title: Anti-inflammatory effects of FTY720 do not prevent neuronal cell loss in a rat model of optic neuritis.
abstract: In multiple sclerosis, long-term disability is caused by axonal and neuronal damage. Established therapies target primarily the inflammatory component of the disease, but fail to prevent neurodegeneration. Fingolimod (codenamed FTY720) is an oral sphingosine 1-phosphate (S1P) receptor modulator with promising results in phase II trials in multiple sclerosis patients and is under further development as a novel treatment for multiple sclerosis. To evaluate whether FTY720 has neuroprotective properties, we tested this drug in a rat model of myelin oligodendrocyte glycoprotein-induced optic neuritis. FTY720 exerted significant anti-inflammatory effects during optic neuritis and reduced inflammation, demyelination, and axonal damage; however, FTY720 treatment did not prevent apoptosis of retinal ganglion cells (RGCs), the neurons that form the axons of the optic nerve. Consistent with this lack of effect on RGC survival, FTY720 treatment did not improve visual function, nor did it prevent apoptosis of RGCs in vitro. We observed a persistent activation of apoptotic signaling pathways in RGCs under FTY720 treatment, a possible underlying mechanism for the lack of neuroprotection in the presence of strong anti-inflammatory effects, Furthermore, FTY720 shifted the remaining inflammation in the optic nerve toward neurotoxicity by modest up-regulation of potential neurotoxic cytokines. We conclude that FTY720-induced anti-inflammation and axon protection did not of itself protect neurons from apoptotic cell death.
authors.affiliation: Department of Neurology, University Medicine Göttingen, Göttingen, Germany.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Rau
authors.forename: Katharina
authors.initials: K
authors.lastname: Hein
authors.forename: Muriel B
authors.initials: MB
authors.lastname: Sättler
authors.forename: Benedikt
authors.initials: B
authors.lastname: Kretzschmar
authors.forename: Carina
authors.initials: C
authors.lastname: Hillgruber
authors.forename: Bradford L
authors.initials: BL
authors.lastname: McRae
authors.forename: Ricarda
authors.initials: R
authors.lastname: Diem
authors.forename: Mathias
authors.initials: M
authors.lastname: Bähr
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004594:Electrophysiology / Q000379:methods; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D005260:Female; D000068876:Fingolimod Hydrochloride; D006023:Glycoproteins / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology; D009186:Myelin Sheath / Q000378:metabolism; D009474:Neurons / Q000166:cytology*; D009836:Oligodendroglia / Q000378:metabolism; D009902:Optic Neuritis / Q000378:metabolism*; D011409:Propylene Glycols / Q000494:pharmacology*; D051381:Rats; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D006023:Glycoproteins; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine