischemic right cortex during the first 3 h of reperfusion and then remained relatively unchanged over the next 24 h. This increase may in part be due to entrapped plasma, which contained 4.5 +/- 0.8 nmol.min-1.ml-1 xanthine oxidase entirely in the free radical-producing form. Infarct volume was unaffected by pretreatment with 50 mg allopurinol/kg per day over 3 days before surgery but was decreased by 8% with 100 mg/kg and 24% with 150 mg/kg of allopurinol (P less than 0.05). However, inhibition of xanthine oxidase by dietary depletion of the essential molybdenum cofactor increased infarct volume by 19%, suggesting that protection by allopurinol at higher dosages was independent of xanthine oxidase inhibition. Neither xanthine oxidase present in rat brain nor circulating in plasma appears to be the primary source of oxygen radicals that contributes to infarction in focal cerebral ischemia.
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PMID:Role of xanthine dehydrogenase and oxidase in focal cerebral ischemic injury to rat. 175 May 51

The ability of stobadine (ST) to prevent lipid peroxidation was tested in incomplete rat cerebral ischemia induced by 4 hour ligation of the common carotid arteries with a subsequent 10 min reperfusion. The extent of lipid peroxidation was determined by the measurement of the level of conjugated dienes (CD) and thiobarbituric acid reactive substances (TBARS). The levels of CD and TBARS were significantly elevated in brain cortex samples from animals subjected to ischemia followed by reoxygenation in comparison with ischemic samples without reperfusion, samples from sham operated or control animals. The concentration of CD and TBARS significantly decreased in animals treated with therapeutic doses of ST (2 mg/kg) administered i.v. immediately before reperfusion or 10 min after the onset of reperfusion. Stobadine was more effective than the known lipid antioxidant vitamin E, given in a dose of 30 mg/kg.day i.m. over 3 consecutive days prior to ischemia. The beneficial effect of ST on survival of rats was more effective in comparison with vitamin E. Significant changes were found in the activities of the antioxidative enzymes, i.e. increase in superoxide dismutase (SOD) and decrease in glutathione peroxidase (GP) in brain cortex samples from animals subjected to ischemia followed by reoxygenation. Stobadine prevented these changes. Catalase (CAT) activity was not detectable. It may be concluded from the increased SOD activity that oxygen radicals play a significant role in cerebral ischemia followed reperfusion. In addition to its antioxidant effect, stobadine probably prevents superoxide radical generation. The mechanism of xanthine oxidase inhibition is not involved in preventing superoxide radical generation by stobadine. Stobadine maintained high GP activity, probably by preventing glutathione oxidation.
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PMID:Effect of stobadine on brain lipid peroxidation induced by incomplete ischemia and subsequent reperfusion. 178 73

Pharmacological effects of Reiousan, a crude drug preparation consisting of bezoar and ginseng, on experimental cerebral ischemia and anoxia were studied. After administration of Reiousan, the survival time of mice subjected to hypobaric hypoxia and the gasping duration of isolated rat head tended to increase. Reiousan inhibited all the following: lipid peroxides production in rat brain homogenate, tissue swelling induced by the xanthine-xanthine oxidase system in rat brain cortical slices, rat brain swelling induced by freezing, lipid peroxides production in the rat brain after ligation of bilateral common carotid arteries, and lipid peroxides production in Mongolian gerbil brain after reperfusion following ligation of bilateral common carotid arteries. These effects may result from antioxidant activity of bilirubin, a constituent of bezoar.
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PMID:[Pharmacological studies of reiousan which contains bezoar and ginseng: III. Effects on experimental cerebral ischemia]. 178 24

Superoxide anion radicals are generated in association with prostaglandin production, and are implied in the mediation of secondary brain damage following cerebral ischemia or injury. In a model of closed head injury in rats we have demonstrated the activation of phospholipase A2 (PLA2) and the increased production of eicosanoids in the post-trauma period. In the present study we investigated the role of superoxide dismutase (SOD) in this model. Head trauma was induced over the left cerebral hemisphere of ether anesthetized rats by a calibrated weight drop device. Cortical tissue samples were taken 15 min, 4 and 24 h later. SOD activity was assayed by its ability to inhibit the xanthine oxidase-cytochrome c reduction. There was no significant change in SOD activity in any of the regions studied - the site of injury, and contralateral region as well as the remote frontal lobes of both hemispheres. Although intense PLA2 activity and production of eicosanoids was previously found in some of these regions, activity of SOD was unaffected. These results do not support an important role for endogenous SOD up to 24 h after head injury.
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PMID:Superoxide dismutase activity is not affected by closed head injury in rats. 178 58

Xanthine oxidase (XO) has been proposed as an important source of free radicals during ischemia. This enzyme normally exists as a dehydrogenase (XD), but it is converted to XO in some ischemic tissues. Recently, treatment of animals with the XD and XO inhibitor allopurinol or with free radical scavengers before cerebral ischemia has been shown to reduce brain injury. Therefore, we studied conversion of XD to XO in three ischemic and nonischemic brain regions during focal cerebral ischemia resulting from permanent occlusion of the middle cerebral artery (MCAO) in anesthetized rats. In nonischemic brain, 16-22% of the enzyme was in the XO form. After 24 h of ischemia this value was not significantly different (10-15%). Neither the total activity of XO nor that of XD changed, indicating that there was no irreversible conversion of XD to XO. To further explore the possible role of XO, we examined the effect of various doses of allopurinol (5, 20, or 100 mg/kg given 1 h before MCAO or 100 mg/kg given 48, 24, and 1 h before MCAO) on uric acid accumulation, brain edema formation, and cerebral blood flow (CBF) 24 h after MCAO. All but the lowest dose of allopurinol greatly reduced the appearance of uric acid in the ischemic brain; however, only the highest dose of allopurinol had any beneficial effect on brain edema. This reduction in brain edema occurred without a significant improvement in CBF. Thus XO is probably not an important source of free radicals in this model of focal cerebral ischemia.
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PMID:Xanthine oxidase is not a major source of free radicals in focal cerebral ischemia. 199 99

The reperfusion of previously ischemic tissue may lead to the formation of highly reactive free radicals that promote tissue injury. Xanthine oxidase has been implicated as one source of these free radicals. We examined the role of xanthine oxidase in brain injury using a cerebrospinal fluid compression model of global cerebral ischemia with 15 minutes of ischemia and 4 hours of reperfusion. Seven dogs were pretreated with the xanthine oxidase inhibitor allopurinol (50 mg/kg for 5 days). Neurophysiological recovery was monitored with cortical somatosensory evoked potentials. As an attempt to correlate brain recovery with the mechanism of protection, free brain malondialdehyde was measured at the end of reperfusion by high-performance liquid chromatography. Brain water content was measured by wet-dry weights. Compared with seven untreated control dogs, allopurinol pretreatment significantly improved recovery of somatosensory evoked potentials after 4 hours of reperfusion. However, the amount of free malondialdehyde in the allopurinol-treated dogs was 32% greater than that in the controls. Brain water content was similar in the two groups. These results suggest that xanthine oxidase contributes to brain injury after ischemia and reperfusion. However, tissue damage caused by xanthine oxidase may be mediated through mechanisms other than free radical production.
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PMID:Allopurinol pretreatment improves evoked response recovery following global cerebral ischemia in dogs. 202 98

One cause of ischemic brain injury is free radical formation during recirculation. Allopurinol inhibits xanthine oxidase, an important source of free oxygen radicals. It is known that allopurinol pre-treatment has a protective action during cerebral ischemia. In the present study we exposed slices from the rat hippocampus to 9 minutes of hypoxia to test whether it is sufficient that allopurinol is present in the tissue at the time of reoxygenation. Forty-six slices loaded with allopurinol (10(-5) M) prior to reoxygenation (during hypoxia) were compared to 34 control slices. The response of the pyramidal cell population to orthodromic stimulation was reduced in both groups and there was not a significant difference between the two groups.
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PMID:Failure of allopurinol to protect against cerebral injury when given after the start of hypoxia. 206 50

The formation of oxygen-derived free radicals in cerebral ischaemia has been implicated in altering the BBB permeability, cause oedema and tissue damage. However little attention has been paid regarding the involvement of xanthine oxidase in the cerebral ischaemic events. Recently we demonstrated that cerebral ischaemia promotes the conversion of xanthine oxidase type D (nicotinamide adenine dinucleotide-dependent dehydrogenase) to type 0 (oxygen-dependent superoxide-producing oxidase). This investigation was concerned with elucidating the relationship between the conversion of xanthide oxidase and the duration of brain ischaemia. Four vessel-occlusion served as a model for the induction of cerebral ischaemia in rats. Xanthine oxidase was assayed by high pressure liquid chromatography using ultraviolet and electrochemical detection. The enzymatic conversion of xanthine oxidase from type D to type O increased with time from 7.6-15% during 5 min ischaemia to 27% and 36% at 15 min and 30 min after ischaemia, respectively. These results support the contention that xanthine oxidase may participate in free radical-induced ischaemic brain oedema.
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PMID:Ischaemic brain oedema and xanthine-xanthine oxidase system. 208 93


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