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

Overstimulation of the NMDA receptor, as well as generation of excessive amounts of free radicals, has been implicated in excitotoxic brain injuries. We report here that two antagonists of the NMDA receptor and an inhibitor of the free radical-generating enzyme, xanthine oxidase, protect the olfactory cortex but not the striatum after intrastriatal injection of kainic acid. Our results suggest the existence of a precise link between excitotoxic activation of the NMDA receptor and neuropathology related to excessive amounts of free radicals. The focal point of this link may be the entry of Ca2+ through the NMDA receptor and the consequent activation of proteases and free radical-generating systems.
 ...
PMID:Antagonists of the NMDA receptor and allopurinol protect the olfactory cortex but not the striatum after intra-cerebral injection of kainic acid. 138 39

A novel modulatory site on the N-methyl-D-aspartate (NMDA) receptor that is sensitive to sulfhydryl redox reagents was recently described. Here we report that this redox modulatory site is susceptible to oxidation by reactive oxygen species endogenous to the CNS. Oxygen free radicals generated by xanthine and xanthine oxidase were observed to decrease NMDA-induced changes in intracellular free Ca2+ concentrations and NMDA-evoked cation currents in cortical neurons in culture. Additionally, a sublethal production of free radicals by xanthine and xanthine oxidase reversed a dithiothreitol-induced enhancement of NMDA-mediated neurotoxicity in vitro. These results show that NMDA receptor function is modulated at its redox site by endogenous substances that normally accompany tissue reperfusion following an ischemic event. This novel mechanism for NMDA receptor regulation may have profound implications in the outcome of glutamate neurotoxicity in vivo.
 ...
PMID:Oxygen free radicals regulate NMDA receptor function via a redox modulatory site. 214 89

In this study, we analysed the implication of superoxide (O2-.) and nitric oxide (NO.) free radicals and their resulting product peroxynitrite (ONOO-) in the neuronal death induced by the activation of the glutamatergic receptor of the N-methyl-D-aspartate (NMDA) subtype using cultured cerebellar granule cells. The NOl donor SIN-1 (3-morpholinosydnonimine N-ethylcarbamide), at concentrations which produced a much higher guanylate cyclase activation (i.e. NO. concentration) than NMDA, was not neurotoxic and did not increase the NMDA-induced neuronal death. The absence of involvement of NO. in NMDA-induced neuronal death was confirmed by the ineffectiveness of L-NG-nitroarginine (L-Narg) as a neuroprotective compound. Electron paramagnetic resonance (EPR) experiments, using 5,5-dimethyl pyrroline 1-oxide (DMPO) as a spin trap, indicated that NMDA receptor stimulation led to the generation of O2-. from at least 15-30 min. The generation of O2-. by xanthine (XA)-xanthine oxidase (XO) induced a neuronal death similar to that of NMDA. XA-XO-induced neuronal death was suppressed by addition of either superoxide dismutase (SOD) plus catalase (CAT), or DMPO in the incubation medium. In contrast, NMDA-induced neuronal death was widely blocked by DMPO and other spin trap compounds, but not by SOD +/- CAT. XA-XO-induced neuronal death was not potentiated by SIN-1 indicating that ONOO- is not more toxic than O2-. in our neuronal model.
 ...
PMID:Nitric oxide, superoxide and peroxynitrite: putative mediators of NMDA-induced cell death in cerebellar granule cells. 750 50

Oxygen-derived reactive species generated by xanthine/xanthine oxidase (X/XO) can modulate the N-methyl-D-aspartate (NMDA) receptor via its redox-sensitive site. Here it is shown that hydroxyl radicals are the agents responsible for NMDA receptor oxidation by X/XO. Spectrophotometric assays revealed that the amounts of superoxide anion and H2O2 produced by X/XO were not decreased by the hydroxyl radical-specific scavenger mannitol. This sugar, however, could prevent most of the oxidizing actions of NMDA receptors by X/XO, but not by the thiol oxidizing agent 5,5 -dithio-bis-nitrobenzoic acid. Finally, a non-enzymatic source of hydroxyl radicals was also effective in oxidizing the receptor's redox site. Hydroxyl radicals may thus represent the final common pathway for the modulation of NMDA receptor function by oxygen-derived free radical generating systems.
 ...
PMID:Modulation of N-methyl-D-aspartate receptors by hydroxyl radicals in rat cortical neurons in vitro. 760 27

The pathophysiology of ischaemia depends on the residual cerebral blood flow. As a result, it is different in global ischaemia, when compared with focal ischaemia, where the centre area is surrounded with an area called an ischaemic penumbra. Ischaemia results from a sudden failure in the oxygen and glucose supply. Oxidative phosphorylation fails, a major event that is responsible for all the other reactions. Anaerobic metabolism produces lactate and H+. Cell membrane ionic pumps are inactivated, which results in a breakdown of ionic homeostasis. Ca++ and Na+ penetrate into the cells, as K+ is released. The energy failure causes an extracellular accumulation of excitatory amino-acids, thus eliciting a hyperstimulation of the NMDA receptors. These receptors are hyperactivated as a result of the deterioration in the control systems with, especially, the blockade of the NMDA receptor by Mg++. As a consequence, there is a massive entry of Ca++ into the cell, including a series of enzymatic reactions involving phospholipases, proteases and endonucleases. Reperfusion will cause toxic lesions by producing free radicals, due to the action of arachidonic acid, xanthine oxidase and nitric oxide. The decrease in cell energetic supplies, as well as the overactivation of enzymes and the production of free radicals, result in cell death.
 ...
PMID:[Cerebral ischemic cascade]. 767 74

The neurotoxic effects of oxygen radicals on spinal cord neuron cultures derived from fetal mouse have been studied. Oxygen radicals, superoxide radical and hydrogen peroxide, were generated by adding xanthine oxidase and hypoxanthine in the culture medium. Exposure of neurons to this oxygen radical-generating system resulted in a significant cell death and decrease of choline acetyltransferase (ChAT) activity in a time-dependent manner in spinal cord neuron cultures. The decrease in cell viability and ChAT enzyme activity induced by the oxygen radicals was blocked by scavengers such as superoxide dismutase (SOD), catalase, and tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), a metal chelator. Antagonists of the N-methyl-D-aspartate (NMDA) receptor, including MK801 (a noncompetitive NMDA antagonist), D-2-amino-5-phosphonovaleric acid (APV) (a competitive NMDA antagonist), and 7-chlorokynurenic acid (an antagonist at the glycine site associated with the NMDA receptor), similarly blocked oxygen radical-induced decrease in cell viability and ChAT activity in spinal cord neuron cultures. These results indicate that both oxygen radicals and excitotoxic amino acids were involved in the oxidant-initiated neurotoxicity of spinal cord neurons.
 ...
PMID:Oxygen radical-induced neurotoxicity in spinal cord neuron cultures. 814 4

Using microdialysis in the hippocampus of anaesthetised rats, the concentration of extracellular adenosine was estimated to be 0.8 microM. Kainic acid (0.1-25 mM) in the perfusate evoked a concentration-dependent release of adenosine with an EC50 of 940 microM. Two 5-min pulses of 1 mM kainic acid in the perfusate increased the dialysate levels with an S2/S1 ratio of 0.52 +/- 0.03. Kainate-evoked release of adenosine was reduced significantly by 10 microM tetrodotoxin and by a kappa-receptor agonist, U50, 488H (100 microM). The S2/S1 ratio was reduced by 4.5 microM 6-cyano-7-nitroquinoxaline-2,3-dione, a non-NMDA receptor antagonist, but not by the NMDA receptor blockers (+)-MK-801 (dizocilpine; 100 microM) or (+/-)-2-amino-5-phosphonopentanoic acid (1 mM), indicating a non-NMDA receptor-mediated process. The S2/S1 ratio was also reduced significantly by 10 mM ascorbic acid, 10 mM glutathione (a scavenger of hydroperoxides), and 1 mM oxypurinol (a xanthine oxidase inhibitor), indicating the possible involvement of free radicals. Neither the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (100 microM) nor the A1 adenosine receptor agonist R(-)-N6-(2-phenylisopropyl)adenosine (100 microM) affected release. Adenosine release evoked by kainic acid is therefore mediated by activation of non-NMDA receptors and may involve the propagation of action potentials and the production of free radicals.
 ...
PMID:Kainate-evoked release of adenosine from the hippocampus of the anaesthetised rat: possible involvement of free radicals. 897 31

To gain insight into the mechanism through which the neurotransmitter glutamate causally participates in several neurological diseases, in vitro cultured cerebellar granule cells were exposed to glutamate and oxygen radical production was investigated. To this aim, a novel procedure was developed to detect oxygen radicals; the fluorescent dye 2',7'-dichlorofluorescein was used to detect production of peroxides, and a specific search for the possible conversion of the enzyme xanthine dehydrogenase into xanthine oxidase after the excitotoxic glutamate pulse was undertaken. A 100 microM glutamate pulse administered to 7-day-old cerebellar granule cells is accompanied by the onset of neuronal death, the appearance of xanthine oxidase, and production of oxygen radicals. Xanthine oxidase activation and superoxide (O2.-) production are completely inhibited by concomitant incubation of glutamate with MK-801, a specific NMDA receptor antagonist, or by chelation of external calcium with EGTA. Partial inhibition of both cell death and parallel production of reactive oxygen species is achieved with allopurinol, a xanthine oxidase inhibitor, leupeptin, a protease inhibitor, reducing agents such as glutathione or dithiothreitol, antioxidants such as vitamin E and vitamin C, and externally added superoxide dismutase. It is concluded that glutamate-triggered, NMDA-mediated, massive Ca2+ influx induces rapid conversion of xanthine dehydrogenase into xanthine oxidase with subsequent production of reactive oxygen species that most probably have a causal involvement in the initial steps of the series of intracellular events leading to neuronal degeneration and death.
 ...
PMID:Glutamate neurotoxicity in rat cerebellar granule cells: a major role for xanthine oxidase in oxygen radical formation. 910 30

We examined the neuroprotective efficacy of eugenol against N-methyl-D-aspartate (NMDA)-, oxygen-glucose deprivation-, and xanthine/xanthine oxidase-induced neurotoxicity in primary murine cortical cultures. Eugenol (100-300 microM) attenuated NMDA (300 microM)-induced acute neurotoxicity by 20-60%. At the same concentration range, eugenol also inhibited NMDA (300 microM)-induced elevation in neuronal 45Ca2+ uptake by 10-30%. In the oxygen-glucose deprivation (50 min) neurotoxicity, eugenol (100-300 microM) prevented acute neuronal swelling and reduced neuronal death by 45-60% in a concentration-dependent fashion. Oxidative neuronal injury induced by xanthine/xanthine oxidase was also significantly reduced (75-90%) by eugenol (100- 300 microM) addition. These results suggest that eugenol may play a protective role against ischemic injury by modulating both NMDA receptor and superoxide radical.
 ...
PMID:Eugenol protects neuronal cells from excitotoxic and oxidative injury in primary cortical cultures. 914 82

The present study tests the hypothesis that repeated episodes of asphyxia will lead to alterations in the characteristics of the N-methyl-d-aspartate (NMDA) receptor in the brain cell membrane of newborn piglets and that pre-treatment with allopurinol, a xanthine oxidase inhibitor, will prevent these modifications. Eighteen newborn piglets were studied. Six untreated and six allopurinol treated animals were subjected to eight asphyxial episodes and compared to six normoxic, normocapneic controls. Brain cell membrane Na+,K+-ATPase activity was determined to assess membrane function. Na+,K+-ATPase activity was decreased from control following asphyxia in both the untreated and treated animals (47.7+/-3.2 vs. 43.0+/-2.2 and 41.0+/-5.3 micromol Pi/mg protein/h, p<0.05, respectively). 3H-MK-801 binding studies were performed to measure NMDA receptor binding characteristics. The receptor density (Bmax) in the untreated asphyxia group was decreased compared to control animals (0.80+/-0.11 vs. 1.13+/-0.33, p<0.05); furthermore, the dissociation constant (Kd) was also decreased (3.8+/-0.7 vs. 9.2+/-2.2, p<0.05), indicating an increase in receptor affinity. In contrast, Bmax in the allopurinol treated asphyxia group was similar to control (1. 06+/-0.37); and Kd was higher (lower affinity) than in the untreated group (6.5+/-1.4, p<0.05). The data indicate that recurrent asphyxial episodes lead to alterations in NMDA receptor characteristics; and that despite cell membrane dysfunction as seen by a decrease in Na+,K+-ATPase activity, allopurinol prevents modification of NMDA receptor-ion channel binding characteristics induced by repeated episodes of asphyxia.
 ...
PMID:Effect of allopurinol on NMDA receptor modification following recurrent asphyxia in newborn piglets. 951 56


1 2 3 Next >>