Sphingosine 1‐phosphate but not Fingolimod protects neurons against excitotoxic cell death by inducing neurotrophic gene expression in astrocytes

Sphingosine 1‐phosphate but not Fingolimod protects neurons against excitotoxic cell death by inducing neurotrophic gene expression in astrocytes.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1111/jnc.14917
Journal or Publication Title: Journal of Neurochemistry
Volume: 153
Number: 2
Page Range: pp. 173-188
Date: 2020
Divisions: Lipid Cell Biology
Depositing User: General Admin
Identification Number: 10.1111/jnc.14917
ISSN: 0022-3042
Date Deposited: 22 Dec 2020 02:54

Sphingosine 1-phosphate (S1P) is an essential lipid metabolite that signals through a family of five G protein-coupled receptors, S1PR1-S1PR5, to regulate cell physiology. The multiple sclerosis drug Fingolimod (FTY720) is a potent S1P receptor agonist that causes peripheral lymphopenia. Recent research has demonstrated direct neuroprotective properties of FTY720 in several neurodegenerative paradigms; however, neuroprotective properties of the native ligand S1P have not been established. We aimed to establish the significance of neurotrophic factor up-regulation by S1P for neuroprotection, comparing S1P with FTY720. S1P induced brain-derived neurotrophic factor (BDNF), leukemia inhibitory factor (LIF), platelet-derived growth factor B (PDGFB), and heparin-binding EGF-like growth factor (HBEGF) gene expression in primary human and murine astrocytes, but not in neurons, and to a much greater extent than FTY720. Accordingly, S1P but not FTY720 protected cultured neurons against excitotoxic cell death in a primary murine neuron-glia coculture model, and a neutralizing antibody to LIF blocked this S1P-mediated neuroprotection. Antagonists of S1PR1 and S1PR2 both inhibited S1P-mediated neurotrophic gene induction in human astrocytes, indicating that simultaneous activation of both receptors is required. S1PR2 signaling was transduced through Gα13 and the small GTPase Rho, and was necessary for the up-regulation and activation of the transcription factors FOS and JUN, which regulate LIF, BDNF, and HBEGF transcription. In summary, we show that S1P protects hippocampal neurons against excitotoxic cell death through up-regulation of neurotrophic gene expression, particularly LIF, in astrocytes. This up-regulation requires both S1PR1 and S1PR2 signaling. FTY720 does not activate S1PR2, explaining its relative inefficacy compared to S1P.

© 2019 International Society for Neurochemistry.

Tran, Collin
Heng, Benjamin
Teo, Jonathan D.
Humphrey, Sean J.
Qi, Yanfei
Couttas, Timothy A.
Stefen, Holly
Brettle, Merryn
Fath, Thomas
Guillemin, Gilles J.
Don, Anthony S.
Last Modified: 08 Apr 2021 05:25
URI: https://eprints.centenary.org.au/id/eprint/124

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