Therapeutic value of serum uric acid levels increasing in the treatment of multiple sclerosis

Toncev, Gordana

doi:10.2298/vsp0610879t

Cited by 25 publications

(26 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…They went on to show that by contrast, oral administration of its precursor inosine increased both serum and likely CSF urate levels in MS patients (240). Though several MS trials of urate-elevating inosine did not consistently demonstrate slowed clinical progression, these studies established the feasibility of chronic urate elevation as a neurotherapeutic strategy and identified nephrolithiasis as the most common adverse effect and safety concern (241–244). …”

Section: Urate Elevation Therapymentioning

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

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: Urate Elevation Therapymentioning

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

“…Moreover, inosine showed antinflammatory effects in the central nervous system (CNS) and periphery (Hasko et al, 2000; Rahimian et al, 2010; Jin et al, 1997; Gomez and Sitkovsky, 2003; Shen et al, 2005). Some (Toncev, 2006; Markowitz et al, 2009) but not all (Gonsette et al, 2010) clinical studies have suggested a possible antioxidant protective effect of inosine in multiple sclerosis patients (Markowitz et al, 2009). In these trials inosine consistently elevated serum urate, which was proposed to mediate any protective effect of inosine (Markowitz et al, 2009; Spitsin et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Protection by inosine in a cellular model of Parkinson’s disease

2014

View full text Add to dashboard Cite

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.

show abstract

“…Some studies in MS have reported lower serum UA in cases as compared to controls, and higher serum UA has been associated with delayed onset of the first neurologic episode, stressing some potential for a preventative role [18–20]. Other studies in MS suggest there may be therapeutic value in raising serum UA [21–23]. …”

Section: Introductionmentioning

confidence: 99%

Uric Acid as a CNS Antioxidant

Bowman

Shannon

Frei

et al. 2010

JAD

218

161

View full text Add to dashboard Cite

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.

show abstract

Therapeutic value of serum uric acid levels increasing in the treatment of multiple sclerosis

Abstract: Our results suggested that the treatment approaches based on the elevation of serum uric acid levels might prove beneficial for some MS patients.

Cited by 25 publications

References 18 publications

Targeting urate to reduce oxidative stress in Parkinson disease

Targeting urate to reduce oxidative stress in Parkinson disease

Protection by inosine in a cellular model of Parkinson’s disease

Uric Acid as a CNS Antioxidant

Contact Info

Product

Resources

About