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K. S. Shindler, E. Ventura, M. Dutt, P. Elliott, A. Rostami; Oral SIRT1 Activators Are Neuroprotective for Retinal Ganglion Cells in Experimental Optic Neuritis. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3240.
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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). Activators of SIRT1, an enzyme involved in cellular stress resistance and survival, attenuate retinal ganglion cell (RGC) loss during acute optic neuritis in EAE mice when administered intravitreally. We examined whether orally-administered SIRT1 activators penetrate the eye and prevent RGC loss during optic neuritis.
RGCs were retrogradely-labeled with fluorogold by injection into superior colliculi. EAE was induced by immunization with proteolipid protein peptide in SJL/J mice one week later (day 0). Mice were treated daily with the SIRT1 activator SRT501 or placebo by oral gavage beginning one day prior to or one day after optic neuritis develops. Mice were observed for clinical signs of EAE. Following sacrifice, optic nerves and spinal cords were examined histologically, and RGCs were quantified by counting fluorescent cells in 12 standardized fields of each isolated retina.
SRT501 was present in vitreal samples taken from control and EAE mice treated with oral SRT501. Similar to previous studies, significant RGC loss was detected by day 14 after immunization. Oral administration of SRT501 attenuated RGC loss in EAE eyes with optic neuritis at day 14 in a dose-dependent manner. Neuroprotective effects on RGC survival by oral SRT501 treatment during acute optic neuritis (days 10 - 14) were maintained through day 30. SRT501 did not prevent optic nerve or spinal cord inflammation, but did suppress neurological dysfunction during the remission phase of EAE.
SIRT1 activators provide an important potential therapy to prevent neuronal damage that leads to permanent neurological disability in patients with optic neuritis and MS. The SIRT1 activator SRT501 attenuates RGC loss during acute optic neuritis in EAE mice following oral administration, with similar efficacy to intravitreal injections. SIRT1 activators do not suppress inflammation in this model, suggesting that their neuroprotective effects may be synergistic with current immunomodulatory therapies.
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