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Abstract
MS-induced optic neuritis is one of the major complications in patients suffering with this neurodegenerative disease of the CNS. Fingolimod is an immunomodulatory agent approved for MS therapy. All current therapies of MS function by targeting the inflammatory phase of disease and there is a gap in knowledge in identifying an agent that focuses on the neurodegenerative phase of disease. The objective of the current master of science thesis dissertation was to evaluate the potential additional neuroprotective properties of fingolimod in an in vitro model of MS-induced optic neuritis. An in vitro model was established utilizing the R28 neuroretinal cell line. Neuronal damage was induced by treating with Tumor Necrosis Factor (TNF, 10 ng/mL). Cells were pre-treated (1h) with Fingolimod and cell viability (24h) was quantified. We found that treatment of R28 cells with TNF caused significant cell death (p<0.01), while Fingolimod demonstrated cell survival with the maximum effect observed at 25nM (p<0.05). Upregulation observed in phospho-p38 MAPK in response to TNFtreatment was prevented in the presence of Fingolimod. Further, level of cell survival marker (phospho-AKT) and anti-apoptotic marker (Bcl-xL) was increased, and cell death marker (cleaved caspase-3) was reduced in response to Fingolimod treatment. Fingolimod treatment also protected the retinal neurons against the TNF-induced neurodegeneration studied by the expression of neuronal markers and changes in their morphology. In conclusion, our study highlights the neuroprotective potential of fingolimod in retinal neurons.