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Analytical and Bioanalytical Chemistry

, Volume 411, Issue 2, pp 353–365 | Cite as

Spatial and molecular changes of mouse brain metabolism in response to immunomodulatory treatment with teriflunomide as visualized by MALDI-MSI

  • Ignacy Rzagalinski
  • Nadine Hainz
  • Carola Meier
  • Thomas Tschernig
  • Dietrich A. VolmerEmail author
Research Paper

Abstract

Multiple sclerosis (MS) is an immune-mediated neurodegenerative disease of the central nervous system (CNS). One of the most promising recent medications for MS is teriflunomide. Its primary mechanism of action is linked to effects on the peripheral immune system by inhibiting dihydroorotate dehydrogenase (DHODH)-catalyzed de novo pyrimidine synthesis and reducing the expansion of lymphocytes in the peripheral immune system. Some in vitro studies suggested, however, that it can also have a direct effect on the CNS compartment. This potential alternative mode of action depends on the drug’s capacity to traverse the blood-brain barrier (BBB) and to exert an effect on the complex network of brain biochemical pathways. In this paper, we demonstrate the application of high-resolution/high-accuracy matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometry for molecular imaging of the mouse brain coronal sections from animals treated with teriflunomide. Specifically, in order to assess the effect of teriflunomide on the mouse CNS compartment, we investigated the feasibility of teriflunomide to traverse the BBB. Secondly, we systematically evaluated the spatial and semi-quantitative brain metabolic profiles of 24 different endogenous compounds after 4-day teriflunomide administration. Even though the drug was not detected in the examined cerebral sections (despite the high detection sensitivity of the developed method), in-depth study of the endogenous metabolic compartment revealed noticeable alterations as a result of teriflunomide administration compared to the control animals. The observed differences, particularly for purine and pyrimidine nucleotides as well as for glutathione and carbohydrate metabolism intermediates, shed some light on the potential impact of teriflunomide on the mouse brain metabolic networks.

Graphical Abstract

Keywords

Mass spectrometry imaging MALDI FTICR Teriflunomide Multiple sclerosis Metabolomic imaging 

Notes

Acknowledgments

D.A.V. acknowledges research support by the German Research Foundation (FTICR-MS Facility, INST 256/356-1). The authors thank Alexander Grißmer and Alina Mattheis (Dept. of Anatomy and Cell Biology, Saarland University) for the expert technical assistance.

Compliance with ethical standards

All animal experiments were performed in accordance with international regulations and permission from the local research ethics committee (Landesamt für Verbraucherschutz Saarland, TVV 23/2015).

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

216_2018_1444_MOESM1_ESM.pdf (301 kb)
ESM 1 (PDF 301 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Ignacy Rzagalinski
    • 1
  • Nadine Hainz
    • 2
  • Carola Meier
    • 2
  • Thomas Tschernig
    • 2
  • Dietrich A. Volmer
    • 3
    Email author
  1. 1.Institute of Bioanalytical ChemistrySaarland UniversitySaarbrückenGermany
  2. 2.Institute of Anatomy and Cell BiologySaarland UniversityHomburgGermany
  3. 3.Department of ChemistryHumboldt University of BerlinBerlinGermany

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