3-nitrotyrosine and Multiple-Sclerosis--Relapsing-Remitting

The objective of this study is to evaluate the safety and tolerability of inosine in patients with relapsing-remitting multiple sclerosis (RRMS). The secondary objectives are to assess the effects of inosine administration on serum urate (UA) levels, the progression of neurologic disability, the cumulative number of new, active lesions on magnetic resonance imaging (MRI), and changes in serum levels for markers of inflammation.. Oral administration of inosine was used to raise serum levels of the natural peroxynitrite scavenger UA in 16 patients with RRMS during a 1-year randomized, double-blind trial.. The endpoints studied were relapse rate, disability assessed by the Kurtzke Expanded Disability Status Scale (EDSS), MRI, and analysis of serum levels of nitrotyrosine, and oxidative and pro-inflammatory makers.. Increased serum UA levels correlated with a significant decrease in the number of gadolinium-enhanced lesions and improved EDSS. A number of MRI intensity-based parameters were altered by inosine treatment, in certain cases correlating with changes in serum UA levels. In a patient with low serum UA and high lesion activity, raising UA levels by inosine treatment decreased serum nitrotyrosine while increasing the ratio of Th2 to Th1 cytokines in circulating cells. The only side-effect correlated with inosine treatment was kidney stone formation in 4/16 subjects.. These data suggest that the use of inosine to raise serum UA levels may have benefits for at least some MS patients. The effect of this treatment is likely to be a consequence of inactivation of peroxynitrite-dependent free radicals. Close monitoring of serum UA levels as well as other measures are required to avoid the potential development of kidney stones.

Topics: Adjuvants, Immunologic; Administration, Oral; Adult; Brain; CD4 Lymphocyte Count; Central Nervous System; Cross-Over Studies; Cytokines; Disability Evaluation; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Inosine; Kidney Calculi; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Th1 Cells; Th2 Cells; Tyrosine; Uric Acid; Young Adult

Free radicals have been found in high concentrations within inflammatory multiple sclerosis (MS) lesions. The superoxide anion (O(2)(-)) reacts rapidly with nitric oxide (NO), producing peroxynitrite (ONOO(-)). Glatiramer acetate (GA) is a specific MS immunomodulator that induces the synthesis of Th2 cytokines, and reduces the frequency of relapses and the formation of active brain lesions. Proinflammatory cytokines could play a role in free radicals production in the peripheral immune system as well as in the central nervous system (CNS). The effect of GA on iNOS, superoxide radicals (O(2)(-)) and 3-nitrotyrosine production by peripheral blood adherent mononuclear cells (PBAMs) was assessed. Our findings demonstrate that in vitro GA reduced spontaneous and LPS-induced iNOS, 3-nitrotyrosine, NO and O(2)(-) production, and that similar inhibition can be demonstrated ex vivo in mononuclear cells obtained from GA-treated patients. The inhibition of the production of free radicals in PBAMs may represent a new therapeutic mechanism against inflammation during MS.

Topics: Adult; Cells, Cultured; Female; Free Radicals; Glatiramer Acetate; Humans; Immunosuppressive Agents; Leukocytes, Mononuclear; Lipopolysaccharides; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Nitric Oxide; Nitric Oxide Synthase Type II; Oxidative Stress; Peptides; Superoxides; Tyrosine

Oxidative stress plays an important role in multiple sclerosis (MS).. The present study was designed to evaluate the modifications of plasma proteins by estimation markers of oxidative/nitrosative stress: carbonyl groups and 3-nitrotyrosines (3-NT) levels in relapsing-remitting (RR) (n=10) and secondary progressive (SP) (n=10) clinical course of multiple sclerosis. Moreover, we estimated the level of uric acid (UA) in plasma of MS patients.. Compared to controls (n=10), the levels of carbonyl groups in plasma proteins were elevated (P<0.0001) as well in RRMS as in SPMS. The highest concentration of 3-NT was observed in plasma proteins obtained from SPMS patients (P<0.0005). The level of uric acid in plasma was significantly lower in RRMS (P<0.0001) than SPMS.. This is the first report which presented differences between SPMS and RRMS patients in 3-NT and protein carbonyl groups in plasma proteins.

Topics: Adult; Blood Proteins; Blood-Brain Barrier; Carbon; Disease Progression; Female; Humans; Male; Middle Aged; Models, Statistical; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Oxidative Stress; Oxygen; Reactive Oxygen Species; Tyrosine; Uric Acid

The scope of this study is the examination of NO(2)+NO(3), 3-nitrotyrosine (3-NT), S-nitrosothiols (RSNO), arginase activity and asymmetric (ADMA) and symmetric (SDMA) dimethyl-L-arginine concentrations in plasma of MS patients during interferon-β1b therapy.. The study population included 15 (12 women, 3 men) untreated MS patients and 12 (10 women, 2 men) interferon-β1b treated MS patients with clinically definite relapsing MS (McDonalds criteria) for at least 1 year and a baseline EDSS score of 1.0 to 3.5 inclusive. Patients were treated with 250 μg IU interferon-β1b s.c. every second day during 30 months. The disease course was evaluated using correlations between baseline EDSS score and relapse rates in both groups.. During interferon-β1b treatment, EDSS scores in treated patients were decreased compared to untreated ones - after 18 and 30 months (p<0.05). In interferon-β1b treated MS patients, NO(2)+NO(3), 3-NT and RSNO plasma concentrations were significantly lower (p<0.05), while arginase activity, ADMA and SDMA levels were significantly increased (p<0.05) during the therapy, compared to the baseline levels in treated patients.. The investigated parameters may be the new biomarkers, providing information for the therapeutic approach and valuable in clinical monitoring.

Topics: Adult; Arginase; Arginine; Biomarkers; Drug Monitoring; Female; Follow-Up Studies; Humans; Inflammation; Interferon beta-1b; Interferon-beta; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Nitrates; Nitric Oxide; Nitrites; Nitroso Compounds; Severity of Illness Index; Sulfhydryl Compounds; Tyrosine; Young Adult