Plasma urate and risk of Parkinson’s disease

Department of Environmental Health, Harvard School of Public Health, Boston, MA 02215, USA.
American Journal of Epidemiology (Impact Factor: 4.98). 10/2007; 166(5):561-7. DOI: 10.1093/aje/kwm127
Source: PubMed

ABSTRACT Oxidative stress contributes to dopaminergic neuron degeneration in Parkinson's disease. Urate, a potent antioxidant, could be neuroprotective. To determine whether higher plasma concentrations of urate predict a reduced risk of Parkinson's disease, the authors conducted a nested case-control study among participants in the Health Professionals Follow-up Study, a cohort comprising over 18,000 men who provided blood samples in 1993-1995. Eighty-four incident cases of Parkinson's disease were diagnosed through 2000, and each was randomly matched to two controls by year of birth, race, and time of blood collection. Rate ratios of Parkinson's disease according to quartile of uricemia were estimated by use of conditional logistic regression. The mean urate concentration was 5.7 mg/dl among cases and 6.1 mg/dl among controls (p = 0.01). After adjustment for age, smoking, and caffeine, the rate ratio of Parkinson's disease for the highest quartile of uricemia compared with the lowest was 0.43 (95% confidence interval: 0.18, 1.02; p(trend) = 0.017). This association was stronger in analyses excluding cases diagnosed within 4 years (median) from blood collection (rate ratio = 0.17, 95% confidence interval: 0.04, 0.69; p(trend) = 0.010). These results suggest that high plasma urate concentrations may decrease the risk of Parkinson's disease, and they raise the possibility that interventions to increase plasma urate may reduce the risk and delay the progression of Parkinson's disease.

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    • "The possibility that endogenous urate may protect the integrity of the nigrostriatal dopaminergic system has been suggested by epidemiological studies that have indicated the existence of an inverse correlation between high uricemia and incidence of PD ( Davis et al . 1996 ; De Lau et al . 2005 ; Weisskopf et al . 2007 ; Ascherio et al . 2009 ; Chen et al . 2009 ) . In line with this , previous preclinical findings have demonstrated a crucial role for purinergic signaling in neurotoxicity or neuroprotection phenomena ( Gomes et al . 2011 ) 9 . By demonstrating an elevation in the striatal levels of urate in two experimental models of PD , this study e"
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    • "The possibility that endogenous urate may protect the integrity of the nigrostriatal dopaminergic system has been suggested by epidemiological studies that have indicated the existence of an inverse correlation between high uricemia and incidence of PD (Davis et al., 1996; De Lau et al., 2005; Weisskopf et al., 2007; Ascherio et al., 2009; Chen et al., 2009). In line with this, previous preclinical findings have demonstrated a crucial role for purinergic signaling in neurotoxicity/neuroprotection phenomena (Gomes et al., 2010). "
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    ABSTRACT: Epidemiological studies have indicated an inverse association between high uricemia and incidence of Parkinson's disease (PD). To investigate the link between endogenous urate and neurotoxic changes involving the dopaminergic nigrostriatal system, this study evaluated the modifications in the striatal urate levels in two models of PD. To this end, a partial dopaminergic degeneration was induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice, while a severe dopaminergic degeneration was elicited by unilateral medial forebrain bundle infusion of 6-hydroxydopamine (6-OHDA) in rats. Urate levels were measured by in vivo microdialysis at 7 or 14 days from toxin exposure. The results obtained demonstrated higher urate levels in the dopamine (DA)-denervated striatum of 6-OHDA-lesioned rats compared with the intact striatum. Moreover, an inverse correlation between urate and DA levels was observed in the same area. In contrast, only a trend to significant increase in striatal urate was observed in MPTP-treated mice. These results demonstrate that a damage to the dopaminergic nigrostriatal system elevates the striatal levels of urate, and suggest that this could be an endogenous compensatory mechanism to attenuate dopaminergic neurodegeneration. This finding may be important in light of the epidemiological and preclinical evidences that indicate a link between urate and development of PD. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 07/2014; 131(3):284-289. DOI:10.1111/jnc.12809 · 4.24 Impact Factor
    • "Urate – a major antioxidant circulating in the human body – has emerged as an inverse risk factor for PD. Clinical and population studies have found the urate level in serum or CSF to correlate with a reduced risk of developing PD in healthy individuals and with a reduced risk of clinical progression among PD patients (Weisskopf et al., 2007; Schwarzschild et al., 2008; Ascherio et al., 2009). Moreover, in cellular and animal models of PD, urate elevation has been shown to reduce oxidative stress and toxicant-induced loss of dopaminergic neurons (Wang et al., 2010; Cipriani et al., 2012a,b; Gong et al., 2012; Zhu et al., 2012; Chen et al., 2013). "
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    ABSTRACT: Inosine (hypoxanthine 9-beta-D-ribofuranoside), a purine nucleoside with multiple intracellular roles, also serves as an extracellular modulatory signal. On neurons, it can produce anti-inflammatory and trophic effects that confer protection against toxic influences in vivo and in vitro. The protective effects of inosine treatment might also be mediated by its metabolite urate. Urate in fact possesses potent antioxidant properties and has been reported to be protective in preclinical Parkinson's disease (PD) studies and to be an inverse risk factor for both the development and progression of PD. In this study we assessed whether inosine might protect rodent MES 23.5 dopaminergic cell line from oxidative stress in a cellular model of PD, and whether its effects could be attributed to urate. MES 23.5 cells cultured alone or in presence of enriched murine astroglial cultures MES 23.5-astrocytes co-cultures were pretreated with inosine (0.1-100 uM) for 24 hours before addition of the oxidative stress inducer H2O2 (200uM). Twenty-four hours later, cell viability was quantified by MTT assay or immunocytochemistry in pure and MES 23.5-astrocytes co-cultures, respectively. H2O2-toxic effect on dopaminergic cells was reduced when they were cultured with astrocytes, but not when they were cultured alone. Moreover, in MES 23.5-astrocytes co-cultures, indicators of free radical generation and oxidative damage, evaluated by nitrite (NO2(-)) release and protein carbonyl content, respectively, were attenuated. Conditioned medium experiments indicated that the protective effect of inosine relies on the release of a protective factor from inosine-stimulated astrocytes. Purine levels were measured in the cellular extract and conditioned medium using HPLC method. Urate concentration was not significantly increased by inosine treatment however there was a significant increase in levels of other purine metabolites, such as adenosine, hypoxanthine and xanthine. In particular, in MES 23.5-astrocytes co-cultures, inosine medium content was reduced by 99% and hypoxanthine increased by 127-fold. Taken together these data raise the possibility that inosine might have a protective effect in PD that is independent of any effects mediated through its metabolite urate.
    Neuroscience 05/2014; 274. DOI:10.1016/j.neuroscience.2014.05.038 · 3.33 Impact Factor
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