Uric acid as a CNS antioxidant

Department of Neurology, Layton Center for Aging and Alzheimer's Disease Research, Oregon Health & Science University, Portland, OR 97239, USA.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 01/2010; 19(4):1331-6. DOI: 10.3233/JAD-2010-1330
Source: PubMed


Oxidative damage is a consistent finding in a number of central nervous system (CNS) disorders. Uric acid (UA) is a potent hydrophilic antioxidant that is modified by diet and drug. Several lines of evidence suggest that plasma UA may modulate outcomes in neurologic disease, but little attention has been paid to CNS levels of UA. Our objective was to test the hypothesis that cerebrospinal fluid (CSF) UA is determined by plasma UA, modified by blood-brain barrier (BBB) integrity and associated with rate of cognitive decline in Alzheimer's disease (AD). Also, since UA and ascorbic acid may act as antioxidants for one another, we also explored a potential interaction between them in the brain. Thirty-two patients with mild to moderate AD (Mini-Mental Status Exam 19 +/- 5) participated in a longitudinal biomarker study for one year involving standardized clinical assessments. CSF and blood were collected at baseline for UA, ascorbic acid, and albumin. Cognitive measures were collected at baseline and again one year later. CSF UA was independent of age, gender, and AD severity. CSF and plasma UA were positively correlated (r=0.669, p=0.001) and BBB impairment was associated with higher CSF levels of UA (p=0.028). Neither plasma nor CSF UA reached significant association with rates of cognitive decline over 1 year. CSF UA and CSF ascorbic acid were positively correlated (r=0.388, p=0.001). The hypothesis that CSF UA is determined by plasma UA and BBB integrity is supported, as is the hypothesis that UA and ascorbic acid are associated in CSF but not plasma. Adequately powered prospective studies would help assess any role for UA in primary and secondary prevention of AD.

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    • "In 1968, Anumonye found that remission of manic symptoms is accompanied by increased excretion of uric acid (Anumonye et al., 1968). The relationship between symptoms of mania and changes in the nucleotide derivatives concentration was confirmed currently, while emphasizing that high serum levels of uric acid is reflected in the increased concentration of the compound in the cerebrospinal fluid (Machado-Vieira et al., 2002; Salvadore et al., 2010; Bowman et al., 2010). In case of depression and bipolar disorder uric acid levels were determined only in serum. "
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    ABSTRACT: Ecto-purines and ecto-pyrimidines are present in the extracellular space of the central nervous system (CNS). Together with P1 and P2 receptors and nucleotides metabolizing ecto-enzymes, they make signaling system involved in neurotransmission, the modulation of sensory signals, including pain stimuli conduction, and the induction of apoptosis and necrosis of the cells. Purines and pyrimidines have a dual effect: positive (neuroprotective) of nucleosides, and negative (pro-inflammatory and pro-apoptotic) of nucleotides. Adenosine-5'-triphosphate (ATP) in the CNS triggers the pro-inflammatory reactions, predominantly by activation of the P2X7 receptor, which results in production and release of pro-inflammatory cytokines. In contrast to ATP, adenosine acts generally as an anti-inflammatory agent and plays an important role in neuroprotection. Currently, it is believed that the initiation of CNS diseases, including mental disorders, is caused by any imbalance between the concentration of ATP and adenosine in the extracellular space. Genetic tests provide also the evidence for the participation of purinergic signaling in psychiatric disorders. It is believed that any action leading to the effective increase of adenosine concentration: activation of nucleotide metabolizing ecto-enzymes (mainly NTPDases - nucleoside triphosphate diphosphohydrolases), inhibition of adenosine deaminase and/or adenosine kinase activity as well as therapies using P1 receptor agonists (adenosine or its analogues) might be beneficial in therapy of psychiatric disorders.
    Acta biochimica Polonica 10/2015; DOI:10.18388/abp.2015_1004 · 1.15 Impact Factor
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    • "Uric acid is a potent natural antioxidant found throughout extracellular fluid as sodium urate. Uric acid reduces the burden of oxidative stress through several mechanisms including scavenging free radicals and chelating transition metals [7] [8]. In particular, a powerful protective antioxidant effect of uric acid on neurons has been demonstrated in several in vivo and in vitro studies [9] [10]. "
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    ABSTRACT: Background Uric acid is a potent anti-oxidant and hyperuricemia is well-linked to a lower risk of Parkinson’s disease (PD), one of the most common neurodegenerative disorders. However, data on gout, the major complication of hyperuricemia, remain unclear. Methods Two investigators independently searched published studies indexed in MEDLINE, and EMBASE from inception to April 2015 using the terms for gout combined with the terms for PD. The inclusion criteria were as follows: (1) cohort or case-control study evaluating the risk of PD among patients with gout (2) odds ratio, relative risk, hazard ratio or standardized incidence ratio were provided (3) subjects without gout and subjects with PD were used as controls in cohort and case-control study, respectively. RevMan 5.3 software was used to perform the statistical analysis. Point estimates and standard errors were extracted from individual studies and were combined by generic inverse variance method of DerSimonian and Laird. Statistical heterogeneity was assessed using the Cochran's Q test and I2 statistics. Results Three case-control studies and two cohort studies were identified and included in the data analysis. The pooled risk ratio of PD in patients with gout was 0.93 (95% CI, 0.79 to 1.09). The statistical heterogeneity was high with an I2 of 87%. The results were not significantly different between males and females (RR 0.89; 95% CI, 0.57 to 1.39 and RR 0.95; 95% CI, 0.76 to 1.19, respectively). Conclusion This study did not provide support for an inverse relationship between gout and risk of PD.
    Parkinsonism & Related Disorders 08/2015; DOI:10.1016/j.parkreldis.2015.08.030 · 3.97 Impact Factor
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    • "In terms of non-motor symptoms, our study also showed a negative relationship between serum UA levels and depression score but not with cognitive score, similar to the recent study in de novo adjusted PD models [7] [9]. These observations suggest that UA not only has a protective effect against dopaminergic cell loss but also against non-dopaminergic cells such as serotonergic neurons [5]. Further research is needed to study the impact of UA on other non-motor symptoms as well as the potential benefit of urate-elevating drugs such as inosine, as a disease-modifying treatment of PD. "
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    ABSTRACT: The aim of this study was to evaluate serum uric acid (UA) levels and serum uric acid/creatinine ratios (UA/Cr) in patients with non-tremor dominant (NTD) Parkinson's disease (PD) compared to tremor dominant (TD) PD and healthy controls (HC). UA is believed to have a protective effect on the central nervous system against oxidative damage and neuronal cell death which could impact on progression and motor subtypes of PD. Serum UA levels and UA/Cr were determined in 100 PD patients and 100 age and sex matched HC. Subtypes of PD were classified into TD and NTD. Patients with PD showed statistically significantly lower serum UA (p=0.007) and serum UA/Cr ratios (p<0.001) than HC. Patients with NTD PD had statistically significantly lower serum UA (p<0.001) and serum UA/Cr (p=0.001) than in patients with TD PD. Patients with mild PD severity also had significantly higher serum UA (p=0.015) and serum UA/Cr (p=0.004) than patients with moderate to severe disease. Our study suggests that UA has a pathogenic role in the clinical subtype of PD. Serum UA levels together with serum UA/Cr are potentially useful biomarkers to indicate risk, severity and motor subtype of PD. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Journal of Clinical Neuroscience 06/2015; 22(8). DOI:10.1016/j.jocn.2015.02.015 · 1.38 Impact Factor
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