Fingolimod Up-Regulates BDNF Expression within the CNS And Down-Regulates Tissue Pathology in a Pre-Clinical Model of Chronic Neuroinflammation (P1.159)

OBJECTIVE: Investigate the ability of fingolimod to modulate the brain-derived neurotrophic factor (BDNF) expression and to decrease the established CNS pathology in late-stage chronic neuroinflammation. BACKGROUND: Fingolimod (FTY720, Gilenya®) was the first FDA-approved oral treatment for relapsing forms of MS. It readily crosses the blood-brain barrier (BBB) and can interact with sphingosine 1-phosphate (S1P) receptors expressed on cells within the immune system and CNS. This study represents the very first analysis of BDNF expression and tissue integrity in an EAE model where fingolimod treatment was initiated in chronic, highly paralyzed mice.DESIGN/METHODS: Chronic non-remitting EAE was induced in C57BL/6 mice resulting in hind limb paralysis. Once-daily, oral fingolimod treatment was initiated 40 days post-EAE immunization and animals were monitored for an additional 20 days. Brain and spinal cord tissues were analyzed for BDNF expression (in situ, ELISA) and histopathology changes (T-cells, macrophages/microglia, astrocytes). BDNF levels were also estimated in healthy (unimmunized) mice and vehicle-treated EAE mice. RESULTS: BDNF expression was similar between healthy and vehicle-treated EAE mice. Fingolimod treatment resulted in up-regulation of BDNF within CNS. Preliminary evidence showed that BDNF expression was co-localized to neurons. Proportion of activated microglia/macrophages (FcγR4+) and astrocytes (GFAP+) were significantly reduced following fingolimod treatment. At this late chronic phase of the EAE model, there were few (CD3+) T-cells infiltrating the CNS, but as expected fingolimod treatment further diminished the response. Interestingly, the expression of BDNF and immune cell infiltration did not co-localize, suggesting that the responses are likely to be independent. CONCLUSIONS: These findings provide the first evidence that fingolimod enhances BDNF expression during chronic neuroinflammation via an S1P1 receptor mediated mechanism. Fingolimod also down-regulated microglia and astrocyte activation during a phase of the EAE model that has relatively minor peripheral T-cell infiltration. Study Supported by: Novartis Pharma AG Disclosure: Dr. Smith has received personal compensation for activities with Novartis as an employee. Dr. Dubost has received personal compensation for activities with Novartis as an employee. Dr. Brinkmann has received personal compensation for activities with Novartis as an employee. Dr. Jivkov has received personal compensation for activities with Novartis. Dr. Huck has received personal compensation for activities with Novartis as an employee. Dr. Theil has received personal compensation for activities with Novartis as employee.