Depression and somatosensory evoked potentials: I. Correlations between SEP and monoamine and purine metabolites in CSF.

In 32 patients with major depressive disorders diagnosed according to Research Diagnostic Criteria (RDC), somatosensory evoked potentials elicited at four levels of tactile fingertip stimulation were recorded. Four peak-to-baseline amplitudes (P100, N140, P200, and P300) and two peak-to-trough amplitudes (P100-N140 and N140-P200) plus their amplitude/stimulus intensity slopes were selected for analysis. All 12 measures were adjusted to same sex, age, height, and weight. Values were linearly and curvilinearly correlated with adjusted levels of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5HIAA), 3-methoxy-4-hydroxyphenylglycol (MPHG), hypoxanthine, and xanthine in the cerebrospinal fluid (CSF), monoamine and purine metabolites, respectively. Significant negative linear correlations were found between the P300 amplitude and both HVA and hypoxanthine, and between the P200 slope and both 5HIAA and hypoxanthine. A significant positive correlation existed between the N140-P200 slope and 5HIAA. Curvilinear bivariate regressions demonstrated complex topologies of regression surfaces. Neither attention nor benzodiazepine medication were of significant importance in these relationships.

Adenosine release and changes in pial arteriolar diameter during transient cerebral ischemia and reperfusion.

We utilized the closed cranial window technique in the anesthetized rat to determine changes in CSF concentrations of adenosine, inosine, and hypoxanthine and pial arteriolar diameter during transient (20 min) forebrain ischemia and reperfusion. After mock CSF under the cranial window was allowed to equilibrate with cerebral interstitial fluid, endogenous adenosine concentration was found to be 0.16 +/- 0.05 microM, while inosine and hypoxanthine were 0.35 +/- 0.17 and 1.23 +/- 0.47 microM, respectively. The concentration of adenosine in CSF increased 4.2-fold during ischemia and 13.8-fold during the first 5 min of reperfusion. Inosine and hypoxanthine concentrations were also significantly increased during ischemia and reperfusion. After 1 h of reperfusion, CSF adenosine and inosine levels had decreased from peak value but remained significantly above preischemic values. In contrast, hypoxanthine remained at peak concentrations even after 60 min of reperfusion. Preischemic arteriolar diameter was 42.6 +/- 11.3 microns and was not significantly changed after 20 min of ischemia. However, during the first 5 min of reperfusion, arteriolar diameter increased significantly (p less than 0.05), coincident with peak adenosine concentrations. By 60 min of reperfusion, arteriolar diameter had returned to baseline. These results indicate that during the postischemic period, adenine nucleosides and hypoxanthine in CSF are elevated and could affect reperfusion.

The role of adenosine in the vascular adaptation of neonatal cerebral blood flow during hypotension.

This study investigated the potential role of adenosine in cerebral blood flow (CBF) regulation in the neonate during moderate and severe hypotension. Experiments were done in anesthetized, 1- to 3-day-old piglets. Regional CBF (determined by radiolabeled microsphere technique) and cerebral metabolic rate for O2 (CMRO2) were measured (a) during normotension and (b) during a 3-min period of moderate (58 +/- 9 mm Hg) or severe (36 +/- 7 mm Hg) hypotension produced by the inflation of a balloon catheter placed in the aortic root. Measurements of CBF and CMRO2 were performed successively after intracerebroventricular (i.c.v.) injections of vehicle (n = 17), the adenosine receptor blocker 8-phenyltheophylline (8-PT, 10 micrograms, n = 14), and the A2-receptor agonist 5'-N-(ethylcarboxamide)adenosine (NECA, 2 ng, n = 8). After i.c.v. administration of vehicle, none of the parameters studied was significantly altered by moderate hypotension, but severe hypotension decreased the total CBF (mean +/- SD) from 86 +/- 24 to 40 +/- 15 ml min-1 100 g-1 and CMRO2 from 3.2 +/- 0.8 to 1.8 +/- 1.0 ml min-1 100 g-1 (p less than 0.05). Administration of 8-PT did not alter these parameters during normotension, but significantly decreased CBF during moderate hypotension compared to postvehicle values (53 +/- 11 versus 81 +/- 12 ml min-1 100 g-1, p less than 0.05). This loss of autoregulation was completely reversed by NECA. During severe hypotension, 8-PT altered the CBF redistribution towards the brainstem.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in pial arteriolar diameter and CSF adenosine concentrations during hypoxia.

We measured the changes in pial arteriolar diameter and CSF concentrations of adenosine, inosine, and hypoxanthine during hypoxia in the absence and presence of topically applied dipyridamole (10(-6) M) and erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA; 10(-5) M). Closed cranial windows were implanted in halothane-anesthetized adult male Sprague-Dawley rats for the observation of the pial circulation and collection of CSF. The mean resting arteriolar diameter in mock CSF was 31.2 +/- 5.9 microns. Topically applied dipyridamole and EHNA, in combination, caused a slight but significant (p < 0.05) increase in resting arteriolar diameter (33.8 +/- 4.3 microns). With mock CSF, moderate hypoxia caused a 22.1 +/- 9.7% increase in pial vessel diameter. Topically applied dipyridamole and EHNA significantly (p < 0.01) potentiated pial arteriolar vasodilation in response to hypoxia. Moreover, the potentiating effects of dipyridamole and EHNA during hypoxia were completely abolished by theophylline (0.20 mumol/g, i.p.; p < 0.05), an adenosine receptor antagonist. Resting concentrations of adenosine, inosine, and hypoxanthine in the subwindow CSF were 0.18 +/- 0.09, 0.35 +/- 0.21, and 0.62 +/- 0.12 microM, respectively. In the absence of dipyridamole and EHNA, these levels were not affected by sustained moderate hypoxia (PaO2 = 36 +/- 6 mm Hg). However, in the presence of dipyridamole and EHNA, the concentration of adenosine in the CSF during hypoxia was significantly (p < 0.05) increased. Our data indicate that dipyridamole and EHNA potentiate hypoxic vasodilation of pial arterioles while simultaneously increasing extracellular adenosine levels, thus supporting the hypothesis that adenosine is involved in the regulation of cerebral blood flow.

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 less than 0.01, and 1.09 +/- 0.05 mmol/l, p less than 0.001, respectively) than in 11 normocalcemic reference subjects. The values correlated with serum calcium concentration (p less than 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 less than 0.05), and serum and CSF PTH were positively correlated (p less than 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.

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.

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

AIMS: To assess the rate at which premortem hypoxia occurs in sudden infant death syndrome (SIDS) when compared with death in early childhood. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Influence of adenosine on cerebral blood flow during hypoxic hypoxia in the newborn piglet.

This study investigated the role of adenosine in the regulation of neonatal cerebral blood flow (CBF) during moderate (arterial PO2 = 47 +/- 9 Torr) and severe (arterial PO2 = 25 +/- 4 Torr) hypoxia. Twenty-eight anesthetized and ventilated newborn piglets were assigned to four groups: 8 were injected intravenously with the vehicle (controls, group 1); 13 received an intravenous injection of 8-phenyltheophylline (8-PT), a potent adenosine receptor blocker, either 4 mg/kg (group 2, n = 6, mean cerebrospinal fluid (CSF) levels less than 1 mg/l) or 8 mg/kg (group 3, n = 7, mean CSF levels less than 3.5 mg/l); and 7 received an intracerebroventricular injection of 10 micrograms 8-PT (group 4). During normoxia, CBF was not altered by vehicle or 8-PT injections. In group 1, 10 min of moderate and severe hypoxia increased total CBF by 112 +/- 36 and 176 +/- 28% (SE), respectively. Compared with controls, the cerebral hyperemia during moderate hypoxia was not altered in group 2, attenuated in group 3 (to 53 +/- 13%, P = NS), and completely blocked in group 4 (P less than 0.01). CBF increase secondary to severe hypoxia was attenuated only in group 4 (74 +/- 29%, P less than 0.05). CSF concentrations of adenosine and adenosine metabolites measured by high-performance liquid chromatography increased during hypoxia. Arterial O2 content was inversely correlated (P less than 0.005) to maximal CSF levels of adenosine (r = 0.73), inosine (r = 0.87), and hypoxanthine (r = 0.80).(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in cerebrospinal fluid homovanillic acid in children with Ondine's curse.

The cerebrospinal fluid (CSF) concentrations of three acid monoamine metabolites, two purines, and a group of amino acids were determined in two children with chronic central alveolar hypoventilation (Ondine's curse). The levels of all assayed neuroactive substances, metabolites, and amino acids, with one exception, were normal compared to an age-matched group of neurologically healthy children. The levels of the dopamine metabolite homovanillic acid in the children with Ondine's curse were approximately 2.4 times higher than expected for age range. The present findings may indicate a link between central nervous system dopamine activity and chronic central alveolar hypoventilation. Among other possible explanations, the changes seen might represent a primary alteration in dopamine activity or may reflect a change in dopamine turnover resulting from the chronic hypoventilation.

Brain purinergic activity linked with depressive symptomatology: hypoxanthine and xanthine in CSF of patients with major depressive disorders.

The purine metabolites hypoxanthine and xanthine were analyzed in cerebrospinal fluid (CSF) of 70 patients with major depressive disorders (diagnosed according to Research Diagnostic Criteria) and, for reference, in 26 nonpsychiatric individuals. In the patient group, levels adjusted by analysis of covariance to same sex, age, height, and weight were univariately and multivariately correlated with both depressive subdiagnoses and individual depressive symptoms. Results indicate that raw CSF levels in depressed patients are significantly correlated with the four variables used in adjustment (for hypoxanthine mainly negatively with height; for xanthine mainly positively with age). Hypoxanthine and xanthine both appear to be linked with the expression of depressive symptomatology: lower levels of hypoxanthine are associated with anger and suicidal tendencies, and higher levels are related to memory disturbance; lower xanthine levels characterize patients with subjective feelings of depression, and in patients with higher levels appetite is poor.

Determination of rat cerebrospinal fluid concentrations of adenosine, inosine, hypoxanthine, xanthine and uric acid by high performance liquid chromatography.

Isocratic reverse-phase high performance liquid chromatography techniques were developed to resolve and quantitate the purine nucleosides adenosine (Ado) and inosine (Ino) and their metabolites hypoxanthine (Hyp), xanthine (Xan), and uric acid (UA) in the cerebrospinal fluid of the rat. The moving phase composition for resolving hypoxanthine, xanthine and uric acid was a 0.22 M, pH 5.8 phosphate buffer. The moving phase composition for resolving adenosine and inosine was a 0.22 M, pH 6.8 phosphate buffer, 7% methanol (v/v) and 2.5 mM tetrabutylammonium phosphate. The observed cerebrospinal fluid concentrations in the rat were: Ado = 35 +/- 9 nM (s.e.m.), Ino = 359 +/- 85 nM, Hyp = 243 +/- 77 nM, Xan = 1340 +/- 423 nM and UA = 6130 +/- 678 nM.

Purine metabolites in the CSF in presenile and senile dementia of Alzheimer type, and in multi infarct dementia.

Concentrations of hypoxanthine, xanthine, uric acid and creatinine were measured in CSF of patients suffering form presenile and senile dementia of Alzheimer type (PDAT, SDAT) and multi infarct dementia (MID) and in a reference group of young neurotic patients. There was no difference in hypoxanthine concentration, but there was a marked elevation of xanthine concentration in each dementia group, independent of the type of dementia. There was a significant elevation of uric acid in SDAT and MID but not in PDAT. The concentration of uric acid was higher in MID than in SDAT. There was a higher level of creatinine in the dementia groups, but no difference was seen among the dementia groups. These results are discussed in order to better interpret the etiology and the differentiated diagnosis of the types of dementia.

Hypoxanthine, xanthine, urate and creatinine concentration gradients in cerebrospinal fluid.

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.

[Purine transport through the blood-brain barrier in hypoxanthine phosphoribosyltransferase deficiency]. / Transporte de purinas a través de la barrera hematoencefálica en la deficiencia de hipoxantina fosforribosiltransferasa.

The transfer of purines through the hematoencephalic barrier is poorly understood. Allopurinol inhibits the enzyme xanthine oxidase and increases xanthine and hypoxanthine plasma levels, but it should not increase the cerebrospinal fluid (CSF) levels of these purines owing to the absence of xanthine oxidase in the central nervous system (CNS). In the present study we evaluated the plasma and CSF concentrations of uric acid, hypoxanthine, xanthine and inosine in the baseline state and after 7 days of allopurinol administration (5-10 mg/kg/24 h) in 4 patients with hypoxanthine phosphoribosyltransferase (HPRT) deficiency. The CSF uric acid level was positively correlated with its plasma level (r = 0.93, p less than 0.01). The CSF hypoxanthine and xanthine concentrations were, as a mean, 5 and 2 times higher, respectively, in patients with HPRT deficiency than in 4 control individuals. As hypoxanthine basically comes from adenine nucleotides, while xanthine comes from guanine nucleotides, this finding suggests that in the CNS of patients with HPRT deficiency there is a higher degradation level of adenine nucleotides than of guanine nucleotides. Allopurinol increased plasma concentration of hypoxanthine, xanthine and inosine 4, 10 and 3 times, respectively, in relation to baseline values. In CSF, the mean increase of hypoxanthine and xanthine concentration was 17.5 mumol and 7.7 mumol, respectively, whereas inosine level was unchanged. These results suggest that in HPRT deficiency hypoxanthine and xanthine may be transferred to the brain.

[Cerebrospinal fluid concentrations of creatinine and purine metabolites determined by high performance liquid chromatography: preliminary report on head injury and stroke patients].

A prospective high performance liquid chromatography (HPLC) study was performed in eighteen patients with head injury and stroke and four control volunteers to evaluate creatinine and purine metabolites concentration (adenosine, inosine, hypoxanthine, uric acid) in cerebrospinal fluid (CSF). The present HPLC method is rapid, accurate and sensitive in the same isocratic run and no specimen pretreatment of 0.02 ml CSF is necessary. The creatinine level in CSF was increased from 122 to 169 mumol/l in some patients, and was found unrelated to that of serum. The uric acid levels varied between 5.8 and 121 mumol/l and were associated with decrease in Glasgow Coma Scale score and had a critical point of 30 mumol/l. We present initial results in application of HPLC method to measure the creatinine and purine metabolites in CSF. This preliminary report presents that these high levels in CSF of head injury and stroke patients probably reflect tissue damage and an increased tissue catabolism.