Cisternal Cerebrospinal Fluid Levels Research Articles

Peripheral and central neurochemical effects of the selective serotonin reuptake inhibitors (SSRIs) in humans and nonhuman primates: assessing bioeffect and mechanisms of action

It is clear that selective serotonin reuptake inhibitors (SSRIs) act powerfully to inhibit serotonin (5-hydroxytryptamine, 5-HT) uptake centrally and peripherally. However, there are a number of critical unanswered questions concerning the effects of the drugs in adults and children. The influence of age and duration of treatment on the extent of uptake inhibition and on the enhancement of central serotonergic functioning are unclear. In addition, the relationship of these factors and effects to the therapeutic and adverse effects of the SSRIs remain to be clarified. The general clinical utility of platelet 5-HT measurement is reviewed and studies assessing central and peripheral uptake blockade in infants and children and non-human primates are discussed. Recent investigations of central neurochemical effects of the SSRIs in primates assessed through measurement of 5-HT and related compounds in cisternal cerebrospinal fluid (CSF) of the rhesus monkey are presented. In summary, the studies described have found that: human fetal exposure to SSRIs has substantial effects on 5-HT transport in utero; exposure to SSRIs through breastmilk of mothers treated for postpartum depression usually has negligible effects on 5-HT uptake; prescribed SSRIs appear to exert similar effects on 5-HT transporter blockade in children and adults; and rapid and sustained increases are seen in monkey cisternal CSF levels of 5-HT upon initiation of SSRI administration. The implications of the observations in terms of behavioral effects, clinical practice, and underlying mechanisms of action of the SSRIs are discussed.

Serum and urine nitrate and nitrite are not reliable indicators of intrathecal nitric oxide production in acute brain injury

This study examined the correlation between nitric oxide (NO) metabolites in the three major body fluid compartments and assessed performance of newly described vanadium-based assay for simultaneous detection of nitrite and nitrate (NO x ) in human samples. Vanadium reduces nitrate to nitrite, which can be measured after a colorimetric reaction with Griess reagents. Cisternal cerebro spinal fluid (CSF), serum and urine samples from 10 patients with acute brain injury (ABI) were compared to control subjects. Significantly higher CSF NO x levels were found in brain injury patients compared to control patients (19.7±13.7 vs. 6.5±2.3 μM; p=0.01), which persisted for 10-day period of observation. The serum and urine levels of NO x on admission were not statistically different (42.8±28.2 μM; 584.1±337.8 μmol/g Cr, respectively) from controls (36.8±14.8 μM; 819.7±356.0 μmol/g Cr), but tended to decrease during the disease course reaching the lowest level on day 6 (serum: 19.3±8.4 μM, urine: 300.4±111.9 μmol/g Cr). CSF levels of NO x correlated moderately with those in serum ( p=0.001, R=0.5). Serum NO x concentrations correlated weakly with urine levels ( p=0.04, R=0.3). There was no significant correlation between CSF NO x and urine NO x levels. In conclusion, patients suffering brain injury had increased NO x concentrations in CSF, which remained independent from other body fluid compartments. Serum and urinary NO x levels cannot be used as a reliable index to assess intrathecal NO production.

Acute Decreases in Cerebrospinal Fluid Glutathione Levels after Intracerebroventricular Morphine for Cancer Pain

Intracerebroventricular (ICV) morphine administration is effective for the management of refractory cancer pain. Recent preclinical observations of acute depletion of the major endogenous intracellular antioxidant glutathione (GSH) in brain and peripheral organs after ICV morphine in rodents led us to apply microchemical methods to profile the neurochemical effects of ICV morphine in three patients treated for intractable cancer pain. Assessment of morphine, morphine-6-glucuronide, and a panel of endogenous compounds and metabolites in ventricular and cisternal cerebrospinal fluid (CSF) demonstrated transient, postdose increases in morphine and morphine-6-glucuronide in ventricular and cisternal CSF, accompanied by acute decreases in CSF GSH levels. Significant changes were also observed in the CSF levels of 4-hydroxybenzoic acid, homovanillic acid, 5-hydroxyphenyllactic acid, and uric acid. These pilot clinical observations of acute central GSH depletion after ICV morphine suggest a novel mechanism for neuropsychiatric toxicity or preclinical findings, such as hyperalgesia or increased motoric activity observed in nonhuman species after central morphine administration. Because ICV morphine is a mainstay of treatment for refractory cancer pain, elucidation of a mechanism's (or mechanisms') mediating a potential pro-oxidant state in the central nervous system induced by ICV morphine is important. Implications We observed acute decreases in glutathione levels in cerebrospinal fluid sampled from patients after intracerebroventricular doses of morphine for intractable cancer pain. Such doses may, by depleting the antioxidant glutathione, render the central nervous system vulnerable to damage from oxidative stress.

Acute Decreases in Cerebrospinal Fluid Glutathione Levels after Intracerebroventricular Morphine for Cancer Pain

Intracerebroventricular (ICV) morphine administration is effective for the management of refractory cancer pain. Recent preclinical observations of acute depletion of the major endogenous intracellular antioxidant glutathione (GSH) in brain and peripheral organs after ICV morphine in rodents led us to apply microchemical methods to profile the neurochemical effects of ICV morphine in three patients treated for intractable cancer pain. Assessment of morphine, morphine-6-glucuronide, and a panel of endogenous compounds and metabolites in ventricular and cisternal cerebrospinal fluid (CSF) demonstrated transient, postdose increases in morphine and morphine-6-glucuronide in ventricular and cistemal CSF, accompanied by acute decreases in CSF GSH levels. Significant changes were also observed in the CSF levels of 4-hydroxybenzoic acid, homovanillic acid, 5-hydroxyphenyllactic acid, and uric acid. These pilot clinical observations of acute central GSH depletion after ICV morphine suggest a novel mechanism for neuropsychiatric toxicity or preclinical findings, such as hyperalgesia or increased motoric activity observed in nonhuman species after central morphine administration. Because ICV morphine is a mainstay of treatment for refractory cancer pain, elucidation of a mechanism's (or mechanisms') mediating a potential pro-oxidant state in the central nervous system induced by ICV morphine is important. We observed acute decreases in glutathione levels in cerebrospinal fluid sampled from patients after intracerebroventricular doses of morphine for intractable cancer pain. Such doses may, by depleting the antioxidant glutathione, render the central nervous system vulnerable to damage from oxidative stress.

Plasma- and cerebrospinal fluid-immunoreactive endothelin-1: effects of nonpeptide endothelin receptor antagonists with diverse affinity profiles for endothelin-A and endothelin-B receptors.

Some endothelin (ET) receptor antagonists have been reported to elevate plasma immunoreactive endothelin-1 (irET-1). However, there is no information regarding the effects of ET receptor antagonists on cerebrospinal fluid (CSF) levels. To better understand the regulation of circulating and CSF ET-1, the effects of several nonpeptide antagonists with high, intermediate, or low affinity at the ETB receptor, as well as the potent ETB selective agonist sarafotoxin 6c (S6c), were characterized and compared. The effects of SB209670 (Ki ETA = 0.2 nM; Ki ETB = 12 nM), SB217242 (Ki ETA = 1.1 nM; Ki ETB = 111 nM), SB234551 (Ki ETA = 0.1 nM; Ki ETB = 500 nM), SB247083 (Ki ETA = 0.4 nM; Ki ETB = 467 nM), and S6c (Ki ETA = 950 nM; Ki ETB = 1 nM) on plasma irET-1 were determined by ELISA in the anesthetized dog after i.v. administration. Systemic administration of equivalent doses of the nonpeptide ET receptor antagonists produced dose-related elevations in plasma irET-1 which were correlated (p = 0.019) with affinity at the ETB receptor. There was no significant correlation with affinity at the ETA receptor. In addition, the plasma irET-1 and ET antagonist concentrations were linearly correlated (r = 0.98) throughout the time course after antagonist administration. There was no evidence of densensitization after three bolus administrations performed at 2-h intervals (SB209670, 1 and 3 mg/kg i.v.). Elevations in plasma irET-1 (four- to fivefold) were also observed after systemic administration of S6c (1 nmol/kg i.v.). The administration of L-NAME (200 micrograms/kg/min for 30 min), an inhibitor of nitric oxide (NO) synthase, increased blood pressure (33%) but did not alter plasma irET-1. In contrast, systemic administration of the ET receptor antagonists had little or no effect on the on irET-1 in the CSF. However, intracerebroventricular (i.c.v.) administration of SB209670 produced a dose-related (3-100 micrograms) increase in cisternal CSF levels of irET-1 without altering plasma irET-1. Systemic administration of ETB receptor antagonists and agonists rapidly increased plasma irET-1. These ETB receptor antagonist effects correlate linearly with affinity at the cloned human ETB receptor, do not exhibit desensitization, and do not appear to reflect inhibition of ETB-mediated NO production. The endothelial ETB receptor may represent a high-capacity storage/clearance site for circulating ET-1. ET receptor antagonists may also act extravascularly/abluminally to increase irET-1 in the CNS.

Platelet derived growth factor and subarachnoid haemorrhage: a study on cisternal cerebrospinal fluid.

Platelet derived growth factor (PDGF) was identified as a powerful mitogenic growth factor which is released from activated platelets and has a marked activity as vasoconstrictor agent. In the present study we have measured cisternal cerebrospinal fluid (CSF) levels of PDGF in 72 patients operated on for intracranial aneurysm in order to verify whether it might be related to the clinical aspects of SAH with special regard to symptomatic vasospasm. CSF samples were obtained at surgery by cisternal puncture of the subarachnoid cistern the nearest to the aneurysm before aneurysm isolation and exclusion. The specimen were frozen in liquid nitrogen and stored at -80 degrees C until analysis. PDGF was measured using a commercially available reagent. Values are expressed as pg/ml of CSF. In 18 cases no radiological and clinical signs of SAH were detected and the mean cisternal CSF level of PDGF was 885.0 +/- 104.5 pg/ml; 20 patients were operated on between day 1 and 3 from the last SAH episode: mean cisternal CSF level of PDGF was 1917.5 +/- 459.4 pg/ml. In 34 patients treated with delayed surgery protocol, mean cisternal CSF level of PDGF was 995.3 +/- 73.8 pg/ml. Statistical analysis showed significant differences between groups (P: 0.011). In the subgroup of patients operated on within day 3 after SAH, 6 presented vasospasm and had mean cisternal CSF PDGF level which was significantly higher (P < 0.01) than in 14 patients without vasospasm. In the delayed "surgical" patients there was no significant difference in cisternal CSF levels of PDGF considering the occurrence of vasospasm. The results of the present study suggest that (a) after SAH there is a significant release of PDGF early after SAH and (b) higher levels of PDGF found in cisternal CSF of patients operated on within 72 hours after SAH may be predictive of symptomatic vasospasm.

CSF leukotriene C4 following subarachnoid hemorrhage.

Leukotrienes derive from arachidonic acid metabolism via the lipoxygenase pathway and modulate several cellular events. In the central nervous system, leukotrienes are mainly synthesized in the gray matter and in vascular tissues. Their production is enhanced in ischemic conditions and in experimental subarachnoid hemorrhage (SAH). Previous studies have indicated the ability of the leukotrienes C4 and D4 to constrict arterial vessels in vivo and in vitro and have suggested their involvement in the pathogenesis of cerebral arterial spasm. In the present study, the authors measured lumbar and cisternal cerebrospinal fluid (CSF) levels of leukotriene C4 in 48 patients who had suffered aneurysmal SAH. In 12 of the cases, symptomatic and radiological spasm was evident. The mean lumbar CSF level of immunoreactive-like activity of leukotriene C4 (i-LTC4) was significantly higher (p less than 0.005) than in control cases, while the cisternal CSF level was higher than the lumbar mean concentration (p less than 0.005). Patients presenting with vasospasm had significantly higher levels of i-LTC4 compared to patients without symptomatic vasospasm. This is the first report concerning monitoring of i-LTC4 levels in the CSF after SAH. The results of this study suggest that: 1) metabolism of arachidonic acid via the lipoxygenase pathway is enhanced after SAH; 2) the higher cisternal CSF levels of i-LTC4 may be part of the biological response in the perianeurysmal subarachnoid cisterns after the hemorrhage; and 3) the higher CSF levels of i-LTC4 in patients presenting with vasospasm suggest that a relationship exists between this compound and arterial spasm and/or reflect the development of cerebral ischemic damage.

Cisternal and lumbar CSF levels of arachidonate metabolites after subarachnoid haemorrhage: an assessment of the biochemical hypothesis of vasospasm.

Several naturally occurring compounds have been identified in human cerebrospinal fluid (CSF) after subarachnoid haemorrhage (SAH) as possible vasoactive agents involved in the biochemical mechanism of vasospasm. The authors have measured, in 30 patients admitted for SAH, CSF concentrations of two arachidonic acid metabolites. Prostacyclin and Prostaglandin D2, as representative of vasodilator and vasoconstrictor compounds. CSF samples were made available by lumbar punctures and intraoperative cisternal punctures. Nine patients presented with symptomatic vasospasm: lumbar CSF Prostaglandin D2 levels are significantly higher than in patients without vasospasm. The Cisternal Prostaglandin D2 level is significantly higher than the lumbar CSF concentration; CSF Prostacyclin levels do not significantly differ in the two groups of patients. These data suggest the presence of an imbalanced biochemical situation responsible for promoting vasospasm. The evaluation of cisternal levels of arachidonate metabolites support the hypothesis of the clotting phenomenon around the ruptured aneurysm wall as an important predictive pattern of vasospasm onset after SAH, as shown in computed tomography.

The role of endogenous opioids in the ventilatory response to acute flow-resistive loads.

The ability of acute, short-term, inspiratory flow-resistive loading to generate endogenous opioids was studied in 6 unanesthetized goats. Endogenous opioid generation was assessed by measurement of immunoreactive beta-endorphin levels in the cisternal cerebrospinal fluid (CSF) after high (80 cm H2O/L/s) and moderate (50 cm H2O/L/s) resistive loading. The results show that CSF levels of beta-endorphin were significantly increased by both the high and moderate resistive loads (40 +/- 4 SEM pg/ml and 33.7 +/- 3.4 pg/ml, respectively) when compared with the same animals during unloaded control conditions (19.5 +/- 3.8 pg/ml). Both levels of loading also caused a significant progressive decline in tidal volume (to 82 +/- 8 and 89 +/- 8% of baseline tidal volume with the high and moderate loads, respectively). Naloxone administration (0.1 mg/kg) resulted in a transient but significant increase in tidal volume from the sixth through the twentieth minute (to 37 +/- 5 and 34 +/- 5% peak tidal volume increase with high and moderate loads, respectively). In addition, there was a significant correlation between the percent decline in tidal volume and mean inspiratory flow rate after loading and the level of beta-endorphin in the cisternal CSF. We conclude that relatively short-term, high-level, inspiratory flow-resistive loading results in elaboration of endogenous opioids within the central nervous system and that these opioids play a role in the progressive decline in tidal volume and mean inspiratory flow rate exhibited during these conditions.

Changes in the concentration of somatostatin and Substance P in the cerebrospinal fluid following injection of alcohol into the pituitary gland

The concentration of immunoreactive somatostatin and Substance P in the cisternal cerebrospinal fluid (CSF) of patients with pain due to malignant disease has been measured before and after injection of alcohol into the pituitary fossa. Following the first injection, a rise of 108 ± 66% in CSF somatostatin levels was observed in 7 out of 13 patients, and a rise of 87 ± 26% in 4 out of the 5 patients undergoing a second injection. A rise of 179 ± 99% in levels of Substance P in CSF was observed in 4 out of 8 patients after a single injection. No change in peptide concentration was detected in peripheral plasma. Changes in CSF levels did not correlate with the degree of pain relief obtained, but patients with the greatest increase in somatostatin subsequently developed diabetes insipidus. The data are consistent with our previous experience that injection of alcohol into the pituitary fossa can cause destruction to nervous tissue, in addition to the obvious destruction of pituitary gland tissue. They do not support the suggestion that hypothalamic damage is necessary in order to obtain pain relief.

Effects of diazepam on sleep, temperature, 5-hydroxyindoleacetic and homovanillic acids in cisternal cerebrospinal fluid of cats.

The effects of diazepam (DZ) (0.3--1.5 mg/kg, i.p.) on sleep, cisternal cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA), and rectal temperature of cats were examined. The results showed that administration of DZ produced a significant increase (p = 0.02) in slow-wave sleep (SWS) with a peak occurring at a dose of 0.9 mg/kg. Further increase in doses of DZ decreased SWS. DZ administration produced no change in paradoxical sleep, rectal temperature, 5-HIAA or HVA CSF levels. Lack of correlation between various doses of DZ, and 5-HIAA or HVA concentrations in the presence of an increased percentage of SWS suggests a possible mode of DZ action mediated through a mechanism independent of monoamines. Usually monoamines are associated with normal sleep.

Cyclic AMP in cerebrospinal fluid: Accumulation following probenecid and biogenic amines

Levels of cyclic AMP in rabbit cisternal cerebrospinal fluid (CSF) was determined under a number of conditions. Cyclic AMP in CSF was increased by probenecid (intraperitoneally); this increase was not influenced by tricyclic antidepressant drugs, haloperidol, isoprenaline or L-DOPA. Cyclic AMP, administered intravenously, did not penetrate into CSF. Intracisternally introduced noradrenaline, isoprenaline, dopamine, histamine, and intravenously injected isoprenaline all increased the CSF levels of cyclic AMP. The results indicate that cyclic AMP in the CSF is of central origin and is eliminated by a probenecid sensitive transport mechanism. Because of the effects of biogenic amines, there seems to be a close relationship between cyclic AMP of brain tissue and of CSF. Central beta-adrenergic receptors may be measured in the intact animal by measuring the release of the nucleotide into CSF after intravenously isoprenaline. This observation may lead to a clinical applicable test for measuring properties of central adrenergic receptors.