Abstract
Visual dysfunction resulting from optic neuritis (ON) is one of the most common clinical manifestations of multiple sclerosis (MS), characterized by loss of retinal ganglion cells, thinning of the nerve fiber layer, and inflammation to the optic nerve. Current treatments available for ON or MS are only partially effective, specifically target the inflammatory phase, and have limited effects on long-term disability. Fingolimod (FTY) is an FDA-approved immunomodulatory agent for MS therapy. The objective of the current study was to evaluate the neuroprotective properties of FTY in the cellular model of ON-associated neuronal damage. R28 retinal neuronal cell damage was induced through treatment with tumor necrosis factor-α (TNFα). In our cell viability analysis, FTY treatment showed significantly reduced TNFα-induced neuronal death. Treatment with FTY attenuated the TNFα-induced changes in cell survival and cell stress signaling molecules. Furthermore, immunofluorescence studies performed using various markers indicated that FTY treatment protects the R28 cells against the TNFα-induced neurodegenerative changes by suppressing reactive oxygen species generation and promoting the expression of neuronal markers. In conclusion, our study suggests neuroprotective effects of FTY in an in vitro model of optic neuritis.
Highlights
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) prevalent in about 400,000 people in the US and 2.1 million people worldwide [1,2,3,4]
20% of MS patients present with vision deficits associated with optic neuritis (ON) [5,6], and neurodegeneration characterized by loss of retinal ganglion cells, thinning of the nerve fiber layer, and axonal damage [7,8]
Utilizing the in vitro experimental model of optic neuritis standardized in our laboratory using the tumor necrosis factor-α (TNFα) as an insult, the current study investigated the neuroprotective properties of FTY in reducing the TNFα-induced injury in R28 cells
Summary
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) prevalent in about 400,000 people in the US and 2.1 million people worldwide [1,2,3,4]. The current MS therapies target the inflammatory pathology, effects on the long-term neurodegenerative phases of the disease have not been shown. Fingolimod (FTY720 or FTY), a sphingosine analog that functions as a potent immunosuppressive agent in the CNS, is approved for MS therapy, especially for highly active disease [10,11]. FTY has been shown to exhibit neuroprotective properties in experimental models of Alzheimer’s, stroke, and Parkinson’s disease [19,20,21,22,23,24]. A recent study showed that FTY exerts neuroprotective and anti-inflammatory effects on the retina and optic nerve in a mouse model of MS, perhaps explaining the potent protective effects in patients [25]. The current study was performed to assess the neuroprotective potential of FTY in an in vitro model of optic neuritis
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