Cerebrospinal fluid and serum uric acid levels in patients with multiple sclerosis.

BACKGROUND: Peroxynitrite was hypothesized to be involved in the pathogenesis of multiple sclerosis (MS) through its various neurotoxic effects. Uric acid (UA) was shown to be a strong peroxynitrite scavenger. METHODS: We analyzed cerebrospinal fluid (CSF) and serum UA concentrations in 30 MS patients and 20 controls with non-inflammatory neurological diseases (NIND) and correlated these findings with demographic and clinical characteristics of MS patients. Disease activity was assessed by brain magnetic resonance imaging (MRI) and the CSF/serum albumin quotient as an indicator of the state of blood-brain-barrier (BBB). RESULTS: Serum UA concentrations were found to be significantly lower in MS patients compared with controls (p=0.019). CSF UA concentrations were lower in MS patients as compared to controls, as well as in patients with active MS (clinical and/or MRI activity) in comparison to patients with inactive MS or controls, but these differences were not statistically significant. Significant correlation was found between CSF and serum UA concentrations (p=0.016) in MS patients, but not in controls; and between CSF UA concentrations and the CSF/serum albumin quotient in MS patients (p=0.043), but not in controls. CONCLUSIONS: Our results support the significance of UA in the pathogenesis of MS. Decreased serum UA concentrations in MS patients might be due to both intrinsically reduced antioxidant capacity and increased UA consumption in MS. CSF UA concentrations may not be a reliable marker of disease activity in MS since its concentration is dependent on leakage of UA molecules from serum through the damaged BBB and the balance between consumption/production within the central nervous system (CNS).

Iron catalyzed conversion of NO into nitrosonium (NO+) and nitroxyl (HNO/NO-) species.

The conversion of NO into its congeners, nitrosonium (NO+) and nitroxyl (HNO/NO-) species, has important consequences in NO metabolism. Dinitrosyl iron complex (DNIC) combined with thiol ligands was shown to catalyze the conversion of NO into NO+, resulting in the synthesis of S-nitrosothiols (RSNO) both in vitro and in vivo. The formation mechanism of DNIC was proposed to involve the intermediate release of nitroxyl. Since the detection of hydroxylamine (as the product of a rapid reaction of HNO/NO- with thiols) is taken as the evidence for nitroxyl generation, we examined the formation of hydroxylamine, RSNO, and nitrite (the product of a rapid reaction of NO+ with water) in neutral solutions containing iron ions and thiols exposed to NO under anaerobic conditions. Hydroxylamine was detected in NO treated solutions of iron ions in the presence of cysteine, but not glutathione (GSH). The addition of urate, a major "free" iron-binding agent in humans, to solutions of GSH and iron ions, and the subsequent treatment of these solutions with NO increased the synthesis of GSNO and resulted in the formation of hydroxylamine. This caused a loss of urate and yielded a novel nitrosative/nitration product. GSH attenuated the urate decomposition to such a degree that it could be reflected as the function of GSH:urate. Results described here contribute to the understanding of the role of iron ions in catalyzing the conversion of NO into HNO/NO- and point to the role of uric acid not previously described.

[Effects of molsidomine on changes in oxidant/antioxidant status of rat erythrocytes]. / Promene oksidaciono-antioksidacionog statusa eritrocita pacova u prisustvu molsidomina.

INTRODUCTION: Molsidomine (MO) is an established drug in treatment of coronary heart disease. Considering that MO is a donor of nitric oxide (NO) and a superoxide anion radical (O2*-), which forms peroxynitrite, a very toxic radical, the aim of this study was further elucidation of molecular mechanisms of MO action, particularly effects on prooxidative-antioxidative status of rat erythrocytes. MATERIAL AND METHODS: Rat (Wistar albino, male, 250-300 g of b.m.) erythrocyte suspensions were aerobically incubated (120 min, 37 degrees C) without (control) or with MO (0.1, 0.25, 0.5, 1.0 and 1.5 mM). Concentrations of reactive oxygen species, methemoglobin, Heinz bodies, lipid peroxides, vitamins and glutathione, as well as activities of enzymes of the antioxidative defense system (AOS) were evaluated using standard techniques. RESULTS AND DISCUSSION: Molsidomine increases nitrite concentrations (indicating NO+ level), hydroxylamine (indicating NO- level), 3-nitro-tyrosine (indicating ONOO- level) and H2O2, but decreases O2*- level in a dose-dependent manner (changes are statistically significant only with high doses of molsidomine--1.0 and 1.5 mM). These alterations were followed by partial cells damage, increased formation of Heinz bodies, but there were no changes in MetHb and lipid peroxide levels. The defense response of erythrocytes to evident oxidative stress includes increased Vitamin E and Vitamin C concentrations (nonenzymatic components ofAOS), as well as decreased glutathione (reduced and oxidized) levels. Activities ofAOS enzymes remain unchanged. CONCLUSION: Experimental doses of MO induce oxidative stress in rat erythrocytes. However, the first line of AOS is successful in the cellular defence response.