Metabolomic Profiling of Post-Mortem Brain Reveals Changes in Amino Acid and Glucose Metabolism in Mental Illness Compared with Controls

Abstract

Metabolomic profiling was carried out on 53 post-mortem brain samples from subjects diagnosed with schizophrenia, depression, bipolar disorder (SDB), diabetes, and controls. Chromatography on a ZICpHILIC column was used with detection by Orbitrap mass spectrometry. Data extraction was carried out with m/z Mine 2.14 with metabolite searching against an in-house database. There was no clear discrimination between the controls and the SDB samples on the basis of a principal components analysis (PCA) model of 755 identified or putatively identified metabolites. Orthogonal partial least square discriminant analysis (OPLSDA) produced clear separation between 17 of the controls and 19 of the SDB samples (R2CUM 0.976, Q2 0.671, p-value of the cross-validated ANOVA score 0.0024). The most important metabolites producing discrimination were the lipophilic amino acids leucine/isoleucine, proline, methionine, phenylalanine, and tyrosine; the neurotransmitters GABA and NAAG and sugar metabolites sorbitol, gluconic acid, xylitol, ribitol, arabinotol, and erythritol. Eight samples from diabetic brains were analysed, six of which grouped with the SDB samples without compromising the model (R2 CUM 0.850, Q2 CUM 0.534, p-value for cross-validated ANOVA score 0.00087). There appears on the basis of this small sample set to be some commonality between metabolic perturbations resulting from diabetes and from SDB.

A method for the analysis of sugars in biological systems using reductive amination in combination with hydrophilic interaction chromatography and high resolution mass spectrometry

“…In addition elevated levels of a pentose were observed in the bipolar brains although not quantified. The elevated level of the pentose mirrored the elevation in the levels pentitols observed in our earlier paper [21].…”

“…Unusual sugars do occur in urine and for instance the hexose talose has been observed to be a marker of renal injury [24]. In our earlier paper we showed that post-mortem brains from subjects who had schizophrenia, depression and bipolar disorder had elevated levels of polyols in comparison to controls [21] the details of the samples are given in the earlier paper [21]. Figure 6 shows extracted ion traces for hexoses and pentoses extracted from post-mortem human brain.…”

“…Urine samples were available from a previous study [20] and were collected in this study with permission from the University ethics committee. Post-mortem brain samples were also available from a previous study [21] and were provided by from the Sudden Death Bank collection held in the MRC Edinburgh Brain and Tissue Banks. Full ethics permission has been granted to the Banks for collection of samples and distribution to approved researchers, the University of Strathclyde Ethics Committee also approved the local study of this material.…”

“…The samples were then blown to dryness in a stream of nitrogen gas and re-dissolved in 0.2 ml of water containing 0.1 % formic acid, before adding 1 ml of acetonitrile. Figure 1 shows extracted ion chromatograms obtained for underivatised glucose and galactose on a ZICpHILIC column with our standard metabolomics screening conditions [21] which uses hydrophilic interaction chromatography at pH 9.2 with ESI-MS with positive or negative ion detection. There is little chance of getting a good separation as long as all the four forms are of the sugars are present since the peaks are broad and misshapen even under the conditions used to produce the chromatograms shown in figure 1 which were obtained at a pH of 9.2.…”

Metabolomic Profiling of the Effects of Melittin on Cisplatin Resistant and Cisplatin Sensitive Ovarian Cancer Cells Using Mass Spectrometry and Biolog Microarray Technology

“…Metabolomics is a growing and powerful technology capable of detecting hundreds to thousands of metabolites in tissues and biofluids [23,24,25,26]. With recent advances in both instrumental and computational metabolomics technologies, it is now possible to gain deeper understanding of the metabolic processes occurring within cancer cells, including how they exploit the process of glycolysis.…”