Magalhaes, Daniela M;
Stewart, Nicolas A;
Mampay, Myrthe;
Rolle, Sara O;
Hall, Chloe M;
Moeendarbary, Emad;
Flint, Melanie S;
... Sheridan, Graham K; + view all
(2024)
The sphingosine 1-phosphate analogue, FTY720, modulates the lipidomic signature of the mouse hippocampus.
Journal of Neurochemistry
10.1111/jnc.16073.
(In press).
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Abstract
The small-molecule drug, FTY720 (fingolimod), is a synthetic sphingosine 1-phosphate (S1P) analogue currently used to treat relapsing-remitting multiple sclerosis in both adults and children. FTY720 can cross the blood-brain barrier (BBB) and, over time, accumulate in lipid-rich areas of the central nervous system (CNS) by incorporating into phospholipid membranes. FTY720 has been shown to enhance cell membrane fluidity, which can modulate the functions of glial cells and neuronal populations involved in regulating behaviour. Moreover, direct modulation of S1P receptor-mediated lipid signalling by FTY720 can impact homeostatic CNS physiology, including neurotransmitter release probability, the biophysical properties of synaptic membranes, ion channel and transmembrane receptor kinetics, and synaptic plasticity mechanisms. The aim of this study was to investigate how chronic FTY720 treatment alters the lipid composition of CNS tissue in adolescent mice at a key stage of brain maturation. We focused on the hippocampus, a brain region known to be important for learning, memory, and the processing of sensory and emotional stimuli. Using mass spectrometry-based lipidomics, we discovered that FTY720 increases the fatty acid chain length of hydroxy-phosphatidylcholine (PCOH) lipids in the mouse hippocampus. It also decreases PCOH monounsaturated fatty acids (MUFAs) and increases PCOH polyunsaturated fatty acids (PUFAs). A total of 99 lipid species were up-regulated in the mouse hippocampus following 3 weeks of oral FTY720 exposure, whereas only 3 lipid species were down-regulated. FTY720 also modulated anxiety-like behaviours in young mice but did not affect spatial learning or memory formation. Our study presents a comprehensive overview of the lipid classes and lipid species that are altered in the hippocampus following chronic FTY720 exposure and provides novel insight into cellular and molecular mechanisms that may underlie the therapeutic or adverse effects of FTY720 in the central nervous system.
| Type: | Article |
|---|---|
| Title: | The sphingosine 1-phosphate analogue, FTY720, modulates the lipidomic signature of the mouse hippocampus |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/jnc.16073 |
| Publisher version: | http://dx.doi.org/10.1111/jnc.16073 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Neurosciences, Neurosciences & Neurology, forced swim test, FTY720, hippocampus, lipidomics, sphingomyelin lipids, CENTRAL-NERVOUS-SYSTEM, FINGOLIMOD FTY720, MULTIPLE-SCLEROSIS, FATTY-ACIDS, ETHANOLAMINE PLASMALOGENS, PROTEASOMAL-DEGRADATION, SYNAPTIC PLASTICITY, VENTRAL HIPPOCAMPUS, LYMPHOCYTE EGRESS, MEMBRANE-LIPIDS |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Mechanical Engineering |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10187968 |
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