Prospects for the treatment of multiple sclerosis by raising serum levels of uric acid, a scavenger of peroxynitrite

The formation of plaques, the characteristic central nervous system lesion of multiple sclerosis (MS), has been associated with local production of the toxic free-radical product, peroxynitrite.1, 2 To investigate the possible contribution of peroxynitrite to MS and potential treatment approaches, we have used a mouse model of MS, experimental allergic encephalomyelitis (EAE). Mice with EAE can develop lesions in their spinal cords that resemble MS plaques, containing cells expressing inducible nitric oxide synthase and nitrotyrosine, both evidence of peroxynitrite formation.3, 4 These lesions can be prevented and peroxynitrite-mediated damage in existing lesions resolved by administration of the peroxynitrite scavenger uric acid.4, 5 Uric acid is a product of purine metabolism, which is rapidly broken down in mice but maintained at higher levels in the sera of humans owing to the loss of the catabolic enzyme during evolution. These facts led us to speculate that low uric acid levels may contribute to MS. Indeed, patients with MS have significantly lower serum uric acid levels than age- and sex-matched controls receiving the same diet,5 an observation confirmed by the study of identical twins, one with MS. Moreover, a survey of the incidences of MS and hyperuricemia (gout) showed that the two diseases are very rarely found in the same individual.5 We have therefore begun to investigate whether raising serum uric acid levels (and therefore peroxynitrite scavenging capacity) may have therapeutic value in the treatment of MS. In normal humans, serum uric acid levels are maintained in a range of approximately 4 to 6 mg/dl by dietary uptake of precursors and metabolic breakdown of purines to uric acid, the excess of which is excreted. Oral administration of uric acid to chronic MS patients proved to be generally ineffective in raising serum levels, probably because of destruction of uric acid by gut microbial flora. Therefore, we have assessed whether inosine, a ribosylated precursor of uric acid, may be used to elevate serum uric acid levels in MS patients. Inosine has been proven safe in normal humans because of its extensive use by athletes. We therefore administered inosine orally to chronic MS patients in doses beginning at 1 gm daily and increasing to 3 gm daily (given in two doses) (Fig). After 15 weeks of treatment, mean serum uric acid levels in the patients had been elevated from approximately 4 mg/dl to nearly 9 mg/dl. As readily seen from the Figure, we have been able to maintain serum uric acid levels in these MS patients for nearly a year by the oral administration of either 2 or 3 gm of inosine daily. CSF uric acid levels were also proportionally elevated. None of the patients have shown any adverse effect of inosine treatment. Most importantly, 3 of the 10 chronic MS patients in the study have demonstrated some evidence of improved function and the remainder no sign of relapsing disease. Moreover, a significant reduction in lesion activity has been seen in one of the two patients with active lesions detected by magnetic resonance imaging at the beginning of the trial. Effect of oral inosine administration on serum uric acid levels in chronic MS patients. Ten patients with chronic multiple sclerosis and serum uric acid levels ranging from 2.7 to 7.6 mg/dl were given two daily doses of inosine totaling 1 gm for weeks 1 to 2; 1.5 gm for weeks 3 to 4; 2 gm for weeks 5 to 6; and then 3 gm until week 15. At 15 weeks the daily dose was reduced to 2 gm for patients with serum uric acid levels over 9 mg/dl. Doses of 2 or 3 gm/day were maintained for the rest of the trial. Serum uric acid levels were monitored at the time points shown in the graph. Mean ± SEM serum uric acid levels are shown (•). The average inosine dose is also shown (—–). This work was supported by grants from the Commonwealth of Pennsylvania and the National Multiple Sclerosis Society.