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Inactivation of peroxynitrite in multiple sclerosis patients after oral administration of inosine may suggest possible approaches to therapy of the disease

Biotechnology Foundation Laboratories at Thomas Jefferson University, 1020 Locust Street, JAH Room M-81, Philadelphia, Pennsylvania, PA 19107, USA

D C Hooper

Biotechnology Foundation Laboratories at Thomas Jefferson University, 1020 Locust Street, JAH Room M-81, Philadelphia, Pennsylvania, PA 19107, USA

T Leist

Department of Neurology at Thomas Jefferson University, 310 Collegem Bldg, Philadelphia, Pennsylvania, PA 19107, USA

L J Streletz

Department of Neurology at Thomas Jefferson University, 310 Collegem Bldg, Philadelphia, Pennsylvania, PA 19107, USA

T Mikheeva

Biotechnology Foundation Laboratories at Thomas Jefferson University, 1020 Locust Street, JAH Room M-81, Philadelphia, Pennsylvania, PA 19107, USA

H Koprowski

Biotechnology Foundation Laboratories at Thomas Jefferson University, 1020 Locust Street, JAH Room M-81, Philadelphia, Pennsylvania, PA 19107, USA

Peroxynitrite has been implicated in the pathogenesis of multiple sclerosis (MS) and its animal model experimental allergic encephalomyelitis (EAE). Previously, we have shown that administration of uric acid (UA), a peroxynitrite scavenger, is therapeutic in EAE. We have also shown that MS patients have lower levels of serum uric acid than healthy individuals or those with other neurological diseases. The aim of this investigation was therefore to raise serum UA levels in MS patients. Oral administration of UA failed to increase low serum UA levels, evidently due to its degradation by gastrointestinal bacteria. However, serum UA could be raised and maintained at elevated levels for a year and more without reported side-effects by oral administration of its precursor inosine. Three of 11 patients given inosine showed some evidence of clinical improvement and there was no sign of disease progression in the remaining patients. Gadolinium-enhanced lesions, observed in two patients before receiving inosine, could not be detected after either 10 or 15 months inosine treatment. These data provide evidence that serum UA levels can be readily manipulated and that the benefit of higher levels to individuals with MS should be studied further in greater number of patients.

Key Words: autoimmunity • encephalomyelitis • demyelinating diseases • multiple sclerosis • uric acid • inosine • peroxynitrite

Multiple Sclerosis, Vol. 7, No. 5, 313-319 (2001)
DOI: 10.1177/135245850100700507


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