Sex and race differences of cerebrospinal fluid metabolites in healthy individuals.

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.

Electrolytes and Biochemical Changes in Cerebrospinal Fluid in Drowning: Experimental Rabbit Model.

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.

Cerebrospinal fluid uric acid levels associated with disease severity in patients with anti-N-methyl-d-aspartate receptor encephalitis.

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.

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

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

Therapeutic criteria in communicating childhood hydrocephalus.

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.

Elevated cerebrospinal fluid uric acid during relapse of neuromyelitis optica spectrum disorders.

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.

Urate as a Marker of Risk and Progression of Neurodegenerative Disease.

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.

Total antioxidant/oxidant status in meningism and meningitis.

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.

Concentration gradients for HVA, 5-HIAA, ascorbic acid, and uric acid in cerebrospinal fluid.

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 total peroxyl radical-trapping ability of plasma and cerebrospinal fluid in normal and preeclamptic parturients.

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 effect of ascorbate and ubiquinone supplementation on plasma and CSF total antioxidant capacity.

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.

Oxidative stress in bacterial meningitis in humans.

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

Cerebrospinal fluid concentrations of hypoxanthine, xanthine, uridine and inosine: high concentrations of the ATP metabolite, hypoxanthine, after hypoxia.

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.

Cerebrospinal fluid levels of uric acid in dogs and the effect of allopurinol.

Uric acid (UA) levels in cerebrospinal fluid (CSF) were measured in 15 dogs and the entrance and effect of allopurinol, a specific inhibitor of enzyme xanthine oxidase (XO), in brain were measured by sampling CSF in dogs. Allopurinol was administered intravenously 25 mg/kg every 6 h for 48 h. Drug level as well as UA level in plasma and CSF was measured by high-performance liquid chromatography. A significant concentration of allopurinol was achieved in CSF and a remarkable suppression of CSF UA level was observed at all time points measured. Decrease of UA in CSF level was more pronounced than in plasma, and was not considered secondary to suppression of systemic XO activity. Therefore the regimen employed was proven to be sufficient to suppress XO activity in the subarachnoid space, and drug concentration observed in CSF during this period (5 micrograms/ml) is considered to be in the therapeutic range.

Marked elevation in cortical urate and xanthine oxidoreductase activity in experimental bacterial meningitis.

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.

Experimental meningitis in the rat: protection by uric acid at human physiological blood concentrations.

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.

Cerebrospinal fluid hypoxanthine, xanthine and uric acid levels may reflect glutamate-mediated excitotoxicity in different neurological diseases.

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.

Measurement of free radical scavengers in the spinal cord of rats with experimental autoimmune encephalomyelitis.

Antioxidants (ascorbic acid, glutathione, cysteine, alpha-tocopherol) and uric acid were measured using two high-pressure liquid chromatographic methods in 3 regions (cervical, thoracic, lumbar) of the spinal cord and in blood of Lewis rats during the attack and recovery of experimental autoimmune encephalomyelitis (EAE). Uric acid, which is thought to be a marker of free radical release, was greatly increased and glutathione correspondingly decreased in lumbar and thoracic regions. Cysteine and ascorbic acid were practically unchanged, whereas alpha-tocopherol was significantly increased during attack and recovery. Results, which could have therapeutic implications, generally support the hypothesis that free radicals are released during EAE.

Ascorbate concentration in human cerebrospinal fluid (CSF) and serum. Intrathecal accumulation and CSF flow rate.

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.

Production of uric acid in cerebrospinal fluid after subarachnoid hemorrhage in dogs: investigation of the possible role of xanthine oxidase in chronic vasospasm.

Based on accumulating evidence of the role of xanthine oxidase (XO) in generating oxygen free radicals and causing tissue damage during ischemia, we examined the possible role of XO in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). After inducing SAH in dogs by two autologous blood injections 2 days apart, chronic vasospasm of the basilar artery was reliably produced. There was a 3.5-fold elevation in uric acid (UA), the product of XO, in the cerebrospinal fluid (CSF) of these animals. Parenteral administration of allopurinol (i.v., 25 mg/kg, every 6 hours), a specific blocker of XO, successfully abolished the elevation in CSF uric acid levels due to SAH. However, angiographic vasospasm measured on Day 7, morphological changes observed by electron microscope, and elevated CSF prostaglandin levels were not altered by the treatment. It can be concluded that the observed activation of the enzyme XO, which is a well-known source of oxygen free radicals in ischemia in various organs, is not playing a major role in the pathogenesis of chronic cerebral vasospasm in this animal.