Metabolomics of cerebrospinal fluid reveals change in the central nervous system metabolism in a rat model of multiple sclerosis.

Metabolomics (Impact Factor: 3.86). 04/2012; 8(2):253-263. DOI: 10.1007/s11306-011-0306-3
Source: PubMed

ABSTRACT Experimental Autoimmune Encephalomyelitis (EAE) is the most commonly used animal model for Multiple Sclerosis (MScl). CSF metabolomics in an acute EAE rat model was investigated using targetted LC–MS and GC–MS. Acute EAE in Lewis rats was induced by co-injection of Myelin Basic Protein with Complete Freund’s Adjuvant. CSF samples were collected at two time points: 10 days after inoculation, which was during the onset of the disease, and 14 days after inoculation, which was during the peak of the disease. The obtained metabolite profiles from the two time points of EAE development show profound differences between onset and the peak of the disease, suggesting significant changes in CNS metabolism over the course of MBP-induced neuroinflammation. Around the onset of EAE the metabolome profile shows significant decreases in arginine, alanine and branched amino acid levels, relative to controls. At the peak of the disease, significant increases in concentrations of multiple metabolites are observed, including glutamine, O-phosphoethanolamine, branched-chain amino acids and putrescine. Observed changes in metabolite levels suggest profound changes in CNS metabolism over the course of EAE. Affected pathways include nitric oxide synthesis, altered energy metabolism, polyamine synthesis and levels of endogenous antioxidants.

Electronic supplementary material
The online version of this article (doi:10.1007/s11306-011-0306-3) contains supplementary material, which is available to authorized users.

Download full-text


Available from: Rob J. Vreeken, Sep 27, 2015
27 Reads
  • Source
    • "Linear tetrapeptides were identified according their multiple-stage fragmentation after AQC derivatization [27]. Methanol (400 µL) was added to an aliquot of 100 µL fermentation broth for protein precipitation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The filamentous fungus Penicillium chrysogenum harbors an astonishing variety of nonribosomal peptide synthetase genes, which encode proteins known to produce complex bioactive metabolites from simple building blocks. Here we report a novel non-canonical tetra-modular nonribosomal peptide synthetase (NRPS) with microheterogenicity of all involved adenylation domains towards their respective substrates. By deleting the putative gene in combination with comparative metabolite profiling various unique cyclic and derived linear tetrapeptides were identified which were associated with this NRPS, including fungisporin. In combination with substrate predictions for each module, we propose a mechanism for a 'trans-acting' adenylation domain.
    PLoS ONE 06/2014; 9(6):e98212. DOI:10.1371/journal.pone.0098212 · 3.23 Impact Factor
    • "Metabonomics incorporates whole systems biochemistry and thus provides crucial information on disease processes and gene function[16], and reflects the physiological or pathological status of an organism. Metabolite changes were reported in various neurodegenerative diseases, such as multiple sclerosis[171819], Alzheimer's disease[20212223], Creutzfeldt-Jakob syndrome[2425] and Huntington's disease[2627]. Recently, Watanabe et al.[28] found that N-acetylasparate and myo-inositol concentrations in bilateral, especially left hippocampus changed in patients with amnestic mild cognitive impairment and Alzheimer's diseases. "
    [Show abstract] [Hide abstract]
    ABSTRACT: This study established an aged rat model of cognitive dysfunction using anesthesia with 2% isoflurane and 80% oxygen for 2 hours. Twenty-four hours later, Y-maze test results showed that isoflurane significantly impaired cognitive function in aged rats. Gas chromatography-mass spectrometry results showed that isoflurane also significantly increased the levels of N,N-diethylacetamide, n-ethylacetamide, aspartic acid, malic acid and arabinonic acid in the hippocampus of isoflurane-treated rats. Moreover, aspartic acid, N,N-diethylacetamide, n-ethylacetamide and malic acid concentration was positively correlated with the degree of cognitive dysfunction in the isoflurane-treated rats. It is evident that hippocampal metabolite changes are involved in the formation of cognitive dysfunction after isoflurane anesthesia. To further verify these results, this study cultured hippocampal neurons in vitro, which were then treated with aspartic acid (100 μmol/L). Results suggested that aspartic acid concentration in the hippocampus may be a biomarker for predicting the occurrence and disease progress of cognitive dysfunction.
    Neural Regeneration Research 01/2014; 9(2):143-52. DOI:10.4103/1673-5374.125343 · 0.22 Impact Factor
  • Source
    • "Targeted metabolic profiling was conducted in serum samples prepared from fasting blood samples from volunteers of the placebo and 30 mg groups of protocol 1 and from all volunteers of protocol 2. Seventeen proteinogenic amino acids (alanine, arginine, asparagine, aspartic acid, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine) and 3-methylhistidine were successfully measured in 5 μl of serum using a targeted liquid chromatography-MS/MS method adapted from [14]. Data are available upon request. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Glucocorticoids, such as prednisolone, are widely used anti-inflammatory drugs, but therapy is hampered by a broad range of metabolic side effects including skeletal muscle wasting and insulin resistance. Therefore, development of improved synthetic glucocorticoids that display similar efficacy as prednisolone but reduced side effects is an active research area. For efficient development of such new drugs, in vivo biomarkers, which can predict glucocorticoid metabolic side effects in an early stage, are needed. In this study, we aim to provide the first description of the metabolic perturbations induced by acute and therapeutic treatments with prednisolone in humans using urine metabolomics, and to derive potential biomarkers for prednisolone-induced metabolic effects. A randomized, double blind, placebo-controlled trial consisting of two protocols was conducted in healthy men. In protocol 1, volunteers received placebo (n = 11) or prednisolone (7.5 mg (n = 11), 15 mg (n = 13) or 30 mg (n = 12)) orally once daily for 15 days. In protocol 2, volunteers (n = 6) received placebo at day 0 and 75 mg prednisolone at day 1. We collected 24 h urine and serum samples at baseline (day 0), after a single dose (day 1) and after prolonged treatment (day 15) and obtained mass-spectrometry-based urine and serum metabolic profiles. At day 1, high-dose prednisolone treatment increased levels of 13 and 10 proteinogenic amino acids in urine and serum respectively, as well as levels of 3-methylhistidine, providing evidence for an early manifestation of glucocorticoid-induced muscle wasting. Prednisolone treatment also strongly increased urinary carnitine derivatives at day 1 but not at day 15, which might reflect adaptive mechanisms under prolonged treatment. Finally, urinary levels of proteinogenic amino acids at day 1 and of N-methylnicotinamide at day 15 significantly correlated with the homeostatic model assessment of insulin resistance and might represent biomarkers for prednisolone-induced insulin resistance. This study provides evidence that urinary metabolomics represents a noninvasive way of monitoring the effect of glucocorticoids on muscle protein catabolism after a single dose and can derive new biomarkers of glucocorticoid-induced insulin resistance. It might, therefore, help the development of improved synthetic glucocorticoids. Trial Registration NCT00971724
    Genome Medicine 11/2012; 4(11):94. DOI:10.1186/gm395 · 5.34 Impact Factor
Show more