The sphingosine 1-phosphate analogue, FTY720, modulates the lipidomic signature of the mouse hippocampus.

Autor: Magalhães DM; Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.; Instituto de Medicina Molecular João Lobo Antunes, Lisboa, Portugal.; School of Applied Sciences, University of Brighton, Brighton, UK., Stewart NA; School of Applied Sciences, University of Brighton, Brighton, UK., Mampay M; School of Applied Sciences, University of Brighton, Brighton, UK., Rolle SO; Green Templeton College, University of Oxford, Oxford, UK., Hall CM; School of Applied Sciences, University of Brighton, Brighton, UK.; Department of Mechanical Engineering, University College London, London, UK., Moeendarbary E; Department of Mechanical Engineering, University College London, London, UK.; 199 Biotechnologies Ltd, London, UK., Flint MS; School of Applied Sciences, University of Brighton, Brighton, UK., Sebastião AM; Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.; Instituto de Medicina Molecular João Lobo Antunes, Lisboa, Portugal., Valente CA; Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.; Instituto de Medicina Molecular João Lobo Antunes, Lisboa, Portugal., Dymond MK; School of Applied Sciences, University of Brighton, Brighton, UK., Sheridan GK; School of Life Sciences, University of Nottingham, Nottingham, UK.
Jazyk: angličtina
Zdroj: Journal of neurochemistry [J Neurochem] 2024 Jun; Vol. 168 (6), pp. 1113-1142. Date of Electronic Publication: 2024 Feb 09.
DOI: 10.1111/jnc.16073
Abstrakt: 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.
(© 2024 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)
Databáze: MEDLINE
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