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Mayssa Nassrallah, Zoe Fonseca-Kelly, Reas Sulaimankutty, Kimberly Dine, Mahasweta Dutt, Kenneth S. Shindler; Resveratrol and Other SIRT1 Activators Exert Similar Neuroprotective Effects in Experimental Optic Neuritis. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4677.
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Resveratrol is a naturally-occurring polyphenol that activates SIRT1, an NAD-dependent deacetylase. SRT501, a pharmaceutical formulation of resveratrol with enhanced systemic absorption, as well as several other SIRT1 activators, prevent retinal ganglion cell (RGC) loss without suppressing inflammation during optic neuritis in mice with relapsing experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. However, resveratrol has been reported to suppress inflammation in chronic EAE. The current studies directly compare effects of resveratrol and other SIRT1 activators in chronic EAE optic neuritis.
RGCs were retrogradely-labeled with fluorogold by injection into superior colliculi. EAE was induced by immunization with myelin oligodendroglial protein peptide in C57/Bl6 mice one week later (day 0). Mice were treated daily from day 0 until sacrifice at day 30 with vehicle alone, or with resveratrol (Sigma, St. Louis, MO) or SIRT1 activators (Sirtris, A GSK Company, Cambridge, MA) at doses of 100 and 250 mg/kg administered by oral gavage. Mice were observed daily for clinical signs of EAE. Following sacrifice, optic nerves were examined histologically, and RGCs were quantified by counting fluorescent cells in 12 standardized fields of each isolated retina.
Neither resveratrol nor the other SIRT1 activators significantly suppressed the severity of EAE compared to vehicle-treated EAE mice. Similarly, neither treatment prevented the development of optic nerve inflammation. Significant loss of RGCs was observed in eyes of EAE mice treated with vehicle alone as compared to control non-EAE mice. Both the lower and higher doses of resveratrol prevented this loss of RGCs, with similar protective effects observed in mice treated with other SIRT1 activators.
Results demonstrate that SIRT1 activators, including resveratrol, prevent RGC loss in this model of chronic optic neuritis, similar to prior results seen in an acute optic neuritis model. Differences in immunosuppression compared with prior studies suggest that immunomodulatory effects of this treatment may be limited and may be dependent on specific immunization parameters or timing of treatment. Importantly, neuroprotective effects can occur without suppression of inflammation, suggesting a potential additive benefit of this therapy in combination with anti-inflammatory therapies for optic neuritis and multiple sclerosis.
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