Cerebrospinal Fluid Hypoxanthine Research Articles

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.

Effects of Surgery and Asphyxia on Levels of Nucleosides, Purine Bases, and Lactate in Cerebrospinal Fluid of Fetal Lambs

During severe oxygen shortage, the fetal brain resorts to anaerobic metabolism and ATP becomes catabolized. High levels of nucleosides, hypoxanthine, and xanthine (ATP catabolites) in cerebrospinal fluid (CSF) may therefore be associated with increased neonatal neurologic morbidity. In 22 fetal lambs (3 to 5 d after surgery, gestational age 123.5 +/- 3.5 d), arterial oxygen content was progressively reduced to 35% of the baseline value with a balloon occluder around the maternal common internal iliac artery. This resulted in a 1-h period of asphyxia, leading to a pH of 7.02 +/- 0.03 and a base excess of -17.0 +/- 1.0 mM. Mortality was 50%. CSF was sampled from the spinal cistern and analyzed using HPLC. During reoxygenation, hypoxanthine and xanthine may serve as substrate for xanthine oxidase with concomitant production of oxygen-derived free radicals, which may aggravate cerebral damage. The main difference between surviving and nonsurviving animals was the speed of increment of ATP catabolites in CSF: in the surviving group levels increased steadily, recovery values being significantly elevated compared with asphyxia values, whereas in the nonsurviving group the rise was rapid and levels during asphyxia did not differ significantly from levels during recovery. We conclude that 1) catheterization of the spinal cistern leads to increased levels of CSF hypoxanthine, xanthine, and inosine, and 2) during fetal asphyxia, levels of these ATP catabolites and lactate in CSF increase. 3) Maximum levels are reached during the recovery period and are similar for surviving and nonsurviving animals, but during asphyxia CSF levels of hypoxanthine and lactate were higher in the nonsurviving fetuses.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of asphyxia on the fetal lamb brain

Our purpose was to study the effect of fetal asphyxia on the release of hypoxanthine and xanthine in cerebrospinal fluid and on brain histologic characteristics. In seven fetal lambs (3 to 5 days after surgery, gestational age 124.3 +/- 2.6 days) asphyxia was induced by restriction of uterine blood flow. Fetal pH and base excess were reduced to 6.99 +/- 0.02 and -17.6 +/- 0.9 mmol/L, respectively. Cerebral blood flow increased during asphyxia and returned to normal in the recovery phase. Maximum concentrations of cerebrospinal fluid hypoxanthine and xanthine were reached in the normoxemic recovery phase. This high level of substrates during normoxemia facilitates oxygen free radical formation and may thus aggravate postasphyctic brain damage. Histologic evaluation of the brain 3 days after the insult showed a variable degree of edema. Coagulative neuronal changes, characteristic of irreversible cell death, were only occasionally detected. These changes were most obvious in the Purkinje cells of the cerebellum. Fetal asphyxia induced by uterine blood flow restriction is associated with high levels of cerebrospinal fluid hypoxanthine and xanthine in the recovery phase. Microscopically detectable brain damage, although not extensive, is mainly located in the cerebellum.

Vitreous humour and cerebrospinal fluid hypoxanthine concentration as a marker of pre-mortem hypoxia in SIDS.

To assess the rate at which premortem hypoxia occurs in sudden infant death syndrome (SIDS) when compared with death in early childhood. The hypoxanthine concentration was measured as a marker of premortem hypoxia in vitreous humour and cerebrospinal fluid samples obtained at necropsy from 119 children whose ages ranged from 1 week to 2 years. Increasing interval between death and necropsy was accompanied by an increase in the hypoxanthine concentration of vitreous humour for the first 24 hours, at a rate of 8.3 mumol/l/hour. Thereafter, there was little change with time, and the results wer corrected to 24 hours according to a regression equation. Cerebrospinal fluid concentrations showed no significant change with time following death. Patients were divided into three groups according to the cause of death: SIDS, cardiac or pulmonary disease, and others. Median values for the cerebrospinal fluid hypoxanthine concentrations were not significantly different among the groups and no difference could be shown between the vitreous humour hypoxanthine concentration in cases of SIDS and those children dying from other causes. Patients with established cardiac or pulmonary disease had a significantly reduced vitreous humour hypoxanthine concentration which may have reflected the premortem use of artificial ventilation. The results of this study do not support the view that pre-mortem hypoxia is a common feature in SIDS when compared with other causes of death.

Transport of hypoxanthine from plasma to cerebrospinal fluid and vitreous humor in newborn pigs

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.

Cerebrospinal fluid calcium, parathyroid hormone, and monoamine and purine metabolites and the blood-brain barrier function in primary hyperparathyroidism

Psychiatric disturbances are common in primary hyperparathyroidism (HPT), but their pathogenesis is essentially unknown. This study deals with cerebrospinal fluid (CSF) calcium homeostasis and its connection with parathyroid hormone (PTH), blood-brain barrier (BBB) function, and central monoamine and purine metabolites in patients with primary HPT. In 22 patients with primary HPT (serum calcium 2.85±0.21 mmol/l), the CSF concentrations of total and ionized calcium were higher (1.21±0.08 mmol/l, p<0.01, and 1.09±0.05 mol/ll, p< 0.001, respectively) than in 11 normocalcemic reference subjects. The values correlated with serum calcium concentration ( p< 0.001) and CSF/serum albumin ratio, a measure of BBB permeability. The latter ratio was elevated in one-third of the patients with HPT, indicating BBB damage. CSF immunoreactive intact PTH was higher in the HPT patients than in the reference group ( p< 0.05), and serum and CSF PTH were positively correlated ( p< 0.05). The CSF levels of the monoamine metabolites 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) were lower, and the level of urate in CSF was higher, in the HPT patients than in the reference subjects, while there were no consistent differences in CSF hypoxanthine or xanthine. CSF 5HIAA correlated inversely with CSF ionized calcium ( r = −0.42, p = 0.02). After parathyroid surgery, CSF calcium and urate decreased significantly and CSF monoamine metabolites increased slightly. The decrease in CSF ionized calcium correlated with the alleviation of psychiatric symptoms. The results indicate the importance of increased CSF calcium concentrations in patients with primary HPT and suggest a relation between central calcium regulation and central turnover of monoamines.

Mannitol treatment in experimental haemophilus influenzae type b meningitis

ABSTRACT. A study was undertaken to evaluate hypertonic mannitol treatment in experimental lapin Haemophilus influenzae type b meningitis and to compare these results with those in normal rabbits. Increased intracranial pressure, brain water content, and concentrations of lactate and hypoxanthine in cerebrospinal fluid (CSF) were measured as a reflection of altered cerebral perfusion and hypoxia and potential brain injury associated with meningitis. A single dose of mannitol reduced transiently the CSF pressure of uninfected rabbits from 2.15 ± 0.20 to 1.34 ± 0.10 mm Hg (maximum reduction 34.9 ± 8.4%; p 0.05). CSF lactate and hypoxanthine concentrations were significantly increased during the 20 h of meningeal inflammation (p < 0.005). The mean percentage change from baseline values for lactate concentrations at the end of the experiment (24 h) in infected mannitol-treated rabbits was significantly smaller than that in infected untreated animals (p = 0.035). A single dose of mannitol reduced the CSF hypoxanthine concentrations of infected animals, but this reduction was not statistically significant.

68 INCREASED PURINE NUCLEOTIDE DEGRADATION IN THE CENTRAL NERVOUS SYSTEM (CNS) IN PRPP SYNTHETASE SUPERACTIVITY

The end products of purine metabolism in the CNS are hypoxanthine for adenine nucleotides and xanthine for guanine nucleotides. Previous reports of two families with PRPP synthetase superactivity associated with neurodevelopmental defects have not documented metabolism of purines in the CNS. Fibroblasts extracts from an eight-year-old male with tophaceous gout and sensorineural deafness and from his mother with gout showed an aberrant PRPP synthetase characterized by resistance to purine nucleotide inhibition of enzyme activity. Hypoxanthine and xanthine concentrations in plasma and cerebrospinal fluid (CSF) were simultaneously measured by HPLC in both patients. In 4 normal subjects hypoxanthine and xanthine levels in plasma were (mean±SEM) 1.7±0.4 μM and 0.9±0.2 μM, respectively, and 3.3±1.1 and 2.0±0.2 μM in CSF. The hemizigous male showed a substantially increased hypoxanthine concentration of 5.6 μM in plasma and of 22.1 μM in CSF. Xanthine levels were 1.8 μM in plasma and 4.5 μM in CSF. The heterozigous female had moderately elevated plasma and CSF hypoxanthine concentrations (3.9 and 10.6 μM) and normal xanthine levels (1.3 and 1.8 μM). These results suggest an increased purine nucleotide degradation in the CNS of patients with PRPP synthetase superactivity and neurological symptoms. The predominance of hypoxanthine over xanthine may indicate a relatively enhanced adenine nucleotide over guanine nucleotide degradation.

Alterations in cerebrospinal fluid uridine, hypoxanthine, and xanthine in head-injured patients.

1. Examination of the cerebrospinal fluid (CSF) of head-injured patients reveals that the concentration of intraventricular xanthine is elevated and that of uridine is decreased relative to those of adult lumbar CSF. 2. No correlations were observed between CSF lactate and CSF hypoxanthine, xanthine, or uridine, suggesting that changes in purine metabolites and the pyrimidine nucleoside do not index similar cellular events as does lactic acid production. 3. Ventricular CSF from hydrocephalic infants had uridine and hypoxanthine concentrations not significantly different from those of normal adult lumbar CSF, but xanthine was significantly elevated. 4. Since uridine has anticonvulsant properties and is a crucial substrate for cerebral metabolism, it may be useful to evaluate this pyrimidine for use in the management of patients with head injury.

Mannitol Treatment in Experimental Haemophilus influenzae Type b Meningitis

A study was undertaken to evaluate hypertonic mannitol treatment in experimental lapin Haemophilus influenzae type b meningitis and to compare these results with those in normal rabbits. Increased intracranial pressure, brain water content, and concentrations of lactate and hypoxanthine in cerebrospinal fluid (CSF) were measured as a reflection of altered cerebral perfusion and hypoxia and potential brain injury associated with meningitis. A single dose of mannitol reduced transiently the CSF pressure of uninfected rabbits from 2.15 +/- 0.20 to 1.34 +/- 0.10 mm Hg (maximum reduction 34.9 +/- 8.4%; p less than 0.005). The time to the lowest pressure was 38.7 +/- 2.7 min after initiation of the infusion and the time to return of CSF pressure to initial values was 76.7 +/- 5.6 min. In infected mannitol-treated animals the CSF pressure was reduced from 4.78 +/- 0.53 to 2.61 +/- 0.55 mm Hg (maximum reduction 42.0 +/- 7.7%; p less than 0.005). Time to maximum pressure decrease was 44.0 +/- 5.6 min. CSF pressure returned to the initial level after 178.5 +/- 25.2 min. Four h after initiation of mannitol infusion the mean brain water content in infected mannitol-treated animals was 412 +/- 4 g H2O/100 g dry weight and in infected untreated animals it was 415 +/- 3 g H2O/100 g dry weight (p greater than 0.05). CSF lactate and hypoxanthine concentrations were significantly increased during the 20 h of meningeal inflammation (p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

The concentrations of xanthine and hypoxanthine in cerebrospinal fluid as therapeutic guides in hydrocephalus.

Xanthine, hypoxanthine, and total oxypurine levels were determined in the cerebrospinal fluid of 18 hydrocephalic patients and 8 healthy controls by high-performance liquid chromatography (HPLC). Eight of the hydrocephalic patients were self-compensated and 10 had shunts implanted during the course of the study. The mean xanthine, hypoxanthine, and total oxypurine levels in the normal children were 5.20, 5.94 and 11.29 mumol/l, respectively. In self-compensated hydrocephalics these levels were respectively 6.06, 6.50 and 12.57 mumol/l. In noncompensated hydrocephalics, they were 11.40, 10.79 and 22.19 mumol/l. The differences between the latter group and the first two are statistically significant (P less than 0.001). Fifteen days after implantation of shunts in the noncompensated hydrocephalics, the mean xanthine levels had fallen to 4.61 mumol/l, the mean hypoxanthine levels to 5.03 mumol/l, and the mean total oxypurine levels to 9.64 mumol/l. The change is statistically significant (P less than 0.001). In light of these findings we propose that xanthine, hypoxanthine, and total oxypurine levels be used in cases of hydrocephalus as guides for therapeutic action and to monitor progress.

Studies of biochemical markers in cerebrospinal fluid in patients with meningoencephalitis

Several biochemical markers in the cerebrospinal fluid (CSF) of 120 patients with serous meningoencephalitis (SM) of viral origin were compared with those of 74 patients with viral or bacterial infections accompanied by neck stiffness but no CSF abnormality (i.e., meningism). CSF adenylate kinase was higher (P less than 0.025) in SM and correlated with lactate concentration (r = 0.37; P less than 0.01). CSF hypoxanthine was lower (P less than 0.001) in SM, whereas CSF xanthine was similar in the two conditions. The xanthine/hypoxathine ratio correlated with the CSF leukocyte count (r = 0.32; P less than 0.01), and especially with the mononuclear cell count (r = 0.45; P less than 0.001). CSF adenylate kinase correlated with fever in SM (r = 0.28; P less than 0.01). CSF urate and protein displayed a mutual correlation in both conditions (r = 0.26 and P less than 0.05 for SM; r = 0.55 and P less than 0.001 for meningism). These results support the hypothesis of impaired brain cell metabolism, probably of ischemic nature, in viral meningoencephalitis, causing leakage of adenylate kinase into the CSF, where hypoxanthine may be reutilized by mononuclear leukocytes.

Increased concentration of hypoxanthine in human central cerebrospinal fluid after subarachnoid haemorrhage.

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.

Cerebrospinal fluid hypoxanthine and xanthine concentrations as indicators of metabolic damage due to raised intracranial pressure in hydrocephalic children.

Intracranial pressure and cerebrospinal fluid hypoxanthine and xanthine concentrations were measured in hydrocephalic children with suspected raised intracranial pressure. There was a highly significant correlation between intracranial pressure and cerebrospinal fluid hypoxanthine and xanthine levels.

Increased hypoxanthine concentrations in cerebrospinal fluid of infants with hydrocephalus

Hypoxanthine, the end product of purine metabolism, is usually very elevated in body fluids during severe hypoxia. We measured hypoxanthine in the cerebrospinal fluid of hydrocephalic preterm infants (12 with posthemorrhagic, one with congenital hydrocephalus) to determine whether hydrocephalus is associated with anaerobic metabolism of brain tissue. Cerebrospinal fluid hypoxanthine was undetectable in normal infants. In hydrocephalic infants, the concentration of hypoxanthine ranged from 7.5 mumol/L to 28 mumol (means = 14.3 mumol/L). The hypoxanthine concentrations fell from a mean of 12.8 mumol/L to a mean of 2.0 mumol/L (P less than 0.05) with successful treatment of the ventriculomegaly by lumbar puncture or by ventriculoperitoneal shunt. Patients with acute posthemorrhagic hydrocephalus had similar concentrations of hypoxanthine (means = 14.5 mumol/L) as patients with late or with congenital hydrocephalus (means = 13.8 mumol/L), indicating that brain hypoxia is probably a consequence of the ventriculomegaly and not of the hemorrhagic insult.

Hypoxanthine in cerebrospinal fluid in children.

In forty-five children the hypoxanthine concentration in cerebrospinal fluid (CSF) was measured (fifty-two samples). In newborn infants (nineteen patients) the hypoxanthine levels were higher in patients with clinical conditions associated with hypoxia (idiopathic respiratory distress syndrome, asphyxia, apneic attacks) than in patients without clinical hypoxia (P less than 0.01). In hypoxic patients the hypoxanthine concentration varied between 5 and 28 mu mol/l. In children outside the neonatal period the hypoxanthine concentration in CSF varied considerably in different diseases. High levels were registered in meningitis prior to treatment, febrile convulsions and in lymphoblastic leukaemia, probably reflecting tissue hypoxia and an increased tissue catabolism.

Hypoxanthine in cerebrospinal fluid in children

In forty-five children the hypoxanthine concentration in cerebrospinal fluid (CSF) was measured (fifty-two samples). In newborn infants (nineteen patients) the hypoxanthine levels were higher in patients with clinical conditions associated with hypoxia (idiopathic respiratory distress syndrome, asphyxia, apneic attacks) than in patients without clinical hypoxia (P < 0.01). In hypoxic patients the hypoxanthine concentration varied between 5 and 28 μmol/1. In children outside the neonatal period the hypoxanthine concentration in CSF varied considerably in different diseases. High levels were registered in meningitis prior to treatment, febrile convulsions and in lymphoblastic leukaemia, probably reflecting tissue hypoxia and an increased tissue catabolism.