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Reas Sulaimankutty, Kimberly Dine, Kenneth S. Shindler; Sirt1 Activators Attenuate RGC Cell Loss By Reducing Oxidative Stress In MHV-A59 Induced Optic Neuritis. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3167. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Optic neuritis (ON), an inflammatory demyelinating optic nerve disease, occurs in multiple sclerosis (MS). MHV-A59, a mouse hepatitis virus (MHV) strain that causes brain and spinal cord inflammation and demyelination, induces ON by promoting inflammatory cell infiltration and retinal ganglion cell (RGC) loss. Resveratrol is a natural polyphenolic phytoalexin that activates the SIRT1 deacetylase and displays antioxidant, cardioprotective, anti-cancer, anti-aging and anti-inflammatory properties. Resveratrol and other SIRT1 activators reduce neuronal damage in autoimmune models of MS, but effects in viral induced demyelinating disease are unknown. In the present study, we investigate the effects of the SIRT1 activator SRTAW04 on RGC survival in MHV-A59 induced ON.
RGCs were retrogradely-labeled with fluorogold by injection into superior colliculi. 4-5 week old C57/Bl6 mice were inoculated with plaque-purified virus by intracranial injection one week later (day 0), using 50% of the lethal dose of MHV-A59 (2,000 PFU). Control mice were sham injected with PBS. Mice were treated daily with SRTAW04 (100mg/kg body weight) or an equal volume of PBS by oral gavage. Mice were sacrificed on day 30. RGCs were quantified by counting fluorescent cells in 12 standardized fields of each isolated retina. Optic nerves were isolated and stained with Mitosox Red to detect the reactive oxygen species superoxide. SIRT1 activity was measured in protein extracts from optic nerves.
Significant loss of RGCs was observed in eyes of mice infected with MHV-A59 (p<0.001) compared to control mouse eyes 30 days post-inoculation. In contrast, MHV-A59 infected mice treated with SRTAW04 for 30 days showed no significant loss of RGCs. Mitosox staining showed that optic nerve sections from MHV-A59 infected mice exhibit higher levels of superoxide than control optic nerves; whereas, optic nerves from MHV-A59 infected mice treated with SRTAW04 showed no significant accumulation of superoxide. SIRT1 activity was significantly higher in optic nerves of SRTAW04 treated mice as compared to vehicle treated mice.
Results indicate that SIRT1 activating compounds administered to MHV-A59 infected mice confer substantial long-term neuroprotection that is apparent by attenuating RGC loss. The mechanism of this neuroprotective effect involves attenuation of reactive oxygen species production during MHV infection. These studies also confirm that SRTAW04 mediated neuroprotection in MHV-A59 infection occurs by a mechanism involving SIRT1 activation. SIRT1 activators are a potential therapy to prevent neurodegeneration in ON and MS.
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