Fingolimod downregulates brain sphingosine-1-phosphate receptor 1 levels but does not promote remyelination or neuroprotection in the cuprizone model

Agnes E Nystad; Ragnhild Reehorst Lereim; Stig Wergeland; Eystein Oveland; Kjell-Morten Myhr; Lars Bø; Øivind Torkildsen

doi:10.1016/j.jneuroim.2019.577091

Fingolimod downregulates brain sphingosine-1-phosphate receptor 1 levels but does not promote remyelination or neuroprotection in the cuprizone model

J Neuroimmunol. 2020 Feb 15:339:577091. doi: 10.1016/j.jneuroim.2019.577091. Epub 2019 Oct 31.

Authors

Agnes E Nystad¹, Ragnhild Reehorst Lereim², Stig Wergeland³, Eystein Oveland⁴, Kjell-Morten Myhr⁵, Lars Bø⁶, Øivind Torkildsen³

Affiliations

¹ Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway. Electronic address: agnes.elisabeth.nystad@helse-bergen.no.
² Proteomics Unit at University of Bergen (PROBE), Department of Biomedicine, University of Bergen, Norway; Computational Biology Unit (CBU), Department of Informatics, University of Bergen, Bergen, Norway.
³ Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway.
⁴ Proteomics Unit at University of Bergen (PROBE), Department of Biomedicine, University of Bergen, Norway.
⁵ Department of Clinical Medicine, University of Bergen, Bergen, Norway; Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway.
⁶ Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital, Bergen, Norway.

PMID: 31739156
DOI: 10.1016/j.jneuroim.2019.577091

Abstract

Fingolimod is used to treat patients with relapsing-remitting multiple sclerosis; it crosses the blood-brain barrier and modulates sphingosine-1-phosphate receptors (S1PRs). Oligodendrocytes, astrocytes, microglia, and neuronal cells express S1PRs, and fingolimod could potentially improve remyelination and be neuroprotective. We used the cuprizone animal model, histo-, immunohistochemistry, and quantitative proteomics to study the effect of fingolimod on remyelination and axonal damage. Fingolimod was functionally active during remyelination by downregulating S1PR1 brain levels, and fingolimod-treated mice had more oligodendrocytes in the secondary motor cortex after three weeks of remyelination. However, there were no differences in remyelination or axonal damage compared to placebo. Thus, fingolimod does not seem to directly promote remyelination or protect against axonal injury or loss when given after cuprizone-induced demyelination.

Keywords: Cuprizone; Fingolimod; Multiple sclerosis; Quantitative proteomics; Remyelination; Sphingosine-1-phosphate receptors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain / drug effects
Brain / metabolism*
Cuprizone / toxicity*
Female
Fingolimod Hydrochloride / pharmacology*
Fingolimod Hydrochloride / therapeutic use
Mice
Mice, Inbred C57BL
Multiple Sclerosis, Relapsing-Remitting / drug therapy
Multiple Sclerosis, Relapsing-Remitting / metabolism
Neuroprotection / drug effects
Neuroprotection / physiology*
Random Allocation
Remyelination / drug effects
Remyelination / physiology*
Sphingosine 1 Phosphate Receptor Modulators / pharmacology
Sphingosine 1 Phosphate Receptor Modulators / therapeutic use
Sphingosine-1-Phosphate Receptors / antagonists & inhibitors
Sphingosine-1-Phosphate Receptors / metabolism*

Substances

S1pr1 protein, mouse
Sphingosine 1 Phosphate Receptor Modulators
Sphingosine-1-Phosphate Receptors
Cuprizone
Fingolimod Hydrochloride