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Anti-Inflammatory Effects of FTY720 Do Not Prevent Neuronal Cell Loss in a Rat Model of Optic Neuritis
- Source :
- The American Journal of Pathology. 178:1770-1781
- Publication Year :
- 2011
- Publisher :
- Elsevier BV, 2011.
-
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.
- Subjects :
- Encephalomyelitis, Autoimmune, Experimental
Optic Neuritis
Anti-Inflammatory Agents
Apoptosis
Biology
Neuroprotection
Retinal ganglion
Pathology and Forensic Medicine
Sphingosine
hemic and lymphatic diseases
medicine
Animals
Optic neuritis
Axon
Myelin Sheath
Glycoproteins
Neurons
Fingolimod Hydrochloride
Multiple sclerosis
Regular Article
medicine.disease
Fingolimod
eye diseases
Oligodendrocyte
Rats
Electrophysiology
Disease Models, Animal
Oligodendroglia
medicine.anatomical_structure
Propylene Glycols
Immunology
Optic nerve
Cytokines
Female
sense organs
Neuroscience
Immunosuppressive Agents
medicine.drug
Subjects
Details
- ISSN :
- 00029440
- Volume :
- 178
- Database :
- OpenAIRE
- Journal :
- The American Journal of Pathology
- Accession number :
- edsair.doi.dedup.....8a143555593014f39a9857f6744d60cc