Nrf2 Signaling Contributes to the Neuroprotective Effects of Urate against 6-OHDA Toxicity

Zhang, Ning; Shu, Haiyang; Huang, Tingting; Zhang, Qilin; Li, Da; Zhang, Guanqun; Peng, Xiaoyan; Liu, Chun‐Feng; Luo, Weifeng; Hu, Lifang

doi:10.1371/journal.pone.0100286

Cited by 48 publications

(43 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Higher levels of serum urate are seen in men compared to women (126) with urate’s reference range in clinical practices being for example, 3.4–7.2 mg/dl for men and 2.4–6.1 mg/dl for women (155), apparently due to renal estrogen effects (156). Its concentration is consistently lower in CSF (30 µmol/l), approximately ten times lower than it peripheral concentration in blood (157, 158). This CSF concentration is dependent on blood urate and integrity of the blood-CSF barrier.…”

Section: Determinants Of Urate Levelsmentioning

confidence: 87%

“…Urate’s indirect action may actually be more pathophysiologically relevant as studies have shown that without astrocytes present in culture, urate concentrations need to be 100-fold higher (158, 223) or 200 µM and above, whereas CNS concentrations of endogenous urate are typically 10- to 100-fold lower (201, 219). In the presence of astrocytes, lower levels of urate are required (201, 219).…”

Section: Urate In Cellular and Animal Models Of Pdmentioning

confidence: 99%

See 1 more Smart Citation

Targeting urate to reduce oxidative stress in Parkinson disease

Crotty

Ascherio

Schwarzschild

2017

Experimental Neurology

112

View full text Add to dashboard Cite

Oxidative stress has been implicated as a core contributor to the initiation and progression of multiple neurological diseases. Genetic and environmental factors can produce oxidative stress through mitochondrial dysfunction leading to the degeneration of dopaminergic and other neurons underlying Parkinson disease (PD). Although clinical trials of antioxidants have thus far failed to demonstrate slowed progression of PD, oxidative stress remains a compelling target. Rather than prompting abandonment of antioxidant strategies, these failures have raised the bar for justifying drug and dosing selections and for improving study designs to test for disease modification by antioxidants. Urate, the main antioxidant found in plasma as well as the end product of purine metabolism in humans, has emerged as a promising potential neuroprotectant with advantages that distinguish it from previously tested antioxidant agents. Uniquely, higher urate levels in plasma or cerebrospinal fluid (CSF) have been linked to both a lower risk of developing PD and to a slower rate of its subsequent progression in numerous large prospective epidemiological and clinical cohorts. Laboratory evidence that urate confers neuroprotection in cellular and animal models of PD, possibly via the Nrf2 antioxidant response pathway, further strengthened its candidacy for rapid clinical translation. An early phase trial of the urate precursor inosine demonstrated its capacity to safely produce well tolerated, long-term elevation of plasma and CSF urate in early PD, supporting a phase 3 trial now underway to determine whether oral inosine dosed to elevate urate to concentrations predictive of favorable prognosis in PD slows clinical decline in people recently diagnosed, dopamine transporter-deficient PD.

show abstract

Section: Determinants Of Urate Levelsmentioning

confidence: 87%

Section: Urate In Cellular and Animal Models Of Pdmentioning

confidence: 99%

Targeting urate to reduce oxidative stress in Parkinson disease

Crotty

Ascherio

Schwarzschild

2017

Experimental Neurology

112

View full text Add to dashboard Cite

show abstract

“…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].…”

Section: Urate Is Neuroprotective In Several Preclinical Models Of Nementioning

confidence: 99%

Urate as a Marker of Risk and Progression of Neurodegenerative Disease

Paganoni

Schwarzschild

2017

Neurotherapeutics

View full text Add to dashboard Cite

Urate is a naturally occurring antioxidant whose levels are associated with reduced risk of developing Parkinson's disease (PD) and Alzheimer's disease. Urate levels are also associated with favorable progression in PD, amyotrophic lateral sclerosis, Huntington's disease, and multisystem atrophy. These epidemiological data are consistent with laboratory studies showing that urate exhibits neuroprotective effects by virtue of its antioxidant properties in several preclinical models. This body of evidence supports the hypothesis that urate may represent a shared pathophysiologic mechanism across neurodegenerative diseases. Most importantly, beyond its role as a molecular predictor of disease risk and progression, urate may constitute a novel therapeutic target. Indeed, clinical trials of urate elevation in PD and amyotrophic lateral sclerosis are testing the impact of raising peripheral urate levels on disease outcomes. These studies will contribute to unraveling the neuroprotective potential of urate in human pathology. In parallel, preclinical experiments are deepening our understanding of the molecular pathways that underpin urate's activities. Altogether, these efforts will bring about new insights into the translational potential of urate, its determinants, and its targets and their relevance to neurodegeneration.

show abstract

“…Another limitation of our findings is that we did not observe a correlation between urate levels and GSH levels measured either in plasma or in the brain (by MRSI), despite a reduction in 3‐NT in plasma. Urate cellular targets are not completely known but may include induction of Nrf2‐mediated antioxidant response pathways that ultimately lead to release of GSH by astrocytes 27, 28. These negative GSH findings may be due to lack of sensitivity of the assays, the lack of a biological effect of inosine on these pathways in humans, or the short duration of exposure to inosine.…”

Section: Discussionmentioning

confidence: 99%

“…High urate levels correlate with improved survival in ALS epidemiologic studies17, 18, 19, 20, 21, 22, 23 and with favorable outcomes in other neurodegenerative diseases, most notably Parkinson's disease (PD) 24, 25, 26. Further, urate is neuroprotective in several models of neurodegeneration 12, 27, 28, 29, 30, 31, 32…”

Section: Introductionmentioning

confidence: 99%

Pilot trial of inosine to elevate urate levels in amyotrophic lateral sclerosis

Nicholson

Chan²,

Macklin³

et al. 2018

Ann Clin Transl Neurol

View full text Add to dashboard Cite

ObjectiveTo test the safety, tolerability, and urate‐elevating capability of the urate precursor inosine taken orally or by feeding tube in people with amyotrophic lateral sclerosis (ALS).MethodsThis was a pilot, open‐label trial in 25 participants with ALS. Treatment duration was 12 weeks. The dose of inosine was titrated at pre‐specified time points to elevate serum urate levels to 7–8 mg/dL. Primary outcomes were safety (as assessed by the occurrence of adverse events [AEs]) and tolerability (defined as the ability to complete the 12‐week study on study drug). Secondary outcomes included biomarkers of oxidative stress and damage. As an exploratory analysis, observed outcomes were compared with a virtual control arm built using prediction algorithms to estimate ALSFRS‐R scores.ResultsTwenty‐four out of 25 participants (96%) completed 12 weeks of study drug treatment. One participant was unable to comply with study visits and was lost to follow‐up. Serum urate rose to target levels in 6 weeks. No serious AEs attributed to study drug and no AEs of special concern, such as urolithiasis and gout, occurred. Selected biomarkers of oxidative stress and damage had significant changes during the study period. Observed changes in ALSFRS‐R did not differ from baseline predictions.InterpretationInosine appeared safe, well tolerated, and effective in raising serum urate levels in people with ALS. These findings, together with epidemiological observations and preclinical data supporting a neuroprotective role of urate in ALS models, provide the rationale for larger clinical trials testing inosine as a potential disease‐modifying therapy for ALS.

show abstract

Nrf2 Signaling Contributes to the Neuroprotective Effects of Urate against 6-OHDA Toxicity

Cited by 48 publications

References 32 publications

Targeting urate to reduce oxidative stress in Parkinson disease

Targeting urate to reduce oxidative stress in Parkinson disease

Urate as a Marker of Risk and Progression of Neurodegenerative Disease

Pilot trial of inosine to elevate urate levels in amyotrophic lateral sclerosis

Contact Info

Product

Resources

About