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M. Dutt, D. Fitzgerald, Z. Fonseca-Kelly, E. Ventura, A. Rostami, K. S. Shindler; SIRT1 Activators Prevent Retinal Ganglion Cell Loss but Do Not Alter Optic Nerve Inflammation in Experimental Optic Neuritis. Invest. Ophthalmol. Vis. Sci. 2010;51(13):643.
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© ARVO (1962-2015); The Authors (2016-present)
Optic neuritis is an inflammatory demyelinating disease of the optic nerve that often occurs in patients with multiple sclerosis (MS). Axonal damage and neuronal loss leads to permanent neurological disability in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). We previously showed that SRT501, an activator of SIRT1, an enzyme involved in cellular stress resistance and survival, attenuates retinal ganglion cell (RGC) loss during acute optic neuritis in EAE mice. We evaluated potential mechanisms of the effect through activation of SIRT1 and possible attenuation of the inflammatory infiltrates of optic nerves.
RGCs were retrogradely labeled with fluorogold by injection into the superior colliculi. EAE was induced by immunization with proteolipid protein in SJL/J mice one week later (day 0). Mice were treated daily with three distinct SIRT1 activators or placebo +/- Sirtinol, a SIRT1 inhibitor by oral gavage beginning one day after optic neuritis develops. Mice were observed for clinical signs of EAE. Following sacrifice, optic nerves and spinal cords were examined histologically or inflammatory cells were isolated from the optic nerves and analyzed by flow cytometry.
Similar to previous studies, significant RGC loss was detected by day 14 after immunization. Oral administration of SRT501, SRT1720, SRT2104 attenuated RGC loss in EAE eyes with optic neuritis. Sirtinol prevented this neuroprotective effect. Flow cytometry analysis showed no significant difference in the number of inflammatory cells present in the treated vs. the non-treated EAE optic nerves and there was no difference in the type of cells present.
SIRT1 activators provide an important potential therapy to prevent neuronal damage from optic neuritis. The fact that 3 distinct SIRT1 activators all exert similar effects and that Sirtinol blocks this effect, confirm that the mechanism of neuroprotection does involve SIRT1 activity. The mechanism does not; however involve suppression or phenotypic regulation of inflammatory cell responses in this model of optic neuritis.
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