In vivo voltammetric evidence of production of uric acid by rat caudate

Mueller, Kathyrne; Palmour, Roberta M.; Andrews, Christopher; Knott, P. J.

doi:10.1016/0006-8993(85)90474-3

Cited by 60 publications

(22 citation statements)

References 11 publications

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“…Furthermore, human fetal neurons have a larger capacity of intracellular calciumbuffering systems than cortical rat neurons (35). There are also species differences with respect to the free radical-producing enzyme xanthine oxidase, which is present in rat neurons (15)(16)(17) but absent in human brain (18). Transcriptional regulation may account for the species-specific expression of this enzyme, as there are differences in the promotor region of the human and rat genes (36).…”

Section: Discussionmentioning

confidence: 99%

“…This potential cancer therapy drug was believed to be safe as it did not cause damage in laboratory animals (14). One relevant difference when studying free radicals is the presence of xanthine oxidase in rat neurons (15)(16)(17) in contrast to the absence of this radicalproducing enzyme in human neurons (18). As far as we know posthypoxic formation of free radicals has not previously been evaluated in cultured human neurons.…”

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confidence: 99%

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Neuronal Formation of Free Radicals Plays a Minor Role in Hypoxic Cell Death in Human NT2-N Neurons

Almaas¹,

Saugstad²,

Pleasure

et al. 2002

Pediatr Res

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Free radicals are suggested to play an important role in hypoxic-ischemic neuronal death. However, the importance in human disease is not known. Furthermore, whether posthypoxic free radical formation mainly occurs in endothelium and neutrophils, or whether neuronal production is important, is not finally determined. To study this we differentiated human Ntera2 teratocarcinoma cells into postmitotic NT2-N neurons and exposed them to free radicals, hypoxia, or oxygen and glucose deprivation. These cells are devoid of nitric oxide synthase, and we hypothesized that free radicals are important mediators downstream of N-methyl-D-aspartate stimulation. Production of free radicals, evaluated with the fluorescent dyes dihydrorhodamine and 2',7'-dichlorodihydrofluorescein, was significantly higher in neurons deprived of oxygen and glucose after 40 min of reoxygenation than in normoxic cells. The antioxidant trolox, the flavonoid quercetin, thiopental, and the N-methyl-D-aspartateglutamate receptor antagonist MK-801 reduced the formation of free radicals. Treatment with the flavonoid rutin (86 Ϯ 16% of hypoxic cells without drug, p Ͻ 0.01), trolox (86 Ϯ 20%, p Ͻ 0.01), and MK-801 (57 Ϯ 12%, p Ͻ 0.01) reduced lactate dehydrogenase release after 6 h of hypoxia. Trolox, salicylate, and quercetin also significantly reduced lactate dehydrogenase release after 3 h of oxygen and glucose deprivation. The protection offered by these antioxidants was, however, limited compared with the effect of MK-801. We conclude that oxygen and glucose deprivation causes a moderate increase in the formation of free radicals in NT2-N neurons that can be Several experiments have indicated a role for free radicals in the pathogenesis of hypoxic-ischemic cell death. The xanthine oxidase inhibitor and hydroxyl radical scavenger allopurinol reduces hypoxic-ischemic brain damage in rats (1), and van Bel et al. (2) demonstrated beneficial effects of allopurinol in asphyxiated infants. Infarct size and brain edema after focal cerebral ischemia are attenuated in adult transgenic mice overexpressing CuZn SOD (3). However, brain injury after hypoxia-ischemia was exacerbated in a similar newborn mice model (4).During reperfusion after cerebral ischemia in pigs, superoxide anion is generated (5). Production of free radicals after ischemia has been reported from rat brain microvessels (6) and from fetal bovine endothelial cells (7). A substantial part of posthypoxic free radical formation in endothelium has been attributed to xanthine oxidase (7). On the other hand, ScmidElsaesser et al. (8)

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Neuronal Formation of Free Radicals Plays a Minor Role in Hypoxic Cell Death in Human NT2-N Neurons

Almaas¹,

Saugstad²,

Pleasure

et al. 2002

Pediatr Res

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“…Although it is considered not to exist in mammalian brain tissue [10], Villea [31] found some data suggesting cerebral xanthine oxidase activity in several mammalian species, which recently was detected. The activity of xanthine oxidase in rat caudate was demonstrated by Mueller et al [23] and in brain capillaries and the cerebral cortex by Betz [4]. The xanthine oxidase system is a major source for generation of superoxide anion radicals [18].…”

Section: Discussionmentioning

confidence: 99%

The effect of allopurinol on focal cerebral ischaemia: an experimental study in rabbits

et al. 2001

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In this experimental study, the neuroprotective effect of the xanthine oxidase inhibitor allopurinol on focal cerebral ischaemia created by permanent middle cerebral artery occlusion (MCAO) was investigated. Using high performance liquid chromatography (HPLC), we measured hypoxanthine, xanthine, and uric acid (UA) levels in rabbit brains following focal cerebral ischaemia. Rabbits were randomly and blindly assigned into four groups of eight animals each. The control groups received 2% carboxymethylcellulose solution, while 10% allopurinol 150 mg/kg was given to the treatment group 1 h before ischaemia. Each group was subdivided into two groups which were sacrificed 4 h or 24 h after ischaemia, respectively. UA and xanthine values of the rabbits in the control groups were quite high at both times and highest after 24 h, particularly in the centre of the ischaemia. A significant decrease in UA and xanthine values was observed in rabbits that were given allopurinol (P<0.05). According to our results, it was concluded that allopurinol pretreatment protects neural tissue in the early period after arterial occlusion and prevents cerebral injury in the late period, especially in the perifocal area, possibly by preventing the formation of free radicals with xanthine oxidase inhibition.

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“…Base catabolism appears to be mainly regulated by the availability of substrates. Purine catabolism is believed not to proceed up to urate in brain, though its production was reported to occur locally in rat caudate [25]; moreover uric acid is considered a neuron protector [26]. Owing to the several roles of purines and pyrimidines and their derivatives, it is not surprising that fluctuations in their synthesis, catabolism and cellular concentration may significantly affect cell functions.…”

Section: Nucleotide Metabolismmentioning

confidence: 98%

Neurological Disorders of Purine and Pyrimidine Metabolism

Micheli

Camici²,

Tozzi³

et al. 2011

CTMC

101

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Purines and pyrimidines, regarded for a long time only as building blocks for nucleic acid synthesis and intermediates in the transfer of metabolic energy, gained increasing attention since genetically determined aberrations in their metabolism were associated clinically with various degrees of mental retardation and/or unexpected and often devastating neurological dysfunction. In most instances the molecular mechanisms underlying neurological symptoms remain undefined. This suggests that nucleotides and nucleosides play fundamental but still unknown roles in the development and function of several organs, in particular central nervous system. Alterations of purine and pyrimidine metabolism affecting brain function are spread along both synthesis (PRPS, ADSL, ATIC, HPRT, UMPS, dGK, TK), and breakdown pathways (5NT, ADA, PNP, GCH, DPD, DHPA, TP, UP), sometimes also involving pyridine metabolism. Explanations for the pathogenesis of disorders may include both cellular and mitochondrial damage: e.g. deficiency of the purine salvage enzymes hypoxanthine-guanine phosphoribosyltransferase and deoxyguanosine kinase are associated to the most severe pathologies, the former due to an unexplained adverse effect exerted on the development and/or differentiation of dopaminergic neurons, the latter due to impairment of mitochondrial functions. This review gathers the presently known inborn errors of purine and pyrimidine metabolism that manifest neurological syndromes, reporting and commenting on the available hypothesis on the possible link between specific enzymatic alterations and brain damage. Such connection is often not obvious, and though investigated for many years, the molecular basis of most dysfunctions of central nervous system associated to purine and pyrimidine metabolism disorders are still unexplained.

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In vivo voltammetric evidence of production of uric acid by rat caudate

Cited by 60 publications

References 11 publications

Neuronal Formation of Free Radicals Plays a Minor Role in Hypoxic Cell Death in Human NT2-N Neurons

Neuronal Formation of Free Radicals Plays a Minor Role in Hypoxic Cell Death in Human NT2-N Neurons

The effect of allopurinol on focal cerebral ischaemia: an experimental study in rabbits

Neurological Disorders of Purine and Pyrimidine Metabolism

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