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K. S. Shindler, E. Ventura, P. Elliott, A. M. Rostami; SIRT1 Activators Attenuate Retinal Ganglion Cell Loss During Acute Optic Neuritis. Invest. Ophthalmol. Vis. Sci. 2007;48(13):563.
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© ARVO (1962-2015); The Authors (2016-present)
Optic neuritis is a common inflammatory demyelinating condition 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. Activation of SIRT1, an enzyme involved in cellular stress resistance and survival, attenuates degradation of axotomized dorsal root ganglion neurons. The neuroprotective effects of SRT647 and SRT501, two structurally and mechanistically distinct SIRT1 activators, were examined during optic neuritis in experimental autoimmune encephalomyelitis (EAE), an animal model of MS.
EAE was induced by immunization with proteolipid protein peptide in SJL/J mice. Retinal ganglion cells (RGCs) were retrogradely-labeled with fluorogold by injection into superior colliculi. Following sacrifice, RGCs were quantified by counting fluorescent cells in 12 standardized fields of each isolated retina. Optic neuritis was detected by inflammatory cell infiltration present on histological evaluation of optic nerve sections. Optic neuritis develops in two thirds of eyes with significant retinal ganglion cell (RGC) loss detected 14 days after immunization in this model.
Intravitreal injection of SIRT1 activators 0, 3, 7, and 11 days after immunization significantly attenuated RGC loss in a dose-dependent manner. At day 14, RGC numbers present in EAE eyes treated with 66.67 mM SRT647 or 100 µM SRT501 were equivalent to control eyes. This neuroprotective effect of SRT501 was blocked by 100 µM sirtinol, a SIRT1 inhibitor. Treatment with either SIRT1 activator did not prevent EAE or optic nerve inflammation. Single dose 100 µM SRT501 on day 11 was sufficient to limit RGC loss and preserve axon function at day 14, and continued to significantly reduce RGC loss 30 days after immunization.
SIRT1 activators provide an important potential therapy to prevent neuronal damage that leads to permanent neurological disability in patients with optic neuritis and MS. SIRT1 activators do not suppress inflammation in this model, suggesting that their neuroprotective effects will be additive or synergistic with current immunomodulatory therapies.
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