RESUMO
INTRODUCTION: Uric acid (UA) is an important natural antioxidant and strong peroxynitrite scavenger, but little is known about central nervous system (CNS) levels of UA in patients with anti-N-methyl-d-aspartate receptor encephalitis (NMDARE). METHODS: Cerebrospinal fluid (CSF) and serum levels of UA were determined in 72 patients with anti-NMDARE and 111 controls with non-inflammatory neurological diseases (NINDs). Serum UA levels were also evaluated in 132 healthy controls (HCs). CSF neuron-specific enolase (NSE) and blood-brain barrier (BBB) index were evaluated in patients with anti-NMDARE. The association of CSF UA levels with anti-NMDARE and its clinical parameters were evaluated in the patients. RESULTS: CSF UA levels were lower in patients with anti-NMDARE than in patients with NINDs, especially in patients with severe impairments (modified Rankin Scale [mRS] scores >3 vs. ≤ 3, p = 0.006). Furthermore, serum UA levels in patients with anti-NMDARE were significantly lower than in patients with NINDs and HCs. CSF UA levels were significantly associated with mRS scores, and serum UA levels in patients with anti-NMDARE. Furthermore, CSF/serum UA ratio was significantly associated with BBB index. CONCLUSIONS: CSF UA levels associated with disease severity and serum UA levels in patients with anti-NMDARE. And CSF/serum UA ratio correlated with BBB index, indicating that CSF and serum UA levels change similarly with BBB permeability in anti-NMDARE patients.
Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato , Doenças do Sistema Nervoso , Humanos , Ácido Úrico/líquido cefalorraquidiano , Barreira Hematoencefálica , Gravidade do PacienteRESUMO
INTRODUCTION: Analyses of cerebrospinal fluid (CSF) metabolites in large, healthy samples have been limited and potential demographic moderators of brain metabolism are largely unknown. OBJECTIVE: Our objective in this study was to examine sex and race differences in 33 CSF metabolites within a sample of 129 healthy individuals (37 African American women, 29 white women, 38 African American men, and 25 white men). METHODS: CSF metabolites were measured with a targeted electrochemistry-based metabolomics platform. Sex and race differences were quantified with both univariate and multivariate analyses. Type I error was controlled for by using a Bonferroni adjustment (0.05/33 = .0015). RESULTS: Multivariate Canonical Variate Analysis (CVA) of the 33 metabolites showed correct classification of sex at an average rate of 80.6% and correct classification of race at an average rate of 88.4%. Univariate analyses revealed that men had significantly higher concentrations of cysteine (p < 0.0001), uric acid (p < 0.0001), and N-acetylserotonin (p = 0.049), while women had significantly higher concentrations of 5-hydroxyindoleacetic acid (5-HIAA) (p = 0.001). African American participants had significantly higher concentrations of 3-hydroxykynurenine (p = 0.018), while white participants had significantly higher concentrations of kynurenine (p < 0.0001), indoleacetic acid (p < 0.0001), xanthine (p = 0.001), alpha-tocopherol (p = 0.007), cysteine (p = 0.029), melatonin (p = 0.036), and 7-methylxanthine (p = 0.037). After the Bonferroni adjustment, the effects for cysteine, uric acid, and 5-HIAA were still significant from the analysis of sex differences and kynurenine and indoleacetic acid were still significant from the analysis of race differences. CONCLUSION: Several of the metabolites assayed in this study have been associated with mental health disorders and neurological diseases. Our data provide some novel information regarding normal variations by sex and race in CSF metabolite levels within the tryptophan, tyrosine and purine pathways, which may help to enhance our understanding of mechanisms underlying sex and race differences and potentially prove useful in the future treatment of disease.
Assuntos
Líquido Cefalorraquidiano/química , Metaboloma , Fatores Raciais , Fatores Sexuais , Adulto , Cisteína/líquido cefalorraquidiano , Feminino , Humanos , Ácido Hidroxi-Indolacético/líquido cefalorraquidiano , Ácidos Indolacéticos/líquido cefalorraquidiano , Cinurenina/análogos & derivados , Cinurenina/líquido cefalorraquidiano , Masculino , Melatonina/líquido cefalorraquidiano , Metabolômica , Serotonina/análogos & derivados , Serotonina/líquido cefalorraquidiano , Caracteres Sexuais , Ácido Úrico/líquido cefalorraquidiano , Xantina/líquido cefalorraquidiano , Xantinas/líquido cefalorraquidiano , alfa-Tocoferol/líquido cefalorraquidianoRESUMO
The diagnosis of drowning is still a difficult task in forensic science. Biochemical changes in different body fluids have been examined for the identification of drowning. However, none of them alone gives accurate results in the diagnosis of drowning and differentiation of saltwater and freshwater drowning. This study aimed to examine cerebrospinal fluid changes in drowned rabbits. Six groups of rabbits were used including immersed dead rabbits in freshwater or saltwater (as control groups), alive fully conscious rabbits drowned in freshwater and saltwater, and anesthetized rabbits drowned in freshwater and saltwater. Cerebrospinal fluid electrolytes except for potassium levels were significantly higher in rabbits drowned consciously in saltwater than their level in the control group. In rabbit drowned in freshwater, the examined electrolytes decreased significantly. In addition, urea, creatinine, uric acid, glucose, and tumor necrosis factor were different in cases of freshwater and saltwater drowning from those of control rabbits. Electrolytes and biochemical changes of unconscious rabbits drowned in water showed no significant difference from those of control rabbits. Cerebrospinal fluid examination in drowning gives promising results in the diagnosis of drowning. In addition, the differentiation between freshwater and saltwater drowning was possible.
Assuntos
Afogamento/líquido cefalorraquidiano , Eletrólitos/líquido cefalorraquidiano , Animais , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Proteínas do Líquido Cefalorraquidiano , Creatinina/líquido cefalorraquidiano , Patologia Legal , Água Doce , Glucose/líquido cefalorraquidiano , Modelos Animais , Coelhos , Água do Mar , Fator de Necrose Tumoral alfa/líquido cefalorraquidiano , Ureia/líquido cefalorraquidiano , Ácido Úrico/líquido cefalorraquidianoRESUMO
INTRODUCTION: Previous studies have shown that serum uric acid (UA) modulates outcomes of neurological diseases, although little is known about cerebrospinal fluid (CSF) UA levels in neuromyelitis optica spectrum disorders (NMOSDs). METHODS: Cerebrospinal fluid and serum UA levels were measured in samples from 68 patients, including NMOSDs during relapse (n = 38) and controls with noninflammatory and non-neurodegenerative diseases (CTLs, n = 30). Correlation analysis was performed between CSF UA and clinical characteristics, serum UA, and blood-brain barrier integrity in NMOSDs. RESULTS: Cerebrospinal fluid UA levels in NMOSDs were significantly higher than in CTLs (p = .002), while serum UA differences between NMOSDs and CTLs were not statistically significant. In NMOSDs, CSF UA levels were significantly higher in patients with an impaired blood-brain barrier than in patients with an intact one (p < .001), and significantly higher in longer disease duration than in shorter disease duration patients (p = .002). CSF UA levels were also significantly higher in active patients upon MRI than in inactive patients (p < .001), and significantly higher in patients with brain lesions than without brain lesions (p = .024). CSF UA was significantly associated with the serum UA levels (r = .454, p = .002), disease duration (r = .383, p = .018), and blood-brain barrier index (r = .805, p < .001), but did not correlate with age, gender, annualized relapse rate, duration, or severity of NMOSD. Multiple regression analysis demonstrated that CSF UA was independent of the blood-brain barrier index (ß = .765, p < .001) and serum UA levels (ß = .01, p = .019) in NMOSDs. CONCLUSIONS: Cerebrospinal fluid UA levels were elevated in NMOSD patients during relapse, and were likely modified by serum UA levels and blood-brain barrier integrity.
Assuntos
Barreira Hematoencefálica , Esclerose Múltipla/líquido cefalorraquidiano , Neuromielite Óptica/líquido cefalorraquidiano , Neurite Óptica/líquido cefalorraquidiano , Ácido Úrico/líquido cefalorraquidiano , Adolescente , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Neuromielite Óptica/sangue , Neurite Óptica/sangue , Recidiva , Ácido Úrico/sangue , Adulto JovemRESUMO
Urate is a naturally occurring antioxidant whose levels are associated with reduced risk of developing Parkinson's disease (PD) and Alzheimer's disease. Urate levels are also associated with favorable progression in PD, amyotrophic lateral sclerosis, Huntington's disease, and multisystem atrophy. These epidemiological data are consistent with laboratory studies showing that urate exhibits neuroprotective effects by virtue of its antioxidant properties in several preclinical models. This body of evidence supports the hypothesis that urate may represent a shared pathophysiologic mechanism across neurodegenerative diseases. Most importantly, beyond its role as a molecular predictor of disease risk and progression, urate may constitute a novel therapeutic target. Indeed, clinical trials of urate elevation in PD and amyotrophic lateral sclerosis are testing the impact of raising peripheral urate levels on disease outcomes. These studies will contribute to unraveling the neuroprotective potential of urate in human pathology. In parallel, preclinical experiments are deepening our understanding of the molecular pathways that underpin urate's activities. Altogether, these efforts will bring about new insights into the translational potential of urate, its determinants, and its targets and their relevance to neurodegeneration.
Assuntos
Progressão da Doença , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/metabolismo , Ácido Úrico/metabolismo , Animais , Biomarcadores , Ensaios Clínicos como Assunto , Humanos , Doença de Parkinson/diagnóstico , Doença de Parkinson/metabolismo , Fatores de Risco , Ácido Úrico/sangue , Ácido Úrico/líquido cefalorraquidianoRESUMO
IMPORTANCE: Convergent biological, epidemiological, and clinical data identified urate elevation as a candidate strategy for slowing disability progression in Parkinson disease (PD). OBJECTIVE: To determine the safety, tolerability, and urate-elevating capability of the urate precursor inosine in early PD and to assess its suitability and potential design features for a disease-modification trial. DESIGN, SETTING, AND PARTICIPANTS: The Safety of Urate Elevation in PD (SURE-PD) study, a randomized, double-blind, placebo-controlled, dose-ranging trial of inosine, enrolled participants from 2009 to 2011 and followed them for up to 25 months at outpatient visits to 17 credentialed clinical study sites of the Parkinson Study Group across the United States. Seventy-five consenting adults (mean age, 62 years; 55% women) with early PD not yet requiring symptomatic treatment and a serum urate concentration less than 6 mg/dL (the approximate population median) were enrolled. INTERVENTIONS: Participants were randomized to 1 of 3 treatment arms: placebo or inosine titrated to produce mild (6.1-7.0 mg/dL) or moderate (7.1-8.0 mg/dL) serum urate elevation using 500-mg capsules taken orally up to 2 capsules 3 times per day. They were followed for up to 24 months (median, 18 months) while receiving the study drug plus 1 washout month. MAIN OUTCOMES AND MEASURES: The prespecified primary outcomes were absence of unacceptable serious adverse events (safety), continued treatment without adverse event requiring dose reduction (tolerability), and elevation of urate assessed serially in serum and once (at 3 months) in cerebrospinal fluid. RESULTS Serious adverse events (17), including infrequent cardiovascular events, occurred at the same or lower rates in the inosine groups relative to placebo. No participant developed gout and 3 receiving inosine developed symptomatic urolithiasis. Treatment was tolerated by 95% of participants at 6 months, and no participant withdrew because of an adverse event. Serum urate rose by 2.3 and 3.0 mg/dL in the 2 inosine groups (P < .001 for each) vs placebo, and cerebrospinal fluid urate level was greater in both inosine groups (P = .006 and <.001, respectively). Secondary analyses demonstrated nonfutility of inosine treatment for slowing disability. CONCLUSIONS AND RELEVANCE: Inosine was generally safe, tolerable, and effective in raising serum and cerebrospinal fluid urate levels in early PD. The findings support advancing to more definitive development of inosine as a potential disease-modifying therapy for PD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00833690.
Assuntos
Inosina/uso terapêutico , Doença de Parkinson/sangue , Doença de Parkinson/líquido cefalorraquidiano , Ácido Úrico/sangue , Ácido Úrico/líquido cefalorraquidiano , Idoso , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/tratamento farmacológico , Resultado do TratamentoRESUMO
BACKGROUND: Quantification of Total Antioxidant Capacity (TAC) of human plasma is an important clinical target, since many diseases are suspected to be related with oxidative stress. The CUPRAC-BCS (BCS=Bathocuproinedisulfonic acid) method was chosen since it works using the photometric principle, with stable and inexpensive reagents and at physiological pH. METHODS: The method is based on the complex equilibria between Cu(II)-BCS (reagent) and Cu(I)-BCS. Cu(I)-BCS complex is formed by reducing ability of the plasma redox active substances. The photometric signal is achieved at 478 nm and calibration is performed using urate as a reference substance. RESULTS: Linearity, linear working range, sensitivity, precision, LoD, LoQ, selectivity and robustness have been considered to validate the method. Absorbance at 478 nm was found linear from 0.0025 up to 2.0 mmol L(-1) of urate reference solution. Precision was evaluated as within-day repeatability, Sr=4 µmol L(-1), and intermediate-precision, SI(T)=15 µmol L(-1). LoD and LoQ, resulted equal to 7.0 µmol L(-1) and 21 µmol L(-1) respectively while robustness was tested having care for pH variation during PBS buffer preparation. Tests on plasma (80 samples) and on human cerebrospinal fluid (30 samples) were conducted and discussed. CONCLUSIONS: By the analytical point of view, the photometric method was found to be simple, rapid, widely linear and reliable for the routine analysis of a clinical laboratory. By the clinical point of view, the method response is suitable for the study of chemical plasma quantities related to redox reactivity.
Assuntos
Antioxidantes/metabolismo , Ácido Ascórbico/sangue , Cobre/química , Diabetes Mellitus/sangue , Fenantrolinas/química , Ácido Ascórbico/líquido cefalorraquidiano , Calibragem , Cátions Bivalentes , Cátions Monovalentes , Diabetes Mellitus/líquido cefalorraquidiano , Humanos , Concentração de Íons de Hidrogênio , Oxirredução , Estresse Oxidativo , Fotometria , Padrões de Referência , Diálise Renal , Sensibilidade e Especificidade , Ácido Úrico/sangue , Ácido Úrico/líquido cefalorraquidianoRESUMO
Recent studies have provided evidence that uric acid (UA), a natural antioxidant, may play a role in the development and progression of Parkinson's disease (PD) and of dementia. In this clinical study we were therefore interested in the role of UA in Lewy body disorders (LBD), which includes Parkinson's disease (PD) and a common form of neurodegenerative dementias, dementia with Lewy bodies (DLB). Ninety-five LBD patients (55 non-demented PD patients, PDND; 20 PD patients with dementia, PDD; and 20 DLB patients) and 76 controls underwent clinical and biochemical analyses including, from a subcohort, cerebrospinal fluid (CSF) analyses, and analysis of three single nucleotide polymorphisms (SNPs) known to be associated with altered serum UA levels. We confirmed previous findings of lowered serum UA levels in LBD patients compared to controls. In CSF, UA levels were significantly higher in PDND patients (median 0.7 mg/dl) compared only to demented LBD patients (0.4 mg/dl; p = 0.03), but not to controls (0.5 mg/dl; p = 0.12). CSF UA levels correlated positively with CSF Aß42 levels. This correlation was highest in controls (ρ = 0.67), intermediate in PDND (ρ = 0.49), but not observable in demented LBD patients (ρ = 0.10). These findings suggest an involvement of serum UA in LBD occurrence, and an involvement of CSF UA in cognitive decline in LBD, possibly through the Aß pathway. SNP rs1165205 (SLC17A3) was weakly associated with altered CSF UA levels. Taken together, our results provide first evidence for disease-relevant but potentially distinct roles of UA in the blood and CSF compartment, respectively, in LBD.
Assuntos
Doença por Corpos de Lewy/sangue , Doença por Corpos de Lewy/líquido cefalorraquidiano , Ácido Úrico/sangue , Ácido Úrico/líquido cefalorraquidiano , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/genética , Transtornos Cognitivos/etiologia , Progressão da Doença , Feminino , Proteínas Facilitadoras de Transporte de Glucose/genética , Humanos , Doença por Corpos de Lewy/complicações , Doença por Corpos de Lewy/genética , Masculino , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Fragmentos de Peptídeos/genética , Polimorfismo de Nucleotídeo Único , Receptores de Droga/genética , Membro 3 da Família 12 de Carreador de Soluto , Simportadores/genética , Proteínas tau/genéticaRESUMO
A growing number of studies have correlated higher urate levels with a lower risk of developing Parkinson's disease (PD) and with a favorable rate of disease progression, indicating that urate could be an important biomarker of the pathophysiology underlying PD. Dietary and genetic determinants of urate have also been linked to a reduced risk or delayed onset of PD. Based on the known antioxidant and metal complexing properties of urate, together with evidence for oxidative stress as a contributor to neurodegeneration in PD, urate may serve as an endogenous neuroprotectant that helps reduce the risk and rate of the disease. In this article we review the convergent biological, epidemiological and clinical data that identify urate as a promising biomarker of the risk, diagnosis and prognosis of PD.
Assuntos
Doença de Parkinson/diagnóstico , Ácido Úrico/metabolismo , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/metabolismo , Gota/metabolismo , Humanos , Estresse Oxidativo , Prognóstico , Fatores de Risco , Urato Oxidase/genética , Urato Oxidase/metabolismo , Ácido Úrico/sangue , Ácido Úrico/líquido cefalorraquidianoRESUMO
Oxidative damage is a consistent finding in a number of central nervous system (CNS) disorders. Uric acid (UA) is a potent hydrophilic antioxidant that is modified by diet and drug. Several lines of evidence suggest that plasma UA may modulate outcomes in neurologic disease, but little attention has been paid to CNS levels of UA. Our objective was to test the hypothesis that cerebrospinal fluid (CSF) UA is determined by plasma UA, modified by blood-brain barrier (BBB) integrity and associated with rate of cognitive decline in Alzheimer's disease (AD). Also, since UA and ascorbic acid may act as antioxidants for one another, we also explored a potential interaction between them in the brain. Thirty-two patients with mild to moderate AD (Mini-Mental Status Exam 19 +/- 5) participated in a longitudinal biomarker study for one year involving standardized clinical assessments. CSF and blood were collected at baseline for UA, ascorbic acid, and albumin. Cognitive measures were collected at baseline and again one year later. CSF UA was independent of age, gender, and AD severity. CSF and plasma UA were positively correlated (r=0.669, p=0.001) and BBB impairment was associated with higher CSF levels of UA (p=0.028). Neither plasma nor CSF UA reached significant association with rates of cognitive decline over 1 year. CSF UA and CSF ascorbic acid were positively correlated (r=0.388, p=0.001). The hypothesis that CSF UA is determined by plasma UA and BBB integrity is supported, as is the hypothesis that UA and ascorbic acid are associated in CSF but not plasma. Adequately powered prospective studies would help assess any role for UA in primary and secondary prevention of AD.
Assuntos
Doença de Alzheimer/prevenção & controle , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Encéfalo/efeitos dos fármacos , Ácido Úrico/farmacologia , Ácido Úrico/uso terapêutico , Idoso , Ácido Ascórbico/líquido cefalorraquidiano , Ácido Ascórbico/farmacologia , Ácido Ascórbico/uso terapêutico , Barreira Hematoencefálica/efeitos dos fármacos , Feminino , Humanos , Masculino , Ácido Úrico/líquido cefalorraquidianoRESUMO
BACKGROUND: The risk of Parkinson disease (PD) and its rate of progression may decline with increasing concentration of blood urate, a major antioxidant. OBJECTIVE: To determine whether serum and cerebrospinal fluid concentrations of urate predict clinical progression in patients with PD. DESIGN, SETTING, AND PARTICIPANTS: Eight hundred subjects with early PD enrolled in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial. The pretreatment urate concentration was measured in serum for 774 subjects and in cerebrospinal fluid for 713 subjects. MAIN OUTCOME MEASURES: Treatment-, age-, and sex-adjusted hazard ratios (HRs) for clinical disability requiring levodopa therapy, the prespecified primary end point of the original DATATOP trial. RESULTS: The HR of progressing to the primary end point decreased with increasing serum urate concentrations (HR for highest vs lowest quintile = 0.64; 95% confidence interval [CI], 0.44-0.94; HR for a 1-SD increase = 0.82; 95% CI, 0.73-0.93). In analyses stratified by alpha-tocopherol treatment (2000 IU/d), a decrease in the HR for the primary end point was seen only among subjects not treated with alpha-tocopherol (HR for a 1-SD increase = 0.75; 95% CI, 0.62-0.89; vs HR for those treated = 0.90; 95% CI, 0.75-1.08). Results were similar for the rate of change in the Unified Parkinson's Disease Rating Scale score. Cerebrospinal fluid urate concentration was also inversely related to both the primary end point (HR for highest vs lowest quintile = 0.65; 95% CI, 0.44-0.96; HR for a 1-SD increase = 0.89; 95% CI, 0.79-1.02) and the rate of change in the Unified Parkinson's Disease Rating Scale score. As with serum urate concentration, these associations were present only among subjects not treated with alpha-tocopherol. CONCLUSIONS: Higher serum and cerebrospinal fluid urate concentrations at baseline were associated with slower rates of clinical decline. The findings strengthen the link between urate concentration and PD and the rationale for considering central nervous system urate concentration elevation as a potential strategy to slow PD progression.
Assuntos
Doença de Parkinson/patologia , Ácido Úrico/sangue , Ácido Úrico/líquido cefalorraquidiano , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/sangue , Doença de Parkinson/líquido cefalorraquidiano , Doença de Parkinson/tratamento farmacológico , Valor Preditivo dos TestesRESUMO
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).
Assuntos
Esclerose Múltipla/diagnóstico , Ácido Úrico/análise , Adulto , Encéfalo/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/metabolismo , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/metabolismo , Radiografia , Ácido Úrico/sangue , Ácido Úrico/líquido cefalorraquidianoRESUMO
OBJECTIVES: In this study, the concentrations of uric acid, purine profile and creatinine in samples of cerebrospinal fluid and serum of multiple sclerosis (MS) patients were measured by HPLC and compared with corresponding values recorded in patients without MS (cerebrospinal fluid) and healthy subjects (serum). DESIGN AND METHODS: All samples were deproteinized with ultrafiltration (which ensures minimal sample manipulation and efficient protein removal) and then assayed for the synchronous HPLC separation of uric acid, hypoxanthine, xanthine, inosine, adenosine, guanosine and creatinine. RESULTS: The values of all compounds assayed were significantly higher in both biological fluids of MS patients with respect to values measured in controls. In particular, serum hypoxanthine, xanthine, uric acid and sum of oxypurines were, respectively, 3.17, 3.11, 1.23 and 1.27-fold higher in these patients than corresponding values recorded in controls (p<0.001). CONCLUSIONS: Differently from what previously reported, we here demonstrate that all purine compounds, including uric acid, are elevated in biological fluids of MS patients. Reinforced by the trend observed for creatinine, this corroborates the notion of sustained purine catabolism, possibly due to imbalance in ATP homeostasis, under these pathological conditions. These results cast doubt on the hypothesis that uric acid is depleted in MS because of increased oxidative stress, rather suggesting that this disease causes a generalized increase in purine catabolism. As observed in other pathological states, uric acid, purine compounds and creatinine, can be considered markers of metabolic energy imbalance rather than of reactive oxygen species, even in MS.
Assuntos
Esclerose Múltipla/sangue , Esclerose Múltipla/líquido cefalorraquidiano , Purinas/sangue , Purinas/líquido cefalorraquidiano , Ácido Úrico/sangue , Ácido Úrico/líquido cefalorraquidiano , Estudos de Casos e Controles , Saúde , HumanosRESUMO
BACKGROUND AND PURPOSE: Allopurinol is a potent inhibitor of the enzyme xanthine oxidase, used primarily in the treatment of hyperuricemia and gout. It is well known that purines exert multiple effects on pain transmission. We hypothesized that the inhibition of xanthine oxidase by allopurinol, thereby reducing purine degradation, could be a valid strategy to enhance purinergic activity. The aim of this study was to investigate the anti-nociceptive profile of allopurinol on chemical and thermal pain models in mice. EXPERIMENTAL APPROACH: Mice received an intraperitoneal (i.p.) injection of vehicle (Tween 10%) or allopurinol (10-400 mg kg(-1)). Anti-nociceptive effects were measured with intraplantar capsaicin, intraplantar glutamate, tail-flick or hot-plate tests. KEY RESULTS: Allopurinol presented dose-dependent anti-nociceptive effects in all models. The opioid antagonist naloxone did not affect these anti-nociceptive effects. The non-selective adenosine-receptor antagonist caffeine and the selective A(1) adenosine-receptor antagonist, DPCPX, but not the selective A(2A) adenosine-receptor antagonist, SCH58261, completely prevented allopurinol-induced anti-nociception. No obvious motor deficits were produced by allopurinol, at doses up to 200 mg kg(-1). Allopurinol also caused an increase in cerebrospinal fluid levels of purines, including the nucleosides adenosine and guanosine, and decreased cerebrospinal fluid concentration of uric acid. CONCLUSIONS AND IMPLICATIONS: Allopurinol-induced anti-nociception may be related to adenosine accumulation. Allopurinol is an old and extensively used compound and seems to be well tolerated with no obvious central nervous system toxic effects at high doses. This drug may be useful to treat pain syndromes in humans.
Assuntos
Agonistas do Receptor A1 de Adenosina , Alopurinol/farmacologia , Analgésicos/farmacologia , Xantina Oxidase/antagonistas & inibidores , Adenosina/líquido cefalorraquidiano , Antagonistas do Receptor A1 de Adenosina , Antagonistas do Receptor A2 de Adenosina , Alopurinol/uso terapêutico , Analgésicos/uso terapêutico , Animais , Capsaicina , Relação Dose-Resposta a Droga , Ácido Glutâmico , Temperatura Alta , Injeções Intraperitoneais , Masculino , Camundongos , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Dor/tratamento farmacológico , Dor/etiologia , Medição da Dor , Pirimidinas/farmacologia , Triazóis/farmacologia , Ácido Úrico/líquido cefalorraquidiano , Xantinas/farmacologiaRESUMO
AIM: The aim of this study was to evaluate the usefulness of cerebral blood flow velocity in the middle cerebral artery measured by transcranial Doppler as criteria to therapeutic action in communicating hydrocephalic children. METHODS: In eight non-tumoral communicating hydrocephalic infants, ranging from five to 18 months of age, monitored from 18 to 36 months (mean time of follow-up: 24.25 months), cerebrospinal fluid (CSF) oxypurines (hypoxanthine and xanthine) and uric acid levels were compared by means of the Evans' index, the mean weekly increase in cranial circumference, and the transcranial Doppler measurements. RESULTS: Results indicate that clinical (mean weekly increase in head circumference), radiological (Evans' index), biochemical (oxypurines and uric acid in the CSF), and hemodynamic (transcranial Doppler) criteria have the same role in monitoring infantile hydrocephalus. CONCLUSION: In conclusion the transcranial Doppler measurement can be done noninvasively and examinations can be repeated when needed, obtaining immediate RESULTS: Hence, it is the most adequate monitoring technique in clinical practice.
Assuntos
Hidrocefalia/diagnóstico , Hidrocefalia/terapia , Velocidade do Fluxo Sanguíneo , Tamanho Corporal , Circulação Cerebrovascular , Cabeça/patologia , Humanos , Hidrocefalia/líquido cefalorraquidiano , Hipoxantina/líquido cefalorraquidiano , Lactente , Ultrassonografia Doppler Transcraniana , Ácido Úrico/líquido cefalorraquidiano , Xantina/líquido cefalorraquidianoRESUMO
The objective of this study was to investigate the antioxidant/oxidant status of serum and cerebrospinal fluid in children with meningismus and acute bacterial meningitis. Twenty-three children (age range, 0.75 to 9 years) with fever and meningeal signs that required analysis of the cerebrospinal fluid, but no cytologic or biochemical evidence of meningitis in their serum and cerebrospinal fluid, constituted the meningismus group. Thirty-one children (age range, 0.5 to 10 years) with acute bacterial meningitis constituted the meningitis group. Twenty-nine healthy children (age range, 0.5 to 11 years) were recruited as control subjects. Antioxidant status (ascorbic acid, albumin, thiol, uric acid, total bilirubin, total antioxidant capacity, catalase and ceruloplasmin concentrations) and oxidant status (lipid hydroperoxide and total oxidant status) were measured. The serum antioxidant status was lower, and oxidant status levels higher in both meningitis and meningismus subjects than in the control children (P < 0.001). Cerebrospinal fluid oxidant status was lower in the meningitis group than in the meningismus group (P < 0.05). These results indicate that serum antioxidant status was lower, and serum oxidant status was higher in children in the meningismus and meningitis groups, whereas cerebrospinal fluid oxidant status was higher in the meningismus group than in the meningitis group.
Assuntos
Antioxidantes/metabolismo , Meningismo/metabolismo , Meningites Bacterianas/metabolismo , Oxidantes/sangue , Doença Aguda , Ácido Ascórbico/sangue , Ácido Ascórbico/líquido cefalorraquidiano , Bilirrubina/sangue , Bilirrubina/líquido cefalorraquidiano , Catalase/sangue , Criança , Pré-Escolar , Feminino , Glutationa Peroxidase/sangue , Humanos , Lactente , Peróxidos Lipídicos/sangue , Peróxidos Lipídicos/líquido cefalorraquidiano , Masculino , Malondialdeído/sangue , Oxidantes/líquido cefalorraquidiano , Estresse Oxidativo , Albumina Sérica/metabolismo , Compostos de Sulfidrila/sangue , Compostos de Sulfidrila/líquido cefalorraquidiano , Superóxido Dismutase/sangue , Ácido Úrico/sangue , Ácido Úrico/líquido cefalorraquidianoRESUMO
OBJECTIVE: To measure blood and cerebrospinal fluid (CSF) uric acid (UA) levels of neonates with intraventricular hemorrhage (IVH), and to examine whether or not UA can be used to differentiate traumatic tap from IVH. MATERIAL AND METHODS: The control group (n = 19, group I) consisted of neonates presenting with signs requiring analysis of CSF but whose CSF indices proved to be normal. Traumatic taps (n = 15, group II) were mimicked by adding 2 drops of homologous blood to normal CSF samples. The IVH group (n = 21, group III) consisted of neonates who had been diagnosed by cranial ultrasonography or computed tomography scans. Data are presented as median (range). RESULTS: There was no significant difference between groups with respect to serum UA levels. While no significant difference was observed between CSF UA levels of the control [0.6 (0.1-1.8) mg/dl] and traumatic tap group [0.5 (0.3-1.1) mg/dl], the IVH group [1.6 (0.7-6.9) mg/dl] was found to have significantly higher CSF UA levels than groups I and II. Furthermore, although there were significant correlations between serum and CSF UA levels in the control and traumatic tap groups, no correlation was observed in the IVH group. CONCLUSION: CSF UA levels are increased in neonates with IVH and they may be used to differentiate a real hemorrhage from a traumatic tap.