Abstract
Oxidative stress is one of the main mechanisms implicated in the pathophysiology of inflammatory and neurodegenerative diseases of the central nervous system (CNS). Uric acid (UA) is the end product of purine catabolism in humans, and it is the main endogenous antioxidant in blood. Low circulating UA levels have been associated with an increased prevalence and worse clinical course of several neurodegenerative and inflammatory diseases of the CNS, including Parkinson's disease and multiple sclerosis. Moreover, the exogenous administration of UA exerts robust neuroprotective properties in experimental models of CNS disease, including brain ischemia, spinal cord injury, meningitis, and experimental allergic encephalitis. In experimental brain ischemia, exogenous UA and the thrombolytic agent alteplase exert additive neuroprotective effects when administered in combination. UA is rapidly consumed following acute ischemic stroke, and higher UA levels at stroke admission are associated with a better outcome and reduced infarct growth at follow-up. A recent phase II trial demonstrated that the combined intravenous administration of UA and alteplase is safe and prevents an early decrease of circulating UA levels in acute ischemic stroke patients. Moreover, UA prevents the increase in the circulating levels of the lipid peroxidation marker malondialdehyde and of active matrix metalloproteinase (MMP) 9, a marker of blood-brain barrier disruption. The moderately sized URICOICTUS phase 2b trial showed that the addition of UA to thrombolytic therapy resulted in a 6% absolute increase in the rate of excellent outcome at 90 days compared to placebo. The trial also showed that UA administration resulted in a significant increment of excellent outcome in patients with pretreatment hyperglycemia, in females and in patients with moderate strokes. Overall, the encouraging neuroprotective effects of UA therapy in acute ischemic stroke warrants further investigation in adequately powered clinical trials.
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