Q J Med 2002; 95: 691-693
© 2002 Association of Physicians
Commentary |
Uric acid: an important antioxidant in acute ischaemic stroke
From the Clinical Pharmacology Unit and Research Centre, The University of Edinburgh, Western General Hospital, Edinburgh, UK
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Introduction |
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 Top Introduction Antioxidants and strokeUric acidReferences |
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An association between raised serum uric acid (UA) concentration and increased cardiovascular risk has been recognized for over 50 years.1 A number of major epidemiological studies have identified high UA concentrations as an important risk marker for stroke in unselected populations. Furthermore, raised serum UA concentrations are associated with increased risk of stroke in high risk patient groups, for example those with hypertension or type 2 diabetes mellitus.2,3 However, the significance of these relationships remains subject to considerable debate. Both in vitro and in vivo studies have shown UA to be a powerful free radical scavenger in humans and, paradoxically, these antioxidant properties could be expected to offer a number of benefits within the cardiovascular system.4 No potential biological mechanisms are known by which raised UA concentrations could influence the development of stroke. Therefore, it is unclear whether high UA concentrations promote or protect against the development of cardiovascular disease, or simply act as a passive marker of increased risk. Not only has there been speculation surrounding the possible effects of UA on development of atherosclerosis but, over recent years, increasing attention has been paid to its potential role in the disease manifestations that ensue. In particular, emerging evidence suggests that UA plays an important role in acute ischaemic stroke, as a consequence of its antioxidant properties.
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Antioxidants and stroke |
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TopIntroductionAntioxidants and strokeUric acidReferences |
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Cerebral infarction initiates a complex cascade of metabolic events in the surrounding tissue, and free-radical-mediated oxidative damage plays a key role in the pathogenesis of cerebral ischaemia.5 Free radicals are liberated from a variety of sources, including inflammatory cells, dysfunctional mitochondria and excitotoxic mechanisms stimulated by increased glutamate and aspartate concentrations.6 Hydroxyl radicals (formed from hydrogen peroxide) peroxynitrite and superoxide are powerful radicals that can cause lipid peroxidation, a self-propagating chain reaction, that irreversibly damages plasma and mitochondrial membranes.7 Products of lipid peroxidation, for example malondialdehyde, irreversibly disrupt enzymes, receptors, and membrane transport mechanisms. In acute ischaemic stroke, in vivo concentrations of lipid peroxidation products are significantly increased, arising from excess free radical activity (Figure 1
).8 Plasma concentrations of cholesteryl ester hydroperoxides (CEOOH) are sensitive and specific markers of lipid peroxidation, and correlate positively with infarct volume, calculated by computed tomography, and clinical severity, determined by the National Institute of Health Stroke Scale.8 This emphasizes the role of oxidative stress in mediating cerebral ischaemic tissue damage, and is consistent with the observation that stroke volume is greater in patients with diminished antioxidant capacity.9 These observations have stimulated interest in the possibility that antioxidant treatments could offer benefits in acute ischaemic stroke, through their ability to defend against excess free radical activity.
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Uric acid |
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TopIntroductionAntioxidants and strokeUric acidReferences |
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UA is the most abundant aqueous antioxidant in humans, and contributes as much as two-thirds of all free radical scavenging capacity in plasma. It is particularly effective in quenching hydroxyl, superoxide and peroxynitrite radicals, and may serve a protective physiological role by preventing lipid peroxidation.10 In a variety of organs and vascular beds, local UA concentrations increase during acute oxidative stress and ischaemia, and the increased concentrations might be a compensatory mechanism that confers protection against increased free radical activity.4 In animal models, local UA concentrations significantly increase in acute brain injury (Figure 2
).11 For example, in the rat, middle cerebral artery occlusion causes a significant increase in cerebral UA concentrations, which can persist for several days after the injury.12 These observations have prompted interest in the potential impact of raised local UA concentrations in the setting of acute ischaemic stroke.
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Models of ischaemic neuronal injury have shown that the addition of physiological concentrations of UA protects hippocampal neurons against excitotoxic and metabolic injury in vitro.13 The effects of raising circulating UA concentrations, by direct administration, have also been studied in vivo in a rat model of acute ischaemic stroke, involving transient occlusion of one middle cerebral artery for 2 h. Administration of UA, prior to ischaemia or during the subsequent reperfusion period, caused a significant reduction in infarct volume, and led to improved behavioural outcome at 24 h (Figure 3
).13 These findings suggest that early elevation of UA, during or shortly after acute ischaemic stroke, could confer significant protection against neurological deficit. This is consistent with the protective effects of UA observed in other models of cerebral diseases mediated by free radicals.
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A recent study lends support to this hypothesis in a clinical setting. Serum UA concentrations measured in 881 consecutive ischaemic stroke patients at the onset of ischaemic symptoms were found to correlate inversely with early neurological impairment and final infarction size on computed tomography or magnetic resonance imaging.14 Additionally, serum UA concentrations were positively associated with a good clinical outcome at hospital discharge (Matthew score of >75), where each mg/dl UA increase (equivalent to 60 µmol/l; reference range 120–420 µmol/l) was associated with a 12% increase in the odds of a good outcome. Importantly, these relationships were independent of potential confounders, including age, diuretic use, renal function or the presence of major cardiovascular risk factors. This is the first study to characterize the relationship between serum UA concentration and neurological severity of acute ischaemic stroke in a large series of patients. A potential limitation of this observational data is that it does not directly address the potential mechanisms by which UA could improve stroke outcome, for example measurements of antioxidant capacity or oxidative stress. However, its findings support the potential benefits of raised UA concentrations observed in in vitro and in vivo experimental models.
Despite the widely held view that elevated serum UA concentrations confer increased risk of atherosclerotic disease, there is no compelling biological evidence of a causal link. Free radical activity is characteristically increased in patients with any one of several major cardiovascular risk factors, and is thought to play a key role in the early development of atherosclerosis. As an antioxidant, UA could be expected to confer protection against free radicals. In the context of acute ischaemic stroke, there is growing evidence to support a protective role for UA. This underpins the importance of oxidative stress in the pathogenesis of acute stroke, and strengthens the rationale for further investigation of antioxidant treatments in this condition. The feasibility of UA administration to temporarily increase circulating concentrations has recently been established,15 and might allow its potential therapeutic impact to be examined in a clinical setting. Ongoing basic research is likely to shed new light on the cardiovascular effects of UA, and will hopefully allow the significance of serum concentrations to be interpreted more clearly.
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Notes |
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Address correspondence to Dr W.S. Waring, Clinical Pharmacology Unit, The University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2LH. e-mail: s.waring{at}ed.ac.uk
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References |
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