Introduction

Urate has been gaining momentum as a promising marker of reduced risk and milder progression in several neurodegenerative diseases, most notably Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS). Interestingly, urate-mediated mechanisms may represent a bridge linking diverse neurodegenerative processes. They may also represent an opportunity for synergies among different neurologic diseases along parallel translational paths (Fig. 1). While the biological mechanisms that cause neurodegeneration are not completely understood, they are likely to include damage from oxidative stress, as supported by both autopsy and laboratory studies in several disease models [1, 2]. These findings provide the rationale for investigating antioxidant systems, such as urate, as potential disease biomarkers and therapeutic targets.

Fig. 1
figure 1

Translational potential of urate across neurologic diseases. Epidemiologic and laboratory evidence support a neuroprotective role of urate. Urate elevation has been employed in early clinical trials and has rapidly advanced to phase III testing in Parkinson’s disease (SURE-PD3 trial; NCT02642393; open to enrollment at the time of this publication). Enrollment for SURE-ALS2 is scheduled to begin in early 2017. ALS = amyotrophic lateral sclerosis; PD = Parkinson’s disease; SURE-ALS2 = safety of urate elevation in ALS, phase II; SURE-PD = safety of urate elevation in PD; SURE-PD3 = study of urate elevation in PD, phase III

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Urate is present in bodily fluids as the anionic form of uric acid (2,6,8-trioxy-purine). It possesses antioxidant properties comparable to those of ascorbate [3], and accounts for most of the antioxidant capacity in human plasma [4, 5]. Urate is a product of purine metabolism. In rodents, urate is further metabolized to allantoin by urate oxidase (encoded by Uox), while in higher primates urate is the end product of purine metabolism. The difference across species is due to mutations in Uox that arose during evolution and led to the absence of functional urate oxidase in great apes and humans [6]. In humans, urate circulates in blood at high concentrations near the limits of its solubility (accounting for our susceptibility to gout and urolithiasis) [7]. Its blood concentration depends on dietary intake (e.g., meats, seafood, and beer have high purine content) [8], and excretion (which varies based on kidney function and genetically based differences in urate transporters) [9]. Peripherally generated urate may not readily cross the blood–brain barrier, as suggested by the 10-fold gradient from the blood to cerebrospinal fluid (CSF) [10]. It has been speculated that mutations in Uox during evolution, with resulting higher urate blood and central nervous system (CNS) levels in primates, conferred a selective advantage due to urate’s antioxidant properties, amongst other theories [11].

With respect to neurodegenerative disease, the interest in urate was sparked by the building evidence of oxidative damage in PD. Early work in PD postmortem tissue demonstrated low levels of the antioxidant urate in the substantia nigra [12] and high urate levels were found to be associated with reduced risk of later developing PD [13]. Since these early observations, rapidly accumulating epidemiological studies, laboratory data, and early clinical trial results (summarized below and in Table 1) have provided substantial support for a neuroprotective role of urate and its potential as a disease biomarker.

Table 1 Evidence for the roles of urate in neuroprotection
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Urate and its Determinants are a Risk Factor for Neurodegenerative Disease

If urate were protective against neurodegeneration, one might expect its levels to be low in patients and to correlate with disease risk. Indeed, plasma or serum urate levels are lower in people with PD [44, 45] and ALS [46, 47] than healthy controls. Further, in postmortem substantia nigra tissue, urate levels are lower in patients with PD than in age-matched controls [12].

In longitudinal cohort studies, urate levels correlate with risk of developing PD later in life, with higher levels being associated with reduced disease risk [13–17]. History of gout is associated with reduced risk of developing either PD [48] or Alzheimer’s disease [21]. Urate level determinants also modify susceptibility to PD. Thus, dietary factors that contribute to higher plasma urate are associated with a lower risk of PD (top vs bottom quintile: relative risk 0.47, p = 0.0008), after adjustment for potential confounders [18], and genetic variability in genes known to influence urate levels is associated with PD risk [19, 20].

Urate and its Determinants are Molecular Predictors of Disease Progression in Neurodegenerative Diseases

The strongest evidence for urate as a molecular predictor of disease progression comes from PD studies. In the PRECEPT clinical trial, the risk of PD disability progressing to the need for dopaminergic therapy among those in the highest quintile of serum urate concentration at baseline was half that of the lowest quintile [22]. Similarly, in the DATATOP clinical trial, risk of PD progression was reduced by 18% for each 1.5 mg/dl increase in serum urate concentration, with a similar inverse correlation between CSF urate and progression [23]. A causal link between urate levels and PD outcomes is strengthened by the finding that genetic determinants of urate levels also predict PD disease progression [24]. Thus, urate and its determinants are robust biomarkers of PD at different points in the disease process (Fig. 2).

Fig. 2
figure 2

Biomarker properties of urate across the timeline of Parkinson’s disease (PD). Several studies support urate or its determinants (dietary or genetic) as a biomarker of PD at different points in the PD stage, which refers to Hoehn and Yahr scale stage

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A link between urate levels and disease outcomes has also been suggested across a range of other neurodegenerative diseases, raising the hypothesis of a broad neuroprotective effect of urate on multiple CNS neuronal populations. Higher urate levels are associated with slower clinical progression in Huntington’s disease, multiple system atrophy, and mild cognitive impairment [29–31]. In ALS, most [25–28] but not all [32, 33] studies found urate to represent a prognostic factor for survival. The reasons for these conflicting results in ALS are not completely clear and may be related to methodological differences, variable sample size, and a modest effect size.

Urate is Neuroprotective in Several Preclinical Models of Neurodegeneration

Despite their statistical strength and reproducibility, these epidemiologic studies cannot address the question of whether urate is directly implicated in disease pathogenesis or may simply represent a byproduct of disease mechanisms. Several experimental studies support the former hypothesis and suggest that urate may have a direct impact on neuroprotective mechanisms across a range of neurodegenerative processes.

In vitro, in PD models, urate prevents spontaneous degeneration of cultured nigral neurons, as well as dopaminergic cell death induced by oxidative and mitochondrial toxins [34, 36]. In vivo, genetic manipulation of urate oxidase and resulting increased concentrations of urate in the CNS led to improved phenotype and histopathologic findings in PD mouse models [35, 49]. These data substantiate earlier findings in PC12 cells, in which urate blocked cell death and oxidative damage induced by either dopamine [50] or 6-hydroxydopamine [51]. Similarly, in a rotenone toxicity model, urate prevented death of dopaminergic cells [52]. At physiologically relevant concentrations, urate was also shown to enhance function and survival of dopaminergic neurons in primary cultures of rat ventral mesencephalon [53]. Interestingly, urate-mediated effects may require its accumulation in astrocytes, suggesting a noncell-autonomous mechanism for urate’s neuroprotective activity [36, 37]. The mechanisms underlying urate’s neuroprotective effects are not completely clear, though recent in vitro studies have begun to shed light on urate’s targets. These studies showed that urate treatment results in nuclear translocation of the nuclear factor (erythroid-derived 2)-like 2 protein, a master regulator of the response to oxidative stress, and transcriptional activation of its key target genes in primary astrocytic cultures [54, 55]. In this model, urate treatment led to a marked increase in glutathione synthesis and release [54]. Additional ongoing studies into the downstream effects of urate may identify novel therapeutic targets for neurodegenerative diseases.

Urate confers protection in various models of neurotoxicity. Urate protected cultured spinal cord neurons from glutamate toxicity [37] and was neuroprotective in models of spinal cord injury, multiple sclerosis, brain injury, and stroke [38–41, 56]. This growing literature suggests a potential neuroprotective role for urate beyond PD. The effects of urate in preclinical models of ALS are currently under investigation.

Early Clinical Trial Evidence Related to Urate Elevation as a Therapeutic Target

Based on the strong preclinical and epidemiologic evidence supporting a neuroprotective role for urate in the CNS, recent clinical trials by our group and others have begun to examine the feasibility of urate manipulation in a clinical setting with promising results [10, 42]. The Safety of Urate Elevation in Parkinson’s Disease (SURE-PD) trial was a phase II randomized, double-blind, placebo-controlled, dose-ranging trial of urate-elevating inosine in PD [10]. While urate is rapidly degraded by intestinal flora when taken by mouth, its precursor inosine when taken orally is rapidly metabolized to urate, and is available as an over-the-counter supplement. Results from the SURE-PD trial demonstrated that inosine supplementation is clinically safe and tolerable for up to 24 months and leads to a dose-dependent increase in serum and CSF urate levels in patients with PD. Although the study was not powered to test efficacy, secondary analyses indicated nonfutility of inosine treatment for slowing disability [10]. Of note, no instances of gout occurred during the study, but 6% of study participants who were randomized to active drug developed kidney stones. Given these promising results, urate elevation is being pursued as a potential disease-modifying treatment for PD in a phase III study (SURE-PD3 trial; NCT02642393; open to enrollment as of August 2016).

While urate is a mature target in PD and experience on inosine pharmacology is rapidly accumulating, urate manipulation is a relatively new target for ALS and other neurologic diseases. A pilot, open-label study of urate elevation in ALS (NCT02288091) was recently completed demonstrating the feasibility of using inosine to elevate urate levels in patients with ALS (SP, personal communication). A follow-up, multicenter, biomarker-driven, placebo-controlled phase II study (SURE-ALS2) is in the planning stages and is scheduled to begin enrollment in early 2017. Encouraging clinical results were also recently obtained by the Safety and Efficacy of Uric Acid in Patients with Acute Stroke (URICO-ICTUS) study: a phase IIb/III randomized, double-blind trial of intravenous urate administration within a few hours of stroke onset [42, 43]. In this study, the combination of urate treatment with thrombolysis in acute ischemic stroke resulted in improved clinical outcomes in women but not men. Safety remains an important focus of these studies given associations of higher urate and disorders other than gout and uric acid kidney stones, including cardiovascular and metabolic disorders [57].

Conclusions

Epidemiologic evidence strongly supports urate as a predictor of disease risk and progression in PD (Fig. 2), with data in PD models demonstrating that urate can confer neuroprotection against oxidative stress-induced neuronal death. These findings have substantial therapeutic implications and justify direct translation to clinical trials such as the ongoing phase III study of urate elevation in PD (SURE-PD3 trial; NCT02642393). A growing body of literature supports similar roles for urate in ALS where early clinical trials are underway to begin to test the feasibility and safety of urate elevation as a potential disease-modifying intervention. In parallel, preclinical research is beginning to unravel the downstream mechanisms that mediate urate’s effects. These studies may unravel novel therapeutic targets that may be of relevance for several neurodegenerative diseases.