Profiling of Cerebrospinal Fluid Lipids and Their Relationship with Plasma Lipids in Healthy Humans.
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ABSTRACT:
SUBMITTER: Saito K
PROVIDER: S-EPMC8146161 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:AimsChanges in serotonergic sensory modulation associated with overexpression of 5-HT3 receptors in the central nervous system (CNS) have been implicated in the pathophysiology of neuropathic pain after peripheral nerve damage. 5-HT3 receptor antagonists such as ondansetron can potentially alleviate neuropathic pain, but have limited effectiveness, due potentially to limited CNS access. However, there is currently limited information on CNS disposition of systemically-administered 5-HT3 receptor antagonists. This study evaluated the cerebrospinal fluid (CSF) disposition of ondansetron, as a surrogate of CNS penetration.MethodsFifteen patients were given a single 16 mg intravenous 15 minute infusion of ondansetron, followed by serial blood and a single CSF sampling. Population pharmacokinetic (PK) modelling was implemented to describe the average and individual plasma and CSF profiles of ondansetron. A two-compartmental model was used to capture ondansetron plasma PK with a single CSF compartment to describe distribution to the CNS.ResultsThe individual model-estimated CSF to plasma partition coefficients of ondansetron were between 0.09 and 0.20. These values were mirrored in the calculated CSF penetration ratios, ranging from 0.08 to 0.26.ConclusionsAfter intravenous administration, CSF concentrations of ondansetron were approximately 7-fold lower than those observed in the plasma. A model could be developed to describe individual CSF concentration-time profiles of ondansetron based on a single CSF data point. The low CSF penetration of ondansetron may explain its limited analgesic effectiveness, and affords an opportunity to explore enhancing its CNS penetration for targeting conditions such as neuropathic pain.
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Project description:BackgroundRecent technical advances in the extraction of dermal interstitial fluid (ISF) have stimulated interest in using this rather unexploited biofluid as an alternative to blood for detection and prediction of disease. However, knowledge about the presence of useful biomarkers for health monitoring in ISF is still limited. In this study, we characterized the lipidome of human suction blister fluid (SBF) as a surrogate for pure ISF and compared it to that of plasma.MethodsPlasma and SBF samples were obtained from 18 healthy human volunteers after an overnight fast. Total lipids were extracted and analyzed by liquid chromatography-tandem mass spectrometry. One hundred ninety-three lipid species covering 10 complex lipid classes were detected and quantified in both plasma and SBF using multiple reaction monitoring. A fraction of the lipid extract was subjected to alkaline transesterification and fatty acid methyl esters were analyzed by gas chromatography-mass spectrometry.ResultsThe total concentration of lipids in SBF was 17% of the plasma lipid concentration. The molar fraction of lipid species within lipid classes, as well as total fatty acids, showed a generally high correlation between plasma and SBF. However, SBF had larger fractions of lysophospholipids and diglycerides relative to plasma, and consequently less diacylphospholipids and triglycerides. Principal component analysis revealed that the interindividual variation in SBF lipid profiles was considerably larger than the within-subject variation between plasma and SBF.ConclusionsPlasma and SBF lipid profiles show high correlation and SBF could be used interchangeably with blood for the analysis of major lipids used in health monitoring.
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Project description:BackgroundLipids are a primary storage form of energy and the source of inflammatory and pain signaling molecules, yet knowledge of their importance in chronic migraine (CM) pathology is incomplete. We aim to determine if plasma and cerebrospinal fluid (CSF) lipid metabolism are associated with CM pathology.MethodsWe obtained plasma and CSF from healthy controls (CT, n = 10) or CM subjects (n = 15) diagnosed using the International Headache Society criteria. We measured unesterified fatty acid (UFA) and esterified fatty acids (EFAs) using gas chromatography-mass spectrometry. Glycerophospholipids (GP) and sphingolipid (SP) levels were determined using LC-MS/MS, and phospholipase A2 (PLA2) activity was determined using fluorescent substrates.ResultsUnesterified fatty acid levels were significantly higher in CM plasma but not in CSF. Unesterified levels of five saturated fatty acids (SAFAs), eight monounsaturated fatty acids (MUFAs), five ω-3 polyunsaturated fatty acids (PUFAs), and five ω-6 PUFAs are higher in CM plasma. Esterified levels of three SAFAs, eight MUFAs, five ω-3 PUFAs, and three ω-6 PUFAs, are higher in CM plasma. The ratios C20:4n-6/homo-γ-C20:3n-6 representative of delta-5-desaturases (D5D) and the elongase ratio are lower in esterified and unesterified CM plasma, respectively. In the CSF, the esterified D5D index is lower in CM. While PLA2 activity was similar, the plasma UFA to EFA ratio is higher in CM. Of all plasma GP/SPs detected, only ceramide levels are lower (p = 0.0003) in CM (0.26 ± 0.07%) compared to CT (0.48 ± 0.06%). The GP/SP proportion of platelet-activating factor (PAF) is significantly lower in CM CSF.ConclusionsPlasma and CSF lipid changes are consistent with abnormal lipid metabolism in CM. Since plasma UFAs correspond to diet or adipose tissue levels, higher plasma fatty acids and UFA/EFA ratios suggest enhanced adipose lipolysis in CM. Differences in plasma and CSF desaturases and elongases suggest altered lipid metabolism in CM. A lower plasma ceramide level suggests reduced de novo synthesis or reduced sphingomyelin hydrolysis. Changes in CSF PAF suggest differences in brain lipid signaling pathways in CM. Together, this pilot study shows lipid metabolic abnormality in CM corresponding to altered energy homeostasis. We propose that controlling plasma lipolysis, desaturases, elongases, and lipid signaling pathways may relieve CM symptoms.
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Project description:Background:Cerebrospinal fluid (CSF) is an important source of potential biomarkers that affect the brain. Biomarkers for neurodegenerative disorders are needed to assist in diagnosis, monitoring disease progression and evaluating efficacy of therapies. Recent studies have demonstrated the involvement of tyrosine kinases in neuronal cell death. Thus, neurodegeneration in the brain is related to altered tyrosine phosphorylation of proteins in the brain and identification of abnormally phosphorylated tyrosine peptides in CSF has the potential to ascertain candidate biomarkers for neurodegenerative disorders. Methods:In this study, we used an antibody-based tyrosine phosphopeptide enrichment method coupled with high resolution Orbitrap Fusion Tribrid Lumos Fourier transform mass spectrometer to catalog tyrosine phosphorylated peptides from cerebrospinal fluid. The subset of identified tyrosine phosphorylated peptides was also validated using parallel reaction monitoring (PRM)-based targeted approach. Results:To date, there are no published studies on global profiling of phosphotyrosine modifications of CSF proteins. We carried out phosphotyrosine profiling of CSF using an anti-phosphotyrosine antibody-based enrichment and analysis using high resolution Orbitrap Fusion Lumos mass spectrometer. We identified 111 phosphotyrosine peptides mapping to 66 proteins, which included 24 proteins which have not been identified in CSF previously. We then validated a set of 5 tyrosine phosphorylated peptides in an independent set of CSF samples from cognitively normal subjects, using a PRM-based targeted approach. Conclusions:The findings from this deep phosphotyrosine profiling of CSF samples have the potential to identify novel disease-related phosphotyrosine-containing peptides in CSF.
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2022-03-04 | GSE189919 | GEO