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Simultaneous imaging of multiple neurotransmitters and neuroactive substances in the brain by desorption electrospray ionization mass spectrometry
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
AstraZeneca, Drug Safety & Metab, Cambridge CB4 0WG, England..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2016 (English)In: NeuroImage, ISSN 1053-8119, E-ISSN 1095-9572, Vol. 136, 129-138 p.Article in journal (Refereed) Published
Resource type
Text
Abstract [en]

With neurological processes involving multiple neurotransmitters and neuromodulators, it is important to have the ability to directly map and quantify multiple signaling molecules simultaneously in a single analysis. By utilizing a molecular-specific approach, namely desorption electrospray ionization mass spectrometry imaging (DESI-MSI), we demonstrated that the technique can be used to image multiple neurotransmitters and their metabolites (dopamine, dihydroxyphenylacetic acid, 3-methoxytyramine, serotonin, glutamate, glutamine, aspartate,gamma-aminobutyric acid, adenosine) as well as neuroactive drugs (amphetamine, sibutramine, fluvoxamine) and drug metabolites in situ directly in brain tissue sections. The use of both positive and negative ionization modes increased the number of identified molecular targets. Chemical derivatization by charge-tagging the primary amines of molecules significantly increased the sensitivity, enabling the detection of low abundant neurotransmitters and other neuroactive substances previously undetectable by MSI. The sensitivity of the imaging approach of neurochemicals has a great potential in many diverse applications in fields such as neuroscience, pharmacology, drug discovery, neurochemistry, and medicine.

Place, publisher, year, edition, pages
2016. Vol. 136, 129-138 p.
Keyword [en]
Neurotransmitter, Dopamine, Imaging, Mass spectrometry, Parkinson's disease, Serotonin
National Category
Neurology Radiology, Nuclear Medicine and Medical Imaging
Identifiers
URN: urn:nbn:se:uu:diva-299698DOI: 10.1016/j.neuroimage.2016.05.004ISI: 000378048000012PubMedID: 27155126OAI: oai:DiVA.org:uu-299698DiVA: diva2:950048
Funder
Swedish Research Council, 2013-3105 2014-6215 2009-6050The Swedish Brain FoundationSwedish Foundation for Strategic Research , RIF14-0078EU, FP7, Seventh Framework Programme, 607517
Available from: 2016-07-27 Created: 2016-07-26 Last updated: 2017-08-19Bibliographically approved
In thesis
1. Development and Application of Software Tools for Mass Spectrometry Imaging
Open this publication in new window or tab >>Development and Application of Software Tools for Mass Spectrometry Imaging
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mass spectrometry imaging (MSI) has been extensively used to produce qualitative maps of distributions of proteins, peptides, lipids, neurotransmitters, small molecule pharmaceuticals and their metabolites directly in biological tissue sections. Moreover, during the last 10 years, there has been growing demand to quantify target compounds in tissue sections of various organs. This thesis focuses on development and application of a novel instrument- and manufacturer-independent MSI software suite, msIQuant, in the open access format imzML, which has been developed specifically for quantitative analysis of MSI data. The functionality of msIQuant facilitates automatic generation of calibration curves from series of standards that can be used to determine concentrations of specific analytes. In addition, it provides many tools for image visualization, including modules enabling multiple interpolation, low intensity transparency display, and image fusion and sharpening. Moreover, algorithms and advanced data management modules in msIQuant facilitate management of the large datasets generated following rapid recent increases in the mass and spatial resolutions of MSI instruments, by using spectra transposition and data entropy reduction (at four selectable levels: coarse, medium, fine or superfine) before lossless compression of the data. As described in the thesis, implementation of msIQuant has been exemplified in both quantitative (relative or absolute) and qualitative analyses of distributions of neurotransmitters, endogenous substances and pharmaceutical drugs in brain tissue sections. Our laboratory have developed a molecular-specific approach for the simultaneous imaging and quantitation of multiple neurotransmitters, precursors, and metabolites, such as tyrosine, tryptamine, tyramine, phenethylamine, dopamine, 3-methoxytyramine, serotonin, gamma-aminobutyric acid (GABA), and acetylcholine, in histological tissue sections at high spatial resolution by matrix-assisted laser desorption ionization (MALDI) and desorption electrospray ionization (DESI) MSI. Chemical derivatization by charge-tagging primary amines of analytes significantly increased the sensitivity, enabling mapping of neurotransmitters that were not previously detectable by MSI. The two MSI approaches have been used to directly measure changes in neurotransmitter levels in specific brain structures in animal disease models, which facilitates understanding of biochemical mechanisms of drug treatments. In summary, msIQuant software has proven potency (particularly in combination with the reported derivatization technique) for both qualitative and quantitative analyses. Further developments will enable its implementation in multiple operating system platforms and use for statistical analysis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 66 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 234
Keyword
mass spectrometry imaging, MALDI, DESI, msIQuant, quantitation, neurotransmitters, drugs, derivatization, brain, compression, data entropy reduction
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-328016 (URN)978-91-513-0040-5 (ISBN)
Public defence
2017-10-06, A1:111a, BMC, Husargatan 3, Uppsala, 09:15 (English)
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Supervisors
Available from: 2017-09-13 Created: 2017-08-19 Last updated: 2017-10-17

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Shariatgorji, MohammadrezaNilsson, AnnaKallbäck, PatrikVallianatou, TheodosiaAndrén, Per E.
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