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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., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

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.

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.

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.

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 (β = .765, p  <   .001) and serum UA levels (β = .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.

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.

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., (Copyright © 2013 Elsevier B.V. All rights reserved.)

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 Aβ42 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 Aβ 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.

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.

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.

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.

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.

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).

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.

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.

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.

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., (Copyright (c) 2006 S. Karger AG, Basel.)

To determine the effects of meningitis on cerebral energy metabolism, cerebrospinal fluid concentrations of adenosine monophosphate, inosine monophosphate, inosine, adenosine, guanosine, adenine, guanine, hypoxanthine, xanthine and urate were determined by high-performance liquid chromatography, and neuron-specific enolase by an enzyme immunoassay method, in 100 children with meningitis (45 bacterial, 46 viral and nine tuberculous), aged between 1 month and 13 years, and in 160 age-matched controls. Compared with controls, patients with bacterial meningitis showed high concentrations of hypoxanthine, xanthine and urate; patients with viral meningitis showed high concentrations of inosine, guanosine, xanthine, urate and neuron-specific enolase; and patients with tuberculous meningitis showed very high concentrations of inosine, xanthine and urate. Xanthine and urate concentrations were significantly higher in patients with tuberculous meningitis than in patients with viral or bacterial meningitis. These results suggest that in the acute stage of bacterial, viral and tuberculous meningitis, neuronal energy metabolism may be altered. The measurement of cerebrospinal xanthine and uric acid concentrations may be useful for the early diagnosis of a tuberculous origin.

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.

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 IS 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.

To determine the effects of sepsis on cerebral energy metabolism, the cerebrospinal fluid adenosine monophosphate, inosine monophosphate, inosine, adenosine, guanosine, hypoxanthine, xanthine, and urate concentrations were determined by high-performance liquid chromatography and the neuron-specific enolase levels by means of an enzyme immunoassay method in 32 children with sepsis, without meningitis, aged between 2 months and 13 years, and in 160 age-matched controls. The septic group had significantly higher cerebrospinal fluid concentrations of inosine, adenosine, xanthine, and urate than controls. These results suggest that sepsis could provoke some degree of neuronal hypoxia and significant alterations of cerebral energy metabolism homeostasis.

The natural peroxynitrite scavenger uric acid was previously shown to be protective in a rat model of pneumococcal meningitis; however, rats have much lower blood uric acid levels than humans. Therefore, we evaluated its therapeutic effect at human physiological blood concentrations. Intraperitoneal pretreatment with uric acid increased its blood concentrations from 44.9+/-10.0 microM in untreated rats to 169.8+/-122.6 microM and reduced the cerebrospinal fluid (CSF) pleocytosis from 12767+/-2520 to 8376+/-2450 cells/microl (P<0.05) and the intracranial pressure from 11.6+/-3.0 to 4.3+/-1.2 mm Hg (P<0.05). Coadministration of oxonic acid, an inhibitor of urate oxidase, increased the blood uric acid levels to 355.0+/-79.6 microM and further reduced the CSF pleocytosis (4190+/-1749 cells/microl, P<0.05) and the intracranial pressure (1.4+/-2.4 mm Hg). Uric acid+oxonic acid also had a beneficial effect when administered 2 or 4 h after the induction of meningitis. We demonstrate a dose-dependent anti-inflammatory effect of uric acid at blood levels in the human physiological range.

Experimental bacterial meningitis due to Streptococcus pneumoniae in infant rats was associated with a time-dependent increase in CSF and cortical urate that was approximately 30-fold elevated at 22 h after infection compared to baseline. This increase was mirrored by a 20-fold rise in cortical xanthine oxidoreductase activity. The relative proportion of the oxidant-producing xanthine oxidase to total activity did not increase, however. Blood plasma levels of urate also increased during infection, but part of this was as a consequence of dehydration, as reflected by elevated ascorbate concentrations in the plasma. Administration of the radical scavenger alpha-phenyl-tert-butyl nitrone, previously shown to be neuroprotective in the present model, did not significantly affect either xanthine dehydrogenase or xanthine oxidase activity, and increased even further cortical accumulation of urate. Treatment with the xanthine oxidoreductase inhibitor allopurinol inhibited CSF urate levels earlier than those in blood plasma, supporting the notion that urate was produced within the brain. However, this treatment did not prevent the loss of ascorbate and reduced glutathione in the cortex and CSF. Together with data from the literature, the results strongly suggest that xanthine oxidase is not a major cause of oxidative stress in bacterial meningitis and that urate formation due to induction of xanthine oxidoreductase in the brain may in fact represent a protective response.

If febrile seizures cause significant compromise of neuronal metabolism (whether permanent or reversible), this should be reflected in an increase in the cerebrospinal fluid concentrations of neuron-specific enolase (NSE) and/or adenosine triphosphate (ATP) breakdown products. In the present study, AMP, IMP, inosine, adenosine, guanosine, adenine, guanine, hypoxanthine, xanthine, uric acid and NSE concentrations were determined in the cerebrospinal fluid of 90 children 1 h after febrile seizure (73 simple febrile seizures (SFS); 17 complex febrile seizures (CFS)), and in a control group of 160 children. There was no statistically significant difference between the SFS group and the control group for any of the substances determined, suggesting that SFS neither significantly depletes neuronal ATP concentration, nor significantly increases NSE concentration; thus, SFS do not appear to constitute a threat to neuronal integrity. However, patients with CFS showed significantly lower IMP concentrations and significantly higher adenine concentrations than controls, and significantly higher AMP concentrations than SFS patients; these results suggest that CFS may affect energy metabolism in the brain. However, NSE concentrations were normal in the cerebrospinal fluid of both SFS and CFS patients, suggesting that neither type of seizure causes significant neuronal damage, at least early after the seizure.

Glutamate-mediated excitotoxicity is associated with adenosine triphosphate (ATP) degradation and generation of oxygen radicals. Hypoxanthine and lactate depict energetic impairment, while xanthine and uric acid reflect activity of radical producing xanthine oxidase. Cerebrospinal fluid (CSF) glutamate, hypoxanthine, lactate, xanthine, and uric acid were investigated in neurological patients. In multiple sclerosis, myelopathy, stroke, epilepsy and viral meningitis glutamate, hypoxanthine, xanthine, and uric acid are increased 2-3-fold compared to controls. Lactate is only elevated in meningitis. Normal lactate dehydrogenase (LDH) levels and absent correlation between the albumin ratio and neurochemical parameters exclude an artificial increase due to cell lysis and barrier damage. Absent correlation between neurochemical parameters within each patient group is most likely related to preserved glial and neuronal uptake mechanisms. CSF hypoxanthine, xanthine, and uric acid levels appear superior to lactate in reflecting glutamate-mediated excitotoxicity in neurological patients.

We describe a convenient method for the separation and quantification of xanthine, hypoxanthine, and uric acid in 20 microL of cerebrospinal fluid (CSF) with use of HPLC and ultraviolet detection. The analysis is performed on a Sepharon SGX C18 column and the elution system consists of potassium phosphate buffer, pH 5.1, with 20 mL/L methanol. The lower limit of detection was 4 pmol for hypoxanthine and xanthine and 6 pmol for uric acid. Analytical recoveries of purine metabolites ranged from 98.6% to 102.9%. The intra- and interassay CVs were <3%. The applicability of the method is illustrated with the determination of micromolar concentrations of xanthine, hypoxanthine, and uric acid in CSF samples obtained from 113 patients with various neurological disorders.

Extracellular uric acid levels were measured in the substantia nigra of guinea pigs via microdialysis/liquid chromatography with electrochemical detection (LCED) during infusion (60 min) of N-methyl-4-phenylpyridinium (MPP+), 6-hydroxydopamine (6-OHDA), or iron (III) chloride (FeCl3). Striatal and substantia nigra (SN) tissues were analyzed for uric acid (UA) and dopamine (DA) 3 h postinfusion. MPP+ infusion resulted in an increase in extracellular UA of 222 +/- 6%. The ipsilateral/contralateral ratio of nigral UA tissue levels was significantly increased over vehicle controls. Infusion of 6-OHDA produced an increase of 362 +/- 44% in extracellular UA. No significant changes were seen in UA tissue levels in either the striatum or the SN. Infusion of FeCl3 produced a significant decrease in extracellular nigral UA levels to 21.5 +/- 0.7% of preinfusion levels. The ipsilateral/contralateral ratio of nigral UA tissue levels increased by 38%, whereas the striatal ratio value decreased to 62% of the vehicle control levels. No changes in DA tissue levels were observed in any of the brain regions in the experimental groups. These results indicate that infusion of neurotoxins known to affect dopaminergic cells generates an acute change in UA levels within the nigrostriatal system of guinea pigs.

Free radicals are thought to be involved in the onset of neuronal disturbances such as Alzheimer's disease, Parkinson's disease, and neuronal ceroid lipofuscinosis. It is also assumed that they play a role in cerebral injury caused by ischemia or trauma. Plasma and cerebrospinal fluid (CSF), Total (peroxyl) Radical-trapping Antioxidant Parameter (TRAP), and the known antioxidant components of TRAP, for instance, ascorbic acid, uric acid, protein sulfhydryl groups, tocopherol, and ubiquinol were analyzed and the remaining unidentified fragment was calculated in five healthy volunteers before and after 4 weeks of ascorbate and ubiquinone (Q-10) supplementation. In CSF, TRAP was significantly lower than in plasma. The major contributor to plasma's antioxidant capacity was uric acid (UA), whereas in CSF it was ascorbic acid (AA). In CSF, AA concentrations were four times higher than in plasma. Oral supplementation of AA (500 mg/d first 2 weeks, 1,000 mg/d following 2 weeks) and Q-10 (100 mg/d first 2 weeks, 300 mg/d following 2 weeks) induced a significant increase in plasma AA and Q-10. Surprisingly, in spite of the high lipophilicity of Q-10, its concentration did not change in CSF. The supplementation of AA increased its concentration in CSF by 28% (p < .05). However, the increase in AA did not result in an increase in CSF TRAP. This indicates that AA had lost one-third of its radical trapping capacity as compared to that in plasma. The facts that AA is the highest contributor to CSF TRAP and its effect on TRAP is concentration dependent could indicate that the peroxyl radical-trapping capacity of CSF is buffered by AA.

Catabolites of purine nucleotides were measured in the cerebrospinal fluid (CSF) of newborn infants with sepsis, seizures and hydrocephalus using isocratic reversed-phase HPLC. The inosine levels in the CSF of the infants with any of the illnesses were significantly higher when compared with the controls. There was a tendency for hypoxanthine levels to be higher in the group of children with hydrocephalus. No significant differences in the concentrations of xanthine, adenine and uric acid were found. The inosine concentration in the CSF is proposed to be a more sensitive indicator of brain injury than the levels of other CSF purines. The levels of all purine metabolites measured in the CSF showed large individual variations. The ratio between hypoxanthine (as an indicator of ATP breakdown) and uric acid (as a scavenger of oxygen free radicals) concentration is proposed as a new criterion to be used in the evaluation of brain injury.

Plasma and cerebrospinal fluid total peroxyl radical-trapping antioxidative parameter (TRAP) and the main antioxidant components of TRAP (vitamin E, ascorbic acid, uric acid, protein sulfhydryl groups, and the unidentified antioxidant proportion) were analyzed in 11 preeclamptic parturients, 9 healthy parturients with an uncomplicated pregnancy, and 10 healthy nonpregnant women. In addition, the possible effects of ongoing labor were studied in 10 healthy parturients. The samples of plasma and cerebrospinal fluid (CSF) were collected at cesarean section (pregnant women) or minor surgical procedure (nonpregnant women). Normal pregnancy or ongoing labor induced no significant changes in total TRAP, as compared with nonpregnant women, but significant changes in the percentage contributions of individual antioxidants were noted in plasma and CSF. In preeclampsia, a significant increase in TRAP was noted in both plasma and CSF. This increase was mainly due to an increased proportion of uric acid and unidentified antioxidants in plasma samples, and an increased proportion of unidentified antioxidants in CSF. The concentration of CSF ascorbic acid was decreased in preeclampsia, and a negative correlation between CSF ascorbic acid and blood pressure was observed.

The release of agents mediating inflammation in meningitis may bring about neuronal hypoxia, under which circumstances ATP concentrations decrease and its degradation products increase and are released into the cerebrospinal fluid. In this study of alterations in neuronal energy metabolism in meningitis, AMP, IMP, inosine, adenosine, guanosine, adenine, guanine, hypoxanthine, xanthine and urate were determined by high performance liquid chromatography in the cerebrospinal fluid of 54 children aged between 1 month and 13 years suffering from meningitis (25 viral, 24 bacterial and 5 tuberculous cases) and 63 controls. Compared to the controls, patients with viral meningitis exhibited high concentrations of IMP, adenosine, guanosine, adenine, guanine and xanthine; patients with bacterial meningitis exhibited high concentrations of IMP, inosine, guanosine, adenosine, hypoxanthine, xanthine and urate; and patients with tuberculous meningitis exhibited high concentrations of AMP, guanosine, xanthine and urate. Viral and bacterial cases did not differ significantly for any of the metabolites studied. AMP and urate concentrations were significantly higher in patients with tuberculous cases compared with viral or bacterial meningitis cases.

Concentrations of ascorbate (vitamin C) in cerebrospinal fluid (CSF) from human controls (median 163 mumol/l, n = 63) were found to be in the same range as CSF samples from patients (n = 56) with various neurological diseases, but excluding those with blood-CSF barrier dysfunction. The CSF/serum concentration ratio in the former group is non-linear, decreasing with increasing serum concentration. Surprisingly, ascorbate concentration in blood (median 41 mumol/l, n = 119) was decreased significantly in cases of neurological diseases with a blood-CSF barrier dysfunction (median 26 mumol/l, n = 30). In this latter group a linear CSF to serum ratio with a mean of 5.7:1 (with CSF/serum albumin quotients QAlb = 7.8-70.8 x 10(-3), median 10.0 x 10(-3)) was observed, approaching a value > 12.5:1 in the case of complete stop of CSF flow. Serum ascorbate concentrations decreased with decreasing CSF flow rate (1 square root of QAlb), indicating a CSF flow-dependent constant contribution from high intrathecal ascorbate concentration to the varying diet-dependent concentrations in blood. In the control group the biological coefficient of variation for CSF ascorbate concentrations (C.V. = 21.1%) was smaller than for serum concentrations (C.V. = 42.6%), confirming an efficient ascorbate homeostasis in human brain. This was different from uric acid which was used as a reference molecule with an inversed gradient in the same group of control patients. Similar variations in CSF(y) and serum(x) for urate concentrations are observed due to the strong correlation y = 0.1x +/- 10 mumol/l, including 99% of the cases with an urate serum concentration range from 80 mumol/l to 460 mumol/l.

We determined the urate and xanthine concentrations in the cerebrospinal fluid (CSF) in patients with vascular dementia of the Binswanger type (VDBT), Alzheimer type dementia (ATD), and Parkinson's disease (PD). We found that the urate concentration was significantly increased in VDBT patients, but significantly decreased in ATD patients compared with controls. The ratio of the concentrations of uric acid (UCSF) to xanthine (XCSF) in the CSF (UCSF/XCSF) had a significant correlation with the ratio of the UCSF to the urate concentration in serum (U(serum)) (UCSF/U(serum)) in ATD and PD, whereas UCSF/U(serum) increased independently of UCSF/XCSF in VDBT. We concluded that the significant increase in the urate concentration in VDBT is mainly due to an impairment of the blood-brain barrier (BBB), and its significant reduction in ATD may reflect impaired brain metabolism.

We studied age-related changes in the concentrations of monoamines, amino acids, and their related substances in the cerebrospinal fluid on 144 neurologically normal subjects. The concentrations of tyrosine, 3-O-methyldopa, dopamine (total), norepinephrine (total), homovanillic acid, p-hydroxyphenylacetic acid, and 5-hydroxytryptophan increased significantly with age (p < 0.05), and the concentration of 3.4-dihydroxyphenylacetic acid displayed a non-significant trend to decrease, whereas concentrations of other monoamine precursors and metabolites were unchanged. We found the significant positive correlations between the concentrations of HVA and 5-HIAA (p < 0.001), between tyrosine and tryptophan (p < 0.001), and between tyrosine and 3-O-methyldopa (p < 0.001). The concentrations of asparagine, glycine, taurine, and alanine increased significantly with age (p < 0.05), while glutamine, arginine, and threonine concentrations did not change with age. The aspartate, glutamate, and GABA concentrations displayed the non-significant trends to decrease in the elderly subjects. The concentrations of aspartate, glutamate, and GABA had mutually significant positive correlations (p < 0.05), but had significant negative correlations with the concentrations of some neutral amino acids. The urate and xanthine concentrations increased significantly with age (p < 0.01). These findings suggest that the concentrations of monoamine and amino acid transmitters and their related compounds in the cerebrospinal fluid reflect age-related changes in the synthesis, release, and reuptake mechanisms of the transmitters and their transport mechanisms across the blood-brain barrier.

To determine whether an elevated level of hypoxanthine in cerebrospinal fluid or vitreous humor might reflect a high plasma hypoxanthine concentration, or whether it necessarily represents local tissue hypoxia, we infused hypoxanthine intravenously to normoxemic and normotensive piglets (n = 6). Hypoxanthine was measured in different body fluids using HPLC. During the 8 hours of infusion hypoxanthine increased in plasma (from 30 +/- 6 mumol/l (mean +/- SD) before the infusion to 68 +/- 20 mumol/l at the end of the infusion, p < 0.01), cerebrospinal fluid (CSF) (19 +/- 8 to 43 +/- 9 mumol/l, p < 0.05) and vitreous humor (15 +/- 5 to 30 +/- 6 mumol/l, p < 0.05). After infusion, hypoxanthine values in all three fluids were similar to those seen in pigs after severe hypoxia. Hypoxanthine in vitreous humor and plasma were significantly correlated (r = 0.80, 95% confidence interval 0.47-0.93, p < 0.001). Urinary excretion of hypoxanthine increased almost 40 times from 0.12 +/- 0.14 to 4.6 +/- 2.9 mumol/kg/h indicating that renal excretion of hypoxanthine is not achieved just by passive filtration. We conclude that in newborn piglets hypoxanthine can pass from plasma to CSF and vitreous humor. Thus an increased CSF hypoxanthine concentration is not definite proof that significant cerebral hypoxia has occurred.

Adenosine monophosphate, inosine monophosphate, inosine, adenosine, guanosine, adenine, guanine, hypoxanthine, xanthine, uric acid and pyrimidine bases were determined in the CSF of 18 children after simple febrile seizures and in a control group. There was no statistically significant difference between the two groups for any of these metabolites. This suggests that simple febrile seizures neither significantly disturb the metabolism of nucleotides, nucleosides or bases, nor significantly deplete neuron adenosine triphosphate ATP levels.

Concentrations of HVA, 5-HIAA, ascorbic acid, and uric acid in the lumbar and cisternal cerebrospinal fluid (CSF) were measured in psychiatric and neurologically impaired patients. The concentration of HVA is 6.1 times and of 5-HIAA 2.7 times higher in cisternal than in lumbar samples, the cisternal level of uric acid is half that of the lumbar region, but no significant differences were found in ascorbic acid concentrations. Correlation between lumbar and cisternal metabolite concentrations is high for 5-HIAA and ascorbic acid, and is less for HVA and uric acid. In cisternal CSF there is a significant correlation between levels of HVA-5-HIAA, 5-HIAA-ascorbic acid, and 5-HIAA-uric acid. These correlations disappear in lumbar CSF. These findings indicate that extrapolations to cisternal neurotransmitter metabolite concentration from lumbar measures are unwarranted for HVA, but not for 5-HIAA.

The overactivity of PRPP synthetase is transmitted as a sex-linked abnormality, being characterized by uric acid overproduction and, in some patients, by muscular hypotonia, neurosensitive deafness and/or ataxia. The pathogenesis of these neurologic abnormalities is not yet known. The CSF concentrations of end products of the neuronal metabolism of purines--hypoxanthine for the adenine nucleotides and xanthine for guanine nucleotides--have not been previously studied in patients with overactivity of PRPP synthetase. We have evaluated the plasma and CSF levels of hypoxanthine and xanthine in a 8-year-old male with tophaceous gout and neurosensitive deafness and in his mother, who had gout without neurological involvement. PRPP synthetase overactivity was demonstrated in fibroblast culture; the male was hemizygote and his mother was heterozygotic. In 4 normal individuals, the plasma levels of hypoxanthine and xanthine were 1.7 +/- 0.4 microM and 0.9 +/- 0.2 microM (mean +/- SEM), respectively, while in in CSF they were 3.3 +/- 1.1 microM and 2.0 +/- 0.2 microM. The hemizygote male showed a considerable increase in hypoxanthine level (5.6 microM in plasma and 22.1 microM in CSF); the plasma and CSF xanthine levels were 1.8 and 4.5 microM, respectively. The heterozygotic female showed moderately increased plasma hypoxanthine levels (3.9 and 10.6 microM) and normal xanthine levels (1.3 and 1.8 microM). These results suggest an increase in the degradation of purine nucleotides in the central nervous system of patients with PRPP synthetase overactivity and neurological symptoms. The predominance of hypoxanthine over xanthine may indicate a greater increase of the degradation of adenine rather than guanine nucleotides.

This article presents a study of a family in which association of hyperuricaemia and more interestingly increased C.S.F. uric acid was noticed in two members who had classical dystonia musculorum deformans (DMD). Other members of the family had no clinical evidence of DMD but had increased serum and C.S.F. uric acid. Investigations did not reveal any of the common disorders of the purine metabolism in any of the family members. An attempt has been made to discuss the aetiopathological correlation.

The purine metabolites hypoxanthine, xanthine and urate as well as creatinine were measured in cerebrospinal fluid (CSF) from two groups of patients and a reference sample group. In one of the patient groups lumbar CSF was collected in 2 ml portions until a total volume of 14 ml was withdrawn. Every second portion was analysed for its content of the metabolites in focus. In the other patient group both cisternal CSF and a fixed volume (20 ml) of lumbar CSF were obtained and analysed. An increase in concentration of hypoxanthine, xanthine and creatinine and a decrease in urate concentration was found in the successive CSF specimens. The mean individual increase in hypoxanthine concentration between the first and the last 2 ml portion was as high as 39.6%, while it was lower for xanthine, 21.5%, and creatinine, 6.7%. The decrease in urate concentration was 17.2%. The results from the other patient group were in good agreement with these findings. The concentrations in the cisternal CSF was 162% of that in lumbar CSF for hypoxanthine, 155% for xanthine, 123% for creatinine and 80% for urate. Mechanisms behind inter- and intraindividual differences in gradients are discussed.

The adenine nucleotide metabolites hypoxanthine, xanthine and uric acid were determined by high performance liquid chromatography in cerebrospinal fluid (CSF) from 25 patients with subarachnoid haemorrhage (SAH) and from 26 control subjects. In addition, the haemoglobin and protein levels in the CSF of the patients were determined. In 13 subjects, from which lumbar CSF was collected three, six and nine days after SAH, there was a gradual increase in 8 patients for hypoxanthine and in 3 of the 13 patients for xanthine and uric acid. The mean concentrations were not significantly higher than the controls. In 12 SAH patients, consecutive CSF fractions of 10 ml were collected peroperatively during surgical clipping of aneurysms. The hypoxanthine concentrations increased continuously from lumbar to central CSF samples. Hypoxanthine levels were 6.5 +/- 1.0 microM in lumbar CSF compared to 11.8 +/- 2.3 microM in central CSF (p less than 0.001), while xanthine, uric acid, haemoglobin and protein levels were equally distributed. Furthermore, the SAH patients showed about 3 times higher concentrations of central CSF hypoxanthine (p less than 0.01) and xanthine (p less than 0.05) while that for uric acid was similar compared to all control subjects. Also, as in vitro study showed that the increased concentrations of the adenine nucleotide metabolites could not be caused by degradation of blood components in the subarachnoid space. It is presumed that the increased central CSF concentrations of hypoxanthine that were demonstrated in patients after SAH could be a sensitive marker for brain tissue ischaemia. However, since there was no correlation between the hypoxanthine levels, clinical condition or cerebral vascular diameter, other factors have to be excluded before ischaemia alone could explain the elevated central hypoxanthine levels in patients without major clinical dysfunction after SAH.

It is well known that, among patients of normal pressure hydrocephalus (NPH), there is a group in which a shunting procedure had no effect on improving clinical signs (shunt-ineffective group). To differentiate the shunt-effective group from the shunt-ineffective group, we performed measurements of cerebrospinal fluid (CSF) levels of uric acid (UA) and gamma-aminobutyric acid (GABA) in patients of NPH. We investigated the age-related CSF levels of UA and GABA in the normal subjects and compared them with those in the patients of NPH including the shunt-ineffective group and other related states, that is, multi-infarct dementia (MID) and patients with full recovery after subarachnoid hemorrhage (SAH) due to the ruptured aneurysm. In the normal subjects, CSF UA levels of second and over seventh decades were significantly higher than those of third, fourth, and fifth decades. On the other hand, CSF GABA levels of second and over seventh decades were significantly lower than those of the others. In the patients of MID, CSF UA levels were much higher and CSF GABA levels were much lower in comparison with the normal controls. These results suggested that, in the aged normal subjects, some degree of brain damage is responsible for high CSF UA levels and low CSF GABA levels. There was no difference in the values of CSF UA and GABA between normal subjects and the patients with full recovery after SAH. In the patients of NPH, CSF UA levels were low in general, while CSF GABA levels were all high. After the shunting operation, CSF UA and GABA levels became normal in the shunt-effective group.(ABSTRACT TRUNCATED AT 250 WORDS)

CSF obtained for clinical purposes from newborn, children and adults has been analysed by high pressure liquid chromatography for hypoxanthine, xanthine, inosine, uridine and urate. Large rises in hypoxanthine and to a lesser extent xanthine occur for about 24 h after hypoxia. High concentrations were associated with later evidence of brain damage or subsequent death. Changes in CSF could be independent of those in plasma. Small or negligible rises were associated with localised and generalised infections including bacterial meningitis, fits, or both. Marked and rapid rises were found after death. These estimations may "predict" the extent of brain damage or brain death.