A comparative study of nitric oxide, glutathione, and glutathione peroxidase activities in cerebrospinal fluid from children with convulsive diseases/children with aseptic meningitis.

It has been reported that active oxygen and/or free radicals are produced in the central nervous system (CNS) compartment in patients with bacterial meningitis, so it is supposed that the levels of endogenous antioxidative scavengers in the cerebrospinal fluid (CSF) are elevated as an adaptive reaction to bacterial meningitis, which exerts severe stress on the human body. We assumed that they are also elevated in patients with convulsive diseases. Nitric oxide (NO) and endogenous antioxidative scavengers (glutathione (GSH), glutathione peroxidase (GPX), (total) superoxide dismutase (T-SOD), manganese superoxide dismutase (Mn-SOD), and catalase) were measured in CSF from a group of child patients with various neurological diseases and a control group. NO, GSH, and GPX activities in CSF from the patients with convulsive diseases were significantly higher than in those with aseptic meningitis or in the controls. Furthermore, all parameters in CSF from patients with bacterial meningitis were significantly higher than in any other group. The present study suggests that oxidative stress may be associated with the pathophysiology of convulsion and that its clinical attenuation will lead to improvement in the prognosis for convulsive diseases.

Influence of repetitive transcranial magnetic stimulation on disease severity and oxidative stress markers in the cerebrospinal fluid of patients with spinocerebellar degeneration.

Ataxia severity, cerebellar hemispheric blood flow (CHBF), ascorbate free radical (AFR), superoxide dismutase protein, superoxide scavenging activity, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in cerebrospinal fluid (CSF) were compared before and after an 8-week course of repetitive transcranial magnetic stimulation (rTMS) in 20 patients with spinocerebellar degenerations (SCD). SCD patients showed higher AFR, 8-OHdG, and superoxide scavenging activity than 19 controls. In SCD patients, AFR and ataxia severity declined, and CHBF increased after rTMS. As the SCD patients showed negative correlations between ataxia severity and CHBF or superoxide scavenging activity, the therapeutic mechanism of rTMS may involve decreased oxidative stress and increased CHBF.

Postmortem serotonin (5-HT) concentrations in the cerebrospinal fluid of medicolegal cases.

In a medicolegal study the postmortem serotonin (5-HT) cerebrospinal fluid (CSF) concentrations were determined in routine autopsies using a high performance liquid chromatographic procedure with electrochemical detection. There was no correlation between 5-HT concentrations and age, sex or blood alcohol concentration using a postmortem delay < or = 3 days. In suicides the suboccipital CSF concentrations were significantly decreased compared to the levels measured in the control group (8.55+/-5.99 ng/ml versus 20.15+/-13.56 ng/ml). Additionally, a decrease of 5-HT was found in the suboccipital CSF of opiate fatalities (15.56+/-13.52 ng/ml). The results support the hypothesis that decreased 5-HT concentrations in the CSF are characteristic in suicides. However, due to a rather broad overlapping of values between suicides and controls the results failed to define a possible cut-off level in the 5-HT CSF concentration to distinguish between a suicidal and a non-suicidal incident.

[Decreased antioxidant-defence mechanisms in cerebrospinal fluid (CSF) in patients with tick-borne encephalitis (TBE)]. / Obnizenie mechanizmów obrony antyoksydacyjnej w plynie mózgowo-rdzeniowym u chorych z kleszczowym zapaleniem mózgu.

14 patients with Tick-borne Encephalitis (TBE) aged 21-64 (mean = 42.3) were analysed. The activity of superoxide dismutase (SOD), glutathione reductase (GSSG-R), glutathione peroxidase (GSH-Px), concentrations of malondialdehyde (MDA) and total sulphydryl groups (-SH) were measured in cerebrospinal fluid (CSF). Control group consisted of 10 patients whose CSF parameters remained in normal range. The CSF examination was performed twice: before and 3 weeks after treatment. The analysed activity of SOD, GSH-Px, GSSG-R, MDA and total sulphydryl groups (-SH) during the acute stage of the disease was significantly lower comparing to the control group. Despite the treatment, GSSG-R activity, MDA concentration and total sulphydryl groups--SH further lowered significantly. Although the SOD activity in CSF was higher in the second examination, it remained significantly lower comparing to the control group. We showed that the GSH-Px and GSSG-R activity in CSF after the acute stage of the TBE remained significantly lower than in the control group. Our examinations prove that during the TBE an increased generation of oxygen-derived free radicals occurs what shows decreased activity of the antioxidant parameters (SOD, GSH-Px, GSSG-R) and decreased concentration of total sulphydryl groups--SH in CSF. Our results suggest that during TBE, molecular structures injury of enzymes and antioxidative reactive cofactors may occur.

Oxidative stress in bacterial meningitis in humans.

OBJECTIVE: To study reactive nitrogen species-mediated oxidative brain damage and antioxidant defenses in patients with acute bacterial meningitis. METHODS: Nitrotyrosine (a widely used marker for the formation of reactive nitrogen species, such as peroxynitrite) and the lipid peroxidation product 4-hydroxynonenal were detected by immunohistochemistry in brain specimens obtained at autopsy. CSF concentrations of nitrotyrosine were quantified by ELISA. CSF and serum concentrations of ascorbic acid, uric acid, and its oxidation product allantoin were determined by high-pressure liquid chromatography. RESULTS: Tyrosine nitration was strongly increased during meningitis. It was most evident in inflammatory cells and blood vessels in the subarachnoid space. The same cell types stained positive for the lipid peroxidation marker 4-hydroxynonenal, suggesting that reactive nitrogen species contribute to oxidative brain damage during meningitis. High CSF nitrotyrosine concentrations were associated with an unfavorable outcome according to the Glasgow Outcome Score. In the CSF, the increase of nitrotyrosine was accompanied by a depletion of the antioxidant ascorbic acid and an increased oxidation of the natural peroxynitrite scavenger uric acid to allantoin. CONCLUSION: These findings indicate that oxidative stress due to reactive nitrogen species and altered antioxidant defenses are involved in the pathophysiology of bacterial meningitis in humans.

Increase in oxidized NO products and reduction in oxidized glutathione in cerebrospinal fluid from patients with sporadic form of amyotrophic lateral sclerosis.

To determine the role of free radical mechanisms in the pathogenesis of amyotrophic lateral sclerosis (ALS), cerebrospinal fluid concentrations of oxidized nitric oxide (NO) products (nitrite and nitrate) and reduced and oxidized forms of glutathione (GSH and GSSG, respectively) were compared between patients with the sporadic form of ALS (SALS) and controls. In the SALS patients, the nitrate levels were significantly higher (by 73%) in contrast to remarkably lower GSSG/GSH ratio, approximately 3-fold, compared to controls. These results suggest that NO production or oxidation is activated in SALS patients, leading to a decrease in superoxide radicals to oxidize GSH. The subsequent generation of a highly reactive anion, peroxynitrite, may play a causal role in the pathogenesis of SALS.

Safety and tolerability of the free-radical scavenger OPC-14117 in Huntington's disease. The Huntington Study Group.

Oxidative damage due to free-radical generation in the setting of underlying defects of neuronal energy metabolism has been implicated as a pathogenetic mechanism for Huntington's disease (HD). The authors conducted a randomized, double-blind, placebo-controlled, multicenter trial of the tolerability of OPC-14117, a lipophilic free-radical scavenger that concentrates in the brain. Ambulatory patients with HD received OPC-14117 60 mg/d, 120 mg/d, 240 mg/d, or placebo and were assessed by the Unified Huntington's Disease Rating Scale (UHDRS) for 20 weeks, including 12 or 16 weeks of assigned treatment and 8 or 4 weeks of blinded withdrawal of the study drug. Tolerability was measured by the proportion of patients completing the initial 12-week course of treatment on their originally assigned regimen. Sixty-four patients were enrolled in the study, 56 of whom completed the 12 weeks of treatment. Treatment was discontinued in four patients (1 placebo, 1 60 mg/d, 2 240 mg/d) due to asymptomatic but persistent serum elevations of liver transaminase. Two patients (1 60 mg/d and 1 120 mg/d) withdrew because of increased involuntary movements, one patient (60 mg/d) withdrew due to persistent dry eyes, and one patient (120 mg/d) withdrew because of persistent vomiting. There were no significant differences between treatment arms in the primary measures of tolerability, the frequency and types of clinical adverse events, or the clinical/functional features of HD. OPC-14117 was safe and generally well tolerated; however, elevations of liver transaminase suggested that continued surveillance monitoring is warranted in conducting more long-term studies of this antioxidant therapy.

Cerebrospinal fluid levels of biopterin, nitric oxide metabolites, and immune activation markers and the clinical course of human cerebral malaria.

Cerebrospinal fluid samples from 130 children who presented with cerebral malaria were investigated to elucidate the impact of biopterin production, NO formation, and local immune activation on the clinical course of this disease. Biopterin levels were significantly lower in patients who were in a deeper coma (P = .02). Cerebrospinal fluid concentrations of NO were significantly higher in children who died than in survivors (P = .037); however, this was not the case for macrophage activation markers, neopterin, and soluble tumor necrosis factor receptor p75 (sTNFR-75). Biopterin, neopterin, and sTNFR-75 but not NO concentrations were significantly related to each other. Low biopterin levels in deep coma are compatible with an impaired local Th1 response, but the low levels could also be due to the scavenging of radicals or to decreased neurotransmitter synthesis. Local production of NO, most likely by nonimmune mechanisms, may be detrimental in cerebral malaria; however, this appears not to be the case for local Th1-mediated immune pathways.