Fingolimod reduces axonal transection during demyelination (P1.153)

OBJECTIVE: Determine whether fingolimod reduces axonal transection during active demyelination in a non-immune mediated demyelination model. BACKGROUND: Axonal degeneration is the primary cause of neurological disability in multiple sclerosis. Following inflammatory-induced demyelination, axons lose physical and metabolic support provided by the myelin resulting in decreased nerve conduction, higher metabolic demand and vulnerability to environmental stress. Protecting demyelinated axons from degeneration or transection during active demyelination may reduce accumulation of axonal damage and improve the outcome for MS patients. Fingolimod is an MS drug that modulates sphingosine-1-phosphate receptor function and lymphocytes entry into the brain. However, whether fingolimod mediates neuroprotection, independent of its anti-inflammatory role, is not clear. DESIGN/METHODS: We tested the neuroprotective effect of fingolimod in a modified cuprizone model, where eight week old C57BL/6J male mice were fed cuprizone chow (0.3[percnt] w/w) and received daily rapamycin injections for 6 weeks. Fingolimod was delivered daily at 0.3mg/kg, concurrent with cup/rap treatment. Axonal transection was visualized and quantified by SMI32 staining and myelinated axons were counted in 1 micron thick Epon sections. Volumetric measurement of mitochondria was obtained from 3D-EM (three-dimensional electron microscope) image stacks. RESULTS: Corpus callosum from fingolimod and vehicle treated mice were extensively demyelinated following 6-weeks of cup/rap treatment, indicating that fingolimod does not protect myelin from cuprizone-induced demyelination. However, there is a significant reduction in SMI32+ axonal ovoids (P<0.05) in corpus callosum in fingolimod treated mice, indicating that fingolimod promotes neuroprotection. Concurrently there is a significant reduction in Iba1+ microglia. Ultrastructural 3D-EM analysis of mitochondria in demyelinated axons revealed that there was a significant increase in the volume of mitochondria in fingolimod-treated animals. CONCLUSIONS: Fingolimod protects axons from transection during demyelination in the cup/rap model. Fingolimod treatment significantly increases axonal mitochondrial volume. Increased ATP production may explain the neuroprotective effect on demyelinated axons. Study Supported by: Novartis Disclosure: Dr. Bai has received personal compensation for activities with Renovo Neural Inc. as an employee. Dr. Lunn has received personal compensation for activities with Renovo Neural as an employee. Dr. Avila has nothing to disclose. Dr. Wang has received personal compensation for activities with Renovo Neural as an employee. Dr. Chmura has received personal compensation for activities with Renovo Neural as an employee. Dr. Benson has received personal compensation for activities with Renovo Neural as an employee. Dr. Kidd has received personal compension for activities with Renovo Neural. Dr. Medicetty has received personal compensation for activities with Renovo Neural as an employee. Dr. Trapp has received personal compensation for activities with Renovo Neural, Teva Neuroscience, Biogen Idec, Endece, Merck & Co., Inc., EMD Serono, and Novartis.