Compounds In Cerebrospinal Fluid Research Articles

Metabolic profiling of aromatic compounds in cerebrospinal fluid of neurosurgical patients using microextraction by packed sorbent and liquid-liquid extraction with gas chromatography-mass spectrometry analysis.

A new approach to the quantitative analysis of aromatic metabolites in cerebrospinal fluid samples of neurosurgical patients based on microextraction by packed sorbent coupled with derivatization and GC-MS was developed. Analytical characteristics such as recoveries (40-90%), limit of detection (0.1-0.3 μm) and limit of quantitation (0.4-0.7 μm) values, accuracy (<±20%), precision (<20%) and linear correlations (R2 ≥ 0.99) over a 0.4-10 μm range of concentrations demonstrated that microextraction by packed sorbent provides results for the quantitative analysis of target compounds comparable with those for liquid-liquid extraction. Similar results were achieved using 40 μl of sample for microextraction by packed sorbent instead of 200 μl for liquid-liquid extraction. Benzoic, 3-phenylpropionic, 3-phenyllactic, 4-hydroxybenzoic, 2-(4-hydroxyphenyl)acetic, homovanillic and 3-(4-hydroxyphenyl)lactic acids were found in cerebrospinal fluid samples (n = 138) of neurosurgical patients in lower concentrations than in serum samples (n = 110) of critically ill patients. Analysis of the cerebrospinal fluid and serum samples taken at the same time from neurosurgical patients (n = 5) revealed similar results for patients without infection and multidirectional results for patients with central nervous system infection. Our preliminary results demonstrate the necessity of further evaluating the aromatic compound profile in cerebrospinal fluid for its subsequent verification for potential diagnostic markers.

Validation of a method for the determination of AMG 579 in cerebrospinal fluid with a focus on sample collection procedures for clinical trials

Analysis of pharmaceutical compounds in cerebrospinal fluid (CSF) may present challenges due to the combination of the low protein content in this matrix and relatively low drug concentrations, often corresponding to free drug concentrations in plasma, typically found in CSF. A 30% loss of AMG 579 was observed during preparation of quality control samples and further investigation determined that this loss was likely due to binding to collection tubes. This observation also highlighted the possibility of additional losses of AMG 579 that could occur during collection of clinical samples, such as binding to catheters used in the collection of CSF.Loss of AMG 579 in QC samples was reduced from 30% to 5% when the volume of CSF stored in 1.5mL vials was increased from 0.06mL to 1mL. Modest but unavoidable losses of about 20% of AMG 579 were also found following perfusion through both silicone and polypropylene (Pharmed® BPT) collection catheters. Silicone tubing was used for CSF collection based on clinical site preference. An LC–MS/MS method was validated to quantify AMG 579 in human CSF to support clinical testing. The original range of the assay was 1–1000ng/mL but the LLOQ was subsequently lowered to 0.1ng/mL to better meet project requirements. Interday bias (% RE) and precision (% CV) were −4.2% and 12.3% at the LLOQ, and less than ±0.9% and 8.3% for higher concentrations, respectively. The compound was stable in human CSF for at least 5h at room temperature, 55 days at −70°C (−60 to −80°C range), and through three freeze–thaw cycles.Careful selection of assay conditions and materials minimized losses of the compound during sample collection and storage. While these losses could not be entirely eliminated, practical sample collection and storage conditions were established to allow for analysis of AMG 579 in human clinical trials.

Addressing the need for biomarker liquid chromatography/mass spectrometry assays: A protocol for effective method development for the bioanalysis of endogenous compounds in cerebrospinal fluid

Research on disorders of the central nervous system (CNS) has shown that an imbalance in the levels of specific endogenous neurotransmitters may underlie certain CNS diseases. These alterations in neurotransmitter levels may provide insight into pathophysiology, but can also serve as disease and pharmacodynamic biomarkers. To measure these potential biomarkers in vivo, the relevant sample matrix is cerebrospinal fluid (CSF), which is in equilibrium with the brain's interstitial fluid and circulates through the ventricular system of the brain and spinal cord. Accurate analysis of these potential biomarkers can be challenging due to low CSF sample volume, low analyte levels, and potential interferences from other endogenous compounds. A protocol has been established for effective method development of bioanalytical assays for endogenous compounds in CSF. Database searches and standard-addition experiments are employed to qualify sample preparation and specificity of the detection thus evaluating accuracy and precision. This protocol was applied to the study of the histaminergic neurotransmitter system and the analysis of histamine and its metabolite 1-methylhistamine in rat CSF. The protocol resulted in a specific and sensitive novel method utilizing pre-column derivatization ultra high performance liquid chromatography/tandem mass spectrometry (UHPLC/MS/MS), which is also capable of separating an endogenous interfering compound, identified as taurine, from the analytes of interest.

Modulation of Anxiety Behavior by Intranasally Administered Vaccinia Virus Complement Control Protein and Curcumin in a Mouse Model of Alzheimers Disease

Widespread neuroinflammation in the central nervous system (CNS) of Alzheimer's disease (AD) patients, involving pro-inflammatory mediators such as complement components, might be responsible for AD associated behavioral symptoms such as anxiety. Vaccinia virus complement control protein (VCP) and curcumin (Cur) are the bioactive compounds of natural origin shown to inhibit the in-vitro complement activation. In order to develop complement regulatory compounds which could be delivered to the CNS by a non-invasive route, VCP, its truncated version (tVCP), and Cur were administered to Wistar rats intranasally. The distribution of these compounds in cerebrospinal fluid (CSF) was studied using an enzyme linked immunosorbent assay (ELISA), using VCP and tVCP as antigens and a modified fluorimetric method (Cur). VCP and tVCP were also detected in the olfactory lobes of the rat brain using immunohistochemical analysis. These compounds were then compared for their ability to attenuate the anxiety levels in APPswePS1δE9 mice using an elevated plus maze (EPM) apparatus. VCP treatment significantly improved the exploratory behavior and reduced the anxiety behavior in APPswePS1δE9 mice. tVCP however showed an opposite effect to VCP, whereas Cur showed no effect on the anxiety behavior of these mice. When these mice were subsequently tested for their cognitive performance in the Morris water maze (MWM), they showed tendencies to collide with the periphery of the walls of MWM. This unusual activity was termed "kissperi" behavior. This newly defined index of anxiety was comparable to the anxiety profile of the VCP and tVCP treated groups on EPM. VCP can thus be delivered to the CNS effectively via intranasal route of administration to attenuate anxiety associated with AD.

Monoamine Compounds in Cerebrospinal Fluid of Healthy Subjects Punctured without Preceding Strict Bed Rest: A Pilot Study

The interpretation of data on compounds in the lumbar cerebrospinal fluid (CSF) is limited by several confounding factors, e.g. motor activity for which strict bed rest prior to lumbar puncture is recommended for standardisation. Now we report data from 14 healthy males employing the standardised procedure except for the requirement of strict bed rest. The levels of serotonin, noradrenaline, 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid and 4-hydroxy-3-methoxyphenylglycol in the second CSF fraction (7–12 ml) were significantly higher than those in the first fraction (0–6 ml), indicating the presence of concentration gradients. 5-HIAA was negatively influenced by age and the neuraxis distance in the lying position and positively by atmospheric pressure. Storage time and atmospheric pressure contributed to the variance in dopamine. Both tyrosine, tryptophan and dopamine were linearly correlated with storage time. We also found a significant curvilinear correlation between tapping time and atmospheric pressure. On comparing with previous studies, the results support the notion that the issue of strict bed rest or not prior to lumbar puncture might have to be taken into consideration when interpreting lumbar monoamine CSF data.

Occurrence of 1,5-anhydroglucitol in human cerebrospinal fluid

Presence of an acetylizable compound was demonstrated by gas-liquid chromatography in cerebrospinal fluid, from which glucose had been removed by treatment with hexokinase. Mass spectrometry and other data suggested a 1,5-anhydroglucitol structure for the compound. The level of the compound in cerebrospinal fluid was very low in 15 of 17 patients with insulin dependent diabetes mellitus and in eight patients with an advanced form of chronic renal insufficiency. The data provide further proof that polyols play an important role in diseases with derangement of carbohydrate metabolism.

5-Hydroxyindolacetic acid and homovanillic acid in cerebrospinal fluid in manic-depressive psychosis

Cerebrospinal fluid concentrations of 5-hydroxyindoleacetic acid and homovanillic acid were determined in 37 depressed and 47 manic patients, in 30 other psychiatric patients and in 54 healthy controls. There were no differences in the concentrations of 5-hydroxyindoleacetic acid between the four groups. Manic patients had higher concentrations of homovanillic acid than the other three groups. After loading with probenecid (5 g during 50 h), which blocks the outflow of acid metabolites of monoamines from cerebrospinal fluid, the increase in 5-hydroxyindoleacetic acid levels at a second lumbar puncture was significantly smaller in the manic-depressive patients (about 20%) than in the other two groups (about 60%). The rise in the concentration of homovanillic acid was smaller in manic depressive patients (about 80%) than in the two control groups (about 200%). In a further experiment, methylperidol, a neuroleptic compound which increases the turnover rate of brain dopamine, was administered with probenecid in an attempt to accentuate the differences between the groups. Methylperidol increased the differences between the manic-depressives and the controls for homovanillic acid, and removed the differences for 5-hydroxyindoleacetic acid. These findings indicate a lower turnover rate of dopamine and 5-hydroxytryptamine in both phases of manic-depressive psychosis. — In the probenecid experiments, bipolar depressive patients had lower increases of 5-hydroxyindole acetic acid than cases of unipolar endogenous depression. Treatment with lithium, tricyclic antidepressants and various neuroleptics did not affect the concentrations of 5-hydroxyindoleacetic acid and homovanillic acid. The concentrations of these compounds in cerebrospinal fluid in subjects not premedicated at the second lumbar puncture were relatively unchanged when measured on two occasions at different time intervals.

Drug-induced changes in the concentration of 5-OR indolyl compounds in cerebrospinal fluid and caudate nucleus.

The effects of reserpine and imipramine on the concentration of indolyl compounds bearing an OR group in position 5 (5-OR indolyl compounds) in the cerebrospinal fluid and the caudate nucleus of the dog have been studied. Reserpine was shown to produce an increase in the concentration of these compounds in the cerebrospinal fluid. In the caudate nucleus reserpine produced a fall in the concentration of the basic 5-OR indolyl compounds accompanied by an equivalent increase in the concentration of acidic 5-OR indolyl compounds. No significant change in the concentration of 5-OR indolyl compounds in the cerebrospinal fluid was observed after treatment with imipramine.

Glutamine, glutamic acid, and gamma-aminobutyric acid in cerebrospinal fluids.

THE ROLES of glutamic acid and its derivatives glutamine and γ-aminobutyric acid, which are present in nerve tissue in appreciable quantities, are poorly understood. 1 It is possible that the concentrations of these compounds in cerebrospinal fluid may reflect changes in nerve tissue metabolism resulting from neurological disorders. Since available data are scanty, 2 it seemed worth while to determine the concentrations of glutamic acid and related compounds in the cerebrospinal fluid in a group of patients with various types of neurological disorders. METHODS AND MATERIAL Specimens of cerebrospinal fluid were obtained from patients in the University of Virginia Hospital undergoing pneumoencephalograms for diagnosis. Each specimen was contrifuged for removal of cellular debris and, whenever possible, was analyzed immediately for glutamic acid and glutamine. It was determined that the values obtained were not changed after overnight storage at 5 C. Glutamic acid and glutamine were determined by the procedures recommended