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Therapeutic Intervention in Experimental Allergic Encephalomyelitis by Administration of Uric Acid Precursors

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Therapeutic Intervention in Experimental Allergic Encephalomyelitis by Administration of Uric Acid Precursors Therapeutic intervention in experimental allergic encephalomyelitis by administration of uric acid precursors Gwen S. Scott, Sergei V. Spitsin, Rhonda B. Kean, Tatiana Mikheeva, Hilary Koprowski, and D. Craig Hooper* Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107 Contributed by Hilary Koprowski, October 23, 2002 Uric acid (UA) is a purine metabolite that selectively inhibits an ongoing neuroinflammatory condition with UA has benefi- peroxynitrite-mediated reactions implicated in the pathogenesis of cial effects (10, 11). multiple sclerosis (MS) and other neurodegenerative diseases. There are also indications that the elevated UA levels nor- Serum UA levels are inversely associated with the incidence of MS mally seen in humans may be beneficial. For example, MS in humans because MS patients have low serum UA levels and patients generally have serum UA levels that are lower than individuals with hyperuricemia (gout) rarely develop the disease. those of controls, and gout (hyperuricemia) patients very rarely Moreover, the administration of UA is therapeutic in experimental develop MS (10). Moreover, it has been demonstrated recently allergic encephalomyelitis (EAE), an animal model of MS. Thus, that serum UA levels are significantly lower in MS patients with raising serum UA levels in MS patients, by oral administration of a a clinical remission and that this correlates with blood–brain UA precursor such as inosine, may have therapeutic value. We have barrier (BBB) dysfunction (17). We therefore have begun to assessed the effects of inosine, as well as inosinic acid, on param- examine the therapeutic potential of elevating UA levels in MS eters relevant to the chemical reactivity of peroxynitrite and the patients, first assessing whether oral administration of UA could pathogenesis of EAE. Both had no effect on chemical reactions be used to raise serum levels (23, 24). This proved ineffective associated with peroxynitrite, such as tyrosine nitration, or on the likely because of the production of uricase by enteric bacteria activation of inflammatory cells in vitro. Moreover, when mice (23). Our alternative approach was to administer a precursor of NEUROSCIENCE treated with the urate oxidase inhibitor potassium oxonate were UA that is not susceptible to breakdown by uricase because fed inosine or inosinic acid, serum UA levels were elevated mark- metabolism of dietary purines is a major source of UA. Inosine edly for a period of hours, whereas only a minor, transient increase is a purine nucleoside that has been used extensively in humans in serum inosine was detected. Administration of inosinic acid and marketed for a number of years as an energy supplement and suppressed the appearance of clinical signs of EAE and promoted performance enhancer, although there is little scientific evi- recovery from ongoing disease. The therapeutic effect on animals dence that it has these properties (25, 26). A well known side with active EAE was associated with increased UA, but not inosine, effect of inosine use is raised serum UA levels. We have found levels in CNS tissue. We, therefore, conclude that the mode of that the low serum UA levels of MS patients can be raised action of inosine and inosinic acid in EAE is via their metabolism reliably and maintained at desired levels for extended periods of to UA. time by oral administration of inosine (24). Preliminary results suggest that there may be a therapeutic benefit to such treat- ment, and no signs of any deleterious effects have been noted he prospect that the manipulation of serum urate (UA) levels (24). Inosinic acid, the 5Ј-monophosphate of inosine, is used as Tmay provide a natural approach to therapeutic intervention a flavor enhancer and, therefore, also is consumed extensively by in multiple sclerosis (MS) and perhaps other neurodegenerative humans, particularly in Japan (27). processes is supported by several lines of evidence, including (i) Although little is known about the effects of inosinic acid on the specificity of UA for the inhibition of certain peroxynitrite- physiological processes, there is increasing evidence that inosine mediated chemical reactions, such as tyrosine nitration (1–5), (ii) can modulate inflammatory processes (28–31) and neuronal evidence that these reactions may contribute to the pathogenesis growth properties (32, 33) that possibly are relevant to neuro- of MS and other neurodegenerative diseases (6–9), (iii) the degenerative disease. For example, administration of inosine in demonstration that UA is an effective treatment in several a mouse model of acute, lipopolysaccharide (LPS)-induced, lung animal models of CNS inflammation (8, 10–13), and (iv) obser- inflammation had a broad range of antiinflammatory effects vations of a reciprocal relationship between the incidence of MS including the down-regulation of tumor necrosis factor-␣ ex- and serum UA levels (10, 14–17). A common feature of the pression (31). On the other hand, infusion of inosine directly into neuroinflammatory conditions that are influenced by UA is the the cisterna magna or lateral ventricle of the rat brain after presence in CNS tissues of cells expressing inducible nitric oxide experimental stroke induction stimulated axonal outgrowth and (iNOS), an enzyme that produces high levels of NO (11). When rewiring in the intact side of the brain (33). In this study, we NO and superoxide are produced in close proximity, for exam- therefore have performed experiments to establish the nature of ple, by activated monocytes (18), they combine to form per- any inosine or inosinic acid effects on peroxynitrite-mediated oxynitrite, which rapidly decomposes in a biological milieu to chemical reactivities and the pathogenesis of EAE. • •Ϫ generate highly reactive intermediates, such as NO2 and CO3 , some of which are inactivated by UA (4, 5). UA is an interme- Experimental Procedures diate of purine metabolism in most mammals but, because of the Assessment of Peroxynitrite-Mediated Oxidation. Peroxynitrite- unusual penetrance of a single point mutation in the urate mediated oxidation was measured in vitro by the conversion of oxidase gene, is the end product in higher-order primates and humans (19–21). When the normally low serum levels of UA in animals used to model neuroinflammatory disease are raised by Abbreviations: UA, uric acid͞urate; BBB, blood–brain barrier; EAE, experimental allergic encephalomyelitis; iNOS, inducible NO synthase͞NOS2; K-Ox, potassium oxonate; LPS, repeated administration of UA, they become resistant to the lipopolysaccharide; MS, multiple sclerosis; MBP, myelin basic protein; DHR, dihydrorho- induction of such diseases, which include experimental allergic damine; SIN-1, 3-morpholinosydnonimine⅐HCl. encephalomyelitis (EAE) and Borna disease (8, 10–13, 22). *To whom correspondence should be addressed at: 1020 Locust Street, JAH Room 454, Moreover, studies in EAE have demonstrated that treatment of Philadelphia, PA 19107-6799. E-mail: [email protected]. www.pnas.org͞cgi͞doi͞10.1073͞pnas.212645999 PNAS ͉ December 10, 2002 ͉ vol. 99 ͉ no. 25 ͉ 16303–16308 Downloaded by guest on September 25, 2021 Fig. 1. DHR123 oxidation by the peroxynitrite donor SIN-1 and activated monocytes is inhibited by UA but not by inosine or inosinic acid. UA, inosine, and inosinic acid were titrated into cultures containing 100 ␮M SIN-1 as a source of peroxynitrite (A) or added at a final concentration of 200 ␮M to cultures containing RAW 264.7 cells activated with LPS (B) as described in Experimental Procedures. The conversion of 5 ␮M DHR123 to rhodamine 123 was measured with a fluorometer (excitation, 485 nm; emission, 530 nm; gain 70). The conversion of DHR123 to rhodamine 123 was used as an indicator of oxidation. Data are expressed as DHR123 oxidation and are presented as means Ϯ SD. dihydrorhodamine 123 (DHR123, Molecular Probes) to fluores- Induction of EAE. Female 8- to 10-week-old PLSJL mice (The ␮ cent rhodamine 123 (10, 12, 13). DHR123 (5 M) and different Jackson Laboratory) each were immunized s.c. at three sites concentrations of UA, inosine, and inosinic acid were added to along the back with 200 ␮l of an emulsion of 100 ␮g myelin basic cultures containing either 100 ␮M 3-morpholinosydnoni- protein (MBP) in complete Freund’s adjuvant (1:1) containing ͞ mine⅐HCl (SIN-1, Alexis Biochemicals, San Diego) or LPS- 0.05% Mycobacterium butyricum plus an additional 4 mg ml stimulated RAW 264.7 cells, as sources of peroxynitrite, and Mycobacterium tuberculosis H37 RA. Pertussis toxin (List Bio- incubated for1hat37°C. Rhodamine 123 fluorescence then was logical Laboratories, Campbell, CA), 400 ng, was given i.p. twice, measured in a microplate fluorometer (Cytofluor II, PerSeptive on days 0 and 2. Mice were scored for clinical signs of EAE twice Biosystems, Framingham, MA), with an excitation wavelength of daily on the basis of the presence of the following symptoms: 0, 485 nm and an emission wavelength of 530 nm, gain 70. normal mouse; 1, piloerection, tail weakness; 2, tail paralysis; 3, tail paralysis plus hindlimb weakness; 4, tail paralysis plus partial ؊ hindlimb paralysis; 5, total hindlimb paralysis; 6, hind- and Western Analysis of ONOO -Mediated Tyrosine Nitration. BSA (Sig- forelimb paralysis; 7, moribund͞dead. ma) at 1 mg͞ml in PBS was incubated with 1 mM SIN-1 for 2 h at 37°C in the presence and absence of UA, inosine, and inosinic Ј ␮ Ϫ Treatment of Mice. Inosine and inosinic acid (5 -monophosphate, acid (100–800 M) and 10 mM HCO3 added as NaHCO3 ␮ disodium salt, from yeast, Sigma) were administered twice daily (Sigma). Immediately after incubation, 5 l of each sample was either as i.p. doses of 500 mg͞kg in 100 ␮l of saline or by gastric separated on a 12.5% SDS-polyacrylamide gel and transferred intubation of 1,500 mg͞kg in 100 ␮l of saline with and without onto a poly(vinylidene difluoride) membrane (NEN; ref. 13). two daily i.p. injections of 250 mg͞kg potassium oxonate (K-Ox) Nitrotyrosine-containing proteins were detected with rabbit in 100 ␮l of saline to inhibit breakdown of UA by urate oxidase.
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