Low uric acid levels in serum of patients with ALS: Further evidence for oxidative stress?☆
Introduction
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the upper and lower motor neurons, which leads to progressive paralysis of most muscles in the body and to death within 3–5 years from onset. The cause of the sporadic form of ALS is largely unknown. The mechanisms most frequently implicated in the motor neuron death in ALS are glutamate excitotoxicity, oxidative stress, protein misfolding, mitochondrial dysfunction and micro-inflammatory processes [1].
There is probably no single causative factor for sporadic ALS, but an interplay of endogenous (genetic, metabolic) and exogenous factors (environment, lifestyle) is believed to be involved in the onset and progression of the disease. The evidence for oxidative stress-related abnormalities in the pathogenesis of ALS is extensive, albeit indirect [2], [3], [4], [5].
Uric acid (UA), produced from purines by the enzyme xanthine oxidase, is an important natural antioxidant in humans [6], [7], with metal-chelating properties [8] and the ability to scavenge nitrogen radicals [9], [10]. UA can scavenge superoxide, thus helping to prevent its reaction with nitric oxide and blocking the formation of the strong oxidant peroxynitrite [11]. It reduces damage to cellular components by also preventing peroxynitrite from nitrating the tyrosine residues of proteins [12].
In healthy individuals, increased UA concentrations are positively correlated with the male sex, body mass index (BMI), use of thiazide diuretics, a history of gout and hypertension, alcohol consumption and smoking.
Due to its antioxidant effects, higher concentrations of UA might protect against the development of neurodegenerative diseases and modulate their natural history. Indeed, a reduced level of serum UA has been found and correlated with more rapid disease progression in patients with Parkinson's disease [13], [14] and Alzheimer's disease [15], [16], [17]. Moreover, low levels of UA have been reported in individuals who developed Parkinson's disease many years later, implicating that high levels of UA might have a neuroprotective role [18], [19]. However, the literature on serum levels of UA in patients with ALS is scant. The aim of our study was to prospectively determine the levels of UA in the serum of patients with ALS and to correlate them to measurements of disease progression.
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Patients
The study group consisted of adult ALS patients, who were routinely followed in the ALS outpatient clinic at the Tel Aviv Sourasky Medical Center, Tel Aviv, Israel between 2006 and 2007. Included were patients who fulfilled the El Escorial criteria [20] for definite or probable ALS and gave their written informed consent to participate in the study. Data were obtained on each patient's age, sex, weight, height, present and past smoking status, medical history, medications, consumption of dairy
Patients
During the study period, 128 patients attended the ALS outpatient clinic at our center. Of these, 28 were excluded due to refusal to participate in the study, 10 were on invasive mechanical ventilation and/or had a percutaneous endoscopic gastrostomy, and 4 suffered a concurrent respiratory tract infection, leaving a total of 86 patients (65%, n = 56 males) who comprised the study group. Their mean ± SD age was 58 ± 12 years (range 25–90), their mean BMI was 23.8 ± 3.6 (range 16.5–35.2), and 76
Discussion
We prospectively documented the presence of decreased serum UA levels among a large cohort of patients with ALS in comparison to a large group of healthy, well-matched controls. In addition, the relative decrease in the patients' mean serum UA level (the difference between patients and controls) correlated with the rate of disease progression, as expressed by a decline in ALSFRS-R. These data support a possible role of UA in the pathogenesis of ALS, i.e., inhibition of the death of motor
Acknowledgments
We are grateful to Prof. Oded Sperling from the Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine, Tel-Aviv University, for his helpful comments on the manuscript.
We wish to thank Esther Eshkol for excellent editorial assistance.
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Statistical analysis was performed by M. Ish-Shalom, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
- 1
Contributed equally to this study.