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Esteban Luna, Reas Sulaimankutty, Kimberly Dine, Kenneth S Shindler; Resveratrol and BBI combination therapy in experimental optic neuritis. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5772.
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© ARVO (1962-2015); The Authors (2016-present)
Optic neuritis, an inflammatory demyelinating optic nerve disease in multiple sclerosis, is modeled in mice with experimental autoimmune encephalomyelitis (EAE). Resveratrol (RSV), a naturally-occurring polyphenol that activates the SIRT1 deacetylase, can prevent retinal ganglion cell (RGC) loss without suppressing inflammation in chronic EAE. Bowman-Birk Inhibitor (BBI) is a naturally-occurring protease inhibitor that prevents RGC loss by suppressing inflammation in relapsing EAE. This study used combination therapy of RSV+BBI in chronic EAE optic neuritis to measure synergistic effects.
EAE was induced in C57/Bl6 mice by immunization with myelin oligodendroglial glycoprotein peptide. Wild type immunized mice were left untreated, or treated daily with 250 mg/kg RSV, 1 mg BBI, or both RSV+BBI. Negative control mice were sham immunized with PBS. Mice were observed and scored daily for clinical signs of EAE (ascending paralysis). Visual function was assessed by optokinetic responses (OKR) at baseline and each week until sacrifice 6 weeks post-immunization. Retinas and optic nerves were isolated. Inflammation was assessed by H&E staining, demyelination was assessed by luxol fast blue staining, and axonal loss was assessed by neurofilament staining of optic nerve sections. RGCs were immunolabeled with Brn3a antibodies to quantify RGC survival.
RGC function, assessed by OKR, decreased in untreated EAE mice. The decrease in OKR was significantly reduced by treatment with RSV, BBI and RSV+BBI. There was an increase in the degree of inflammation in optic nerves of untreated EAE mice compared to non-EAE control mice. RSV and BBI treatment alone each showed a trend toward decreased optic nerve inflammation, but inflammation was significantly attenuated only by combined treatment with RSV+BBI. There was no significant RGC loss, axonal loss, or demyelination in untreated EAE mice or treated mice. BBI and RSV+BBI treatment decreased clinical signs of EAE.
RSV+BBI helped preserve vision, decreased inflammation severity, and decreased clinical signs of EAE. This combination therapy was more effective than treatment with either compound alone. Results suggest that combined RSV+BBI is a potential therapeutic approach for limiting vision loss from optic neuritis.
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