Urinary uric acid and antioxidant capacity in children and adults with Down syndrome

doi:10.1016/j.clinbiochem.2009.09.017

Clinical Biochemistry

Volume 43, Issue 3, February 2010, Pages 228-233

https://doi.org/10.1016/j.clinbiochem.2009.09.017 Get rights and content

Abstract

Objectives

To evaluate the urinary levels of uric acid (UA) and total antioxidant capacity (TAC) with and without UA relative contribution (TAC^−UA) in children and adults with Down syndrome (DS) and to prove the clinical use of TAC.

Design and methods

Urine samples were obtained from 32 individuals with DS and 29 controls. Two age groups were established (children and adults). Spectrophotometric methods were used for biochemical determinations.

Results

Children with DS had significantly higher UA/Cr and TAC/Cr levels than controls, whereas levels of TAC^−UA/Cr were lower in adults with DS than in controls (P < 0.05 for all). In DS, levels of UA/Cr, TAC/Cr and TAC^−UA/Cr were higher in children than in adults (P < 0.05 for all). Positive correlations between UA/Cr and TAC/Cr were found for all groups studied. Negative correlations with age were found for UA/Cr and TAC/Cr in children of both groups.

Conclusions

Our results proved that TAC is decreased in adults with DS. Besides, TAC^−UA seems to provide more reliable information about the antioxidant status, at least in DS.

Introduction

Down syndrome (DS) or trisomy 21 is the most common chromosomal abnormality that comes to term in humans [1] occurring in about one in every 700-1000 live births [2]. It is associated with a wide variety of clinical features, including mental retardation, congenital heart disease, digestive problems, endocrine system deficits, cataracts, immune system disorders and increased risks of leukaemia and Alzheimer disease. Additionally, individuals with DS suffer from premature dementia and accelerated aging, and several studies have shown an increased oxidative stress in individuals with this pathology [3], [4].

Antioxidant enzymatic alterations had been found in DS. The gene for Cu/Zn superoxide dismutase (SOD1) is coded on chromosome 21 and it is overexpressed (∼ 50%) in DS [5] resulting in an increase of reactive oxygen species (ROS) due to an overproduction of hydrogen peroxide. ROS lead to oxidative damage of DNA, proteins and lipids. Moreover, the increase of enzymatic antioxidant defences such as SOD1 and catalase seems to be insufficient to prevent the exercise-induced oxidative damage in DS subjects which could be probably associated to a pro-oxidant status in this pathology [6]. Therefore, oxidative stress may play an important role in the pathogenesis of DS.

Oxidative damage can be monitored by the determination of different oxidative stress biomarkers. Some studies have shown higher levels of protein carbonyls, malondialdehyde, allantoin or 8-hydroxydeoxyguanosine in DS than in normal population [7], [8], [9], [10], [11]. Due to the ROS overproduction, a diminished antioxidants level may be found in DS because of their exhaustion. Separate measurement of different antioxidant molecules is not practical and their antioxidant effects are additive. Therefore, the total antioxidant capacity (TAC) is a useful measurement. Furthermore, the determination of any individual antioxidant could be less representative of the overall antioxidant capacity due to the possible in vivo interaction among different antioxidants. TAC is a measure of the amount (expressed in moles) of a given free radical scavenged by the non-enzymatic antioxidants which are present in a sample and in DS this parameter has not been studied in detail. Moreover, the studies are performed only with plasma or serum samples and in a reduced age range (usually only in children).

Uric acid (UA) is a powerful antioxidant and represents a high relative contribution of TAC in biological samples [12], [13]. Several studies have reported elevated plasmatic levels of UA in DS, but urinary concentration of this antioxidant is not well known. UA has been associated to Alzheimer disease, cognitive decline, autism and sleep apnea [14], [15], [16], [17], [18], [19], and these are pathologies related to DS [20], [21], [22], [23]. Therefore, more studies are necessary on UA in DS to try to establish possible relations between this parameter and the pathogenesis of DS.

The present study was performed with urine samples due to the fact that they have several advantages over plasma, serum, saliva or cerebrospinal fluid spots for the determination of biochemical parameters. Urine collection is non-invasive, poses minimal infectious disease risk to participants and researchers and provides sufficient volume for multiple assays and future research. Furthermore, urine specimens are ideally suited for large studies because they can be collected and stored by participants, and compliance is high. Moreover, this sample is not usually used for the study of biochemical parameters in DS, being the first time that TAC had been evaluated in urine samples in this pathology. In addition, the study has been performed in children and also in adults. Since DS individuals suffer from accelerated aging, the age group of adults could be considered as a senescent group, as it was previously established by Bittles et al. [24].

The aim of this work was to compare the urinary levels of UA and antioxidant capacity, with and without UA contribution, in a sample of children and adults with DS with those of healthy age-matched controls in order to assess the role of oxidative stress in these subjects. Moreover, we evaluate the clinical use of urine TAC in a pathology with increased oxidative stress.

Section snippets

Subjects

The study was performed in 32 individuals with Down syndrome and 29 healthy controls. Two age groups were established: group 1 (children group) consisted of 19 children with DS (13 male and 6 female, mean age = 7.6 ± 3.3 years ranging from 1 to 12) and 14 healthy age-matched controls (6 male and 8 female, mean age = 9.1 ± 3.0 years ranging from 5 to 13); group 2 (adult group) consisted of 13 adults with DS (7 male and 6 female, mean age = 48.8 ± 4.4 years ranging from 43 to 57) and 15 healthy age-matched

Results

Urinary biochemical parameters studied in individuals with DS and controls are listed in Table 1 for both age groups. Besides, no statistically significant differences were found in Cr levels between DS and controls in any age group and any of the parameters studied differ significantly with gender.

As seen in Table 1, levels of UA/Cr and TAC/Cr were significantly higher in children with DS than in the age-matched controls. In adults with DS, only levels of TAC^−UA/Cr were significantly decreased

Discussion

The present study shows that children with DS have higher levels of UA/Cr and TAC/Cr than the control group (Fig. 1), whereas no differences were found in adults for any of these parameters. Previous works have reported that UA levels in serum and plasma samples of DS subjects are increased [7], [10], [31], [32], [33], [34], [35]. Overproduction of UA has been suggested as a possible explanation for these results in several works [35], [36]. Thus, increased activities of erythrocyte adenosine

Acknowledgments

The authors would like to thank all the people with Down syndrome, families and volunteers which cooperated and made the achievement of this work possible. The authors express their gratitude to Fundación Síndrome de Down de Madrid, Centro María Corredentora, Asociación de Empleados de IBERIA Padres de Minusválidos, Fundación Nuestra Señora del Camino, C.P.E.E. Príncipe de Asturias (Aranjuez), C.P.E.E. Francisco del Pozo de Madrid, C.C.E.E. Buenafuente de Madrid and to Hospital Niño Jesús de

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Evaluation of extracellular adenine nucleotides hydrolysis in platelets and biomarkers of oxidative stress in Down syndrome individuals
2015, Biomedicine and Pharmacotherapy
Citation Excerpt :
In addition, adults and children with DS also have a high concentration of uric acid in the serum. This antioxidant is capable of reducing the peroxyl radical, which may lead to reduced levels of lipid peroxidation [50,51]. Another important aspect is that in our study the DS adults performed physical exercise.
Down syndrome (DS) is caused by the triplication of chromosome 21. Studies have demonstrated platelets abnormalities and oxidative stress in DS subjects. The enzymes NTPDase, 5′-nucleotidase and adenosine deaminase (ADA) represent an important therapeutic target since they interfere in the extracellular nucleotide pool altering platelet functions. In this study, we evaluated the ectonucleotidases activities and oxidative stress parameters in samples of DS and healthy individuals.
The population consisted of 28 subjects with DS and 28 healthy subjects as a control group. Blood was obtained from each subject and used for platelet and serum preparation. NTPDase activity using ATP as substrate was increased in platelets of DS patients in relation to the control group; however, no alterations were observed in the ADP hydrolysis. A decrease in the 5′-nucleotidase activity and an increase in the ADA activity was observed in platelet of DS subjects when compared to healthy individuals (P < 0.05). The lipid peroxidation and total thiol content was decreased in serum of DS individuals. Furthermore, superoxide dismutase and catalase activities were increased in whole blood of this group (P < 0.05).
Alterations in the ectonucleotidase activities in platelets as well as changes in the oxidative stress parameters may contribute to the clinical features of DS.
Systemic oxidative stress in children and teenagers with Down syndrome
2013, Life Sciences
Citation Excerpt :
However, other studies revealed increased damage to proteins, lipids and DNA (Brooksbank and Balazs, 1984; Ani et al., 2000), including high in vitro lipid oxidation in the brain of fetuses (Le Pecheur et al., 2005), despite the fact that DS children possess higher levels of monounsaturated fatty acids compared to healthy children (Santos, 2006), an aspect that may predispose the latter children to potentially high oxidation processes. In the only other study that reported protein damage associated to DS, Campos et al. (2010) found higher oxidation levels in diTyr (dityrosine) in DS children when compared to their non-DS brothers. The relatively high levels of urate, a well known and powerful antioxidant (Nagiová et al., 2000; Campos et al., 2011) found in the serum and urine of apparently all DS children, young and adults (Pallardó et al, 2006; Campos et al., 2010, 2011), may reflect an antioxidant compensation for the persistent oxidative insult promoted by the disease.
The aim of this study was to evaluate the antioxidant status and oxidative stress biomarkers in the blood of children and teenagers with Down syndrome.
The analysis of enzymatic antioxidant defenses, such as the activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione transferase (GST), non-enzymatic antioxidants, such as levels of reduced glutathione (GSH), uric acid (UA) and vitamin E, as well as oxidative damage indicators, such as protein carbonyls (PC) levels and lipoperoxidation (TBARS), of DS individuals (n = 20) compared to healthy controls (n = 18). Except the vitamin E was measured by HPLC, all other markers were measured spectrophotometrically.
Antioxidant enzymes analysis showed significant increases in the SOD (47.2%), CAT (24.7%) and GR (49.6%) activities in DS subjects. No significant difference in GPx activity was detected while GST activity (61.2%) was decreased, and both responses may be consequence of the depletion of GSH (24.9%) levels. There were no significant differences in TBARS levels, while PC levels showed decreased (31.7%) levels compared to healthy controls, which may be related to the increase (16.1%) found in serum UA. Levels of vitamin E showed no significant differences between DS individuals compared to controls.
The results revealed a systemic pro-oxidant status in DS individuals, evidenced by the increased activity of some important antioxidant enzymes, together with decreased GSH levels in whole blood and elevated UA levels in plasma, probably as an antioxidant compensation related to the redox imbalance in DS individuals.
Highly sensitive determination of uric acid in the presence of major interferents using a conducting polymer film modified electrode
2012, Bioelectrochemistry
This paper describes the sensitive and selective determination of uric acid (UA) in the presence of important interferences, ascorbic acid (AA), dopamine (DA), tyrosine (Tyr) and methionine (Met) at physiological pH using an electropolymerized film of 3-amino-5-mercapto-1,2,4-triazole on glassy carbon (p-AMTa) electrode. The p-AMTa electrode shows an excellent electrocatalytic activity towards UA. This was understood from the observed higher oxidation current and heterogeneous rate constant (3.24 × 10^− 5 m s^− 1) for UA when compared to bare GC electrode (4.63 × 10^− 6 m s^− 1). The selective determination of UA in the presence of 1000-fold excess of AA was achieved using p-AMTa electrode. Further, the p-AMTa electrode was successfully used for the simultaneous and selective determination of UA in the presence of important interferences, DA, Tyr and Met. Using amperometric method, 40 nM UA was detected for the first time. The current response of UA was increased linearly while increasing its concentration from 40 nM to 0.1 mM and a detection limit was found to be 0.52 nM (S/N = 3). Finally, the practical application of the present method was demonstrated by determining UA in human urine and blood serum samples.
Antioxidants in Down syndrome
2012, Biochimica et Biophysica Acta - Molecular Basis of Disease
Individuals with Down syndrome (DS) have high levels of oxidative stress throughout the lifespan. Mouse models of DS share some structural and functional abnormalities that parallel findings seen in the human phenotype. Several of the mouse models show evidence of cellular oxidative stress and have provided a platform for antioxidant intervention. Genes that are overexpressed on chromosome 21 are associated with oxidative stress and neuronal apoptosis. The lack of balance in the metabolism of free radicals generated during processes related to oxidative stress may have a direct role in producing the neuropathology of DS including the tendency to Alzheimer disease (AD). Mitochondria are often a target for oxidative stress and are considered to be a trigger for the onset of the AD process in DS. Biomarkers for oxidative stress have been described in DS and in AD in the general population. However, intervention trials using standard antioxidant supplements or diets have failed to produce uniform therapeutic effect. This chapter will examine the biological role of oxidative stress in DS and its relationship to abnormalities in both development and aging within the disorder. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.
Neurological phenotypes for Down syndrome across the life span
2012, Progress in Brain Research
Citation Excerpt :
Lack of balance in the metabolism of free radicals may have a direct role in the development of neuropathological changes of AD in DS (Zigman and Lott, 2007). Urinary markers of oxidative stress are increased in adolescents and adults with DS (Campos et al., 2010). Children with DS have an imbalance in the plasma and urinary levels of melatonin and kynurenine, thereby enhancing susceptibility toward oxidative stress (Uberos et al., 2010).
This chapter reviews the neurological phenotype of Down syndrome (DS) in early development, childhood, and aging. Neuroanatomic abnormalities in DS are manifested as aberrations in gross brain structure as well as characteristic microdysgenetic changes. As the result of these morphological abnormalities, brain circuitry is impaired. While an intellectual disability is ubiquitous in DS, there is a wide range of variation in cognitive performance and a growing understanding between aberrant brain circuitry and the cognitive phenotype. Hypotonia is most marked at birth, affecting gait and ligamentous laxity. Seizures are bimodal in presentation with infantile spasms common in infancy and generalized seizures associated with cognitive decline observed in later years. While all individuals have the characteristic neuropathology of Alzheimer's disease (AD) by age 40 years, the prevalence of dementia is not universal. The tendency to develop AD is related, in part, to several genes on chromosome 21 that are overexpressed in DS. Intraneuronal accumulation of β-amyloid appears to trigger a cascade of neurodegeneration resulting in the neuropathological and clinical manifestations of dementia. Functional brain imaging has elucidated the temporal sequence of amyloid deposition and glucose metabolic rate in the development of dementia in DS. Mitochondrial abnormalities contribute to oxidative stress which is part of AD pathogenesis in DS as well as AD in the general population. A variety of medical comorbidities threaten cognitive performance including sleep apnea, abnormalities in thyroid metabolism, and behavioral disturbances. Mouse models for DS are providing a platform for the formulation of clinical trials with intervention targeted to synaptic plasticity, brain biochemistry, and morphological brain alterations.
Evaluation of urinary biomarkers of oxidative/nitrosative stress in children with Down syndrome
2011, Life Sciences
Citation Excerpt :
Serum lipid resistance to oxidation has been found in subjects with DS (Nagyova et al., 2000) and a concomitant increase in serum uric acid was also observed by the same authors. In a previous study of our research group with a representative sample of the population used in this work, significant increase in urinary uric acid levels was found in children with DS (Campos et al., 2010). Thus, we proposed that similar levels of lipid oxidation biomarkers (15-F2t-IsoP and TBARS) in DS and controls could be the result of a higher lipid resistance to oxidation in DS, due to higher levels of uric acid.
It has been suggested that oxidative stress plays a key role in the pathogenesis of Down syndrome (DS). However, urinary biomarkers of oxidative stress have been little studied in this condition. Thus, we aimed to assess a set of urinary oxidative/nitrosative stress biomarkers in children with DS, with and without hypothyroidism, which comprise: 8-hydroxy-2′-deoxyguanosine (8-OHdG), isoprostane 15-F_2t-IsoP, thiobarbituric acid-reacting substances (TBARS), advanced glycation end products (AGEs), dityrosine (diTyr), hydrogen peroxide (H₂O₂) and nitrite/nitrate (NOx).
Fluorimetric and spectrophotometric assays were performed in children with DS (n = 26), some of them taking levothyroxine for hypothyroidism (n = 7), and their non-Down siblings (n = 19).
We found that only levels of diTyr were increased in DS, although no differences were obtained when hypothyroid DS children were excluded. Levels of 8-OHdG, 15-F_2t-IsoP, TBARS, AGEs, H₂O₂ and NOx did not differ neither between DS and controls nor between hypothyroid DS children and DS without hypothyroidism diagnosed. However, diTyr is increased in hypothyroid DS children compared with controls. Negative correlations with age were obtained for 8-OHdG, diTyr and NOx in DS and controls and for 8-OHdG, 15-F_2t-IsoP, TBARS and AGEs in DS.
Increased oxidative stress in children with DS cannot be explained by the urinary levels of 8-OHdG, 15-F_2t-IsoP, TBARS, AGEs, diTyr, H₂O₂ and NOx, at least with the assays used. Nonetheless, urinary diTyr could be used as oxidative/nitrosative stress biomarker in hypothyroid DS children. The present work presents evidence of a probable renal impairment in children with DS receiving levothyroxine for hypothyroidism.

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Urinary uric acid and antioxidant capacity in children and adults with Down syndrome

Abstract

Objectives

Design and methods

Results

Conclusions

Introduction

Section snippets

Subjects

Results

Discussion

Acknowledgments

Clin. Chim. Acta

Mayo Clin. Proc.

Free Radic. Biol. Med.

Biochim. Biophys. Acta

Neurobiol. Aging

Biochim. Biophys. Acta

Chest

Neurobiol. Aging

Clin. Biochem.

Anal. Biochem.

Clin. Chim. Acta

Metabolism

Clin. Biochem.

Clin. Biochem.

J. Pediatr.

The causes of Down syndrome

Sci. Am.

Down's syndrome-frequency in human populations and factors pertinent to variation in rates

Reactive oxygen species and their contribution to pathology in Down syndrome

Adv. Pharmacol.

Metabolism of oxygen derivatives in Down's syndrome

Ann. N.Y. Acad. Sci.

Down syndrome—a gene dosage disease caused by trisomy of genes within a small segment of the long arm of chromosome 21, exemplified by the study of effects from the superoxide-dismutase type 1 (SOD-1) gene

APMIS Suppl.

The exercise redox paradigm in the Down's syndrome: improvements in motor function and increases in blood oxidative status in young adults

J. Neural. Transm.

Markers of oxidative stress in children with Down syndrome

Clin. Chem. Lab. Med.