Optic neuritis is an inflammatory demyelinating disease of the optic nerve that occurs idiopathically or in association with the central nervous system (CNS) demyelinating disease multiple sclerosis (MS). Up to 60% of patients with optic neuritis develop some permanent visual loss including decreased acuity, color vision, contrast sensitivity and/or visual field loss. Axonal damage and loss of neurons occurs in optic neuritis and MS, including loss of retinal ganglion cells (RGCs), and this neuronal loss leads to permanent neurological dysfunction. Identifying novel therapies that prevent neuronal loss following optic neuritis therefore has tremendous potential for preventing permanent visual loss. Neuroprotective therapies that work in optic neuritis also have potential to prevent loss of retina neurons in other eye diseases, and loss of other CNS neurons in MS as well, if the therapy targets a common mechanism of neuronal cell damage. Studies over the first four to five years of this grant demonstrated that resveratrol, a naturally- occurring polyphenol, and other related compounds that share an ability to activate the SIRT1 deacetylase, provide significant neuroprotective effects for RGCs. SIRT1 activity is a critical part of the mechanism of resveratrol mediated prevention of RGC loss and preservation of visual function. Furthermore, results suggest that suppression of the inflammatory component of this disease does not occur, and therefore is not a significant part of the mechanism of action of resveratrol. Resveratrol treatment also reduces accumulation of reactive oxygen species in optic nerves, decreasing oxidative stress that contributes to RGC loss in experimental optic neuritis. Preliminary data suggests one mechanism mediating this effect involves SIRT1 deacetylation of PGC1?, a coactivator of transcription factors that lead to increased mitochondrial biogenesis, with associated increased expression of mitochondrial enzymes involved in reduction of reactive oxygen species, including superoxide dismutase 2 (SOD2). We hypothesize that resveratrol treatment will provide added benefits to optic neuritis eyes without reducing the ability of immunomodulatory therapies to suppress inflammation and demyelination, by promoting RGC survival and preservation of RGC function; and one mechanism of this neuroprotective effect involves resveratrol mediated activation of SIRT1 to deacetylate PGC1? and reduce oxidative stress through increased mitochondrial biogenesis. To test this hypothesis we propose two specific aims: 1) Evaluate synergistic effects and safety of combined treatment with resveratrol and anti-inflammatory therapies in experimental optic neuritis; and 2) Determine the role of PGC1? in modulating mitochondrial function and inducing SOD2 to reduce oxidative stress as mechanisms of resveratrol mediated neuroprotection of RGCs.

Public Health Relevance

Optic neuritis, an inflammatory disease of the optic nerve that occurs in association with the neurodegenerative disease multiple sclerosis (MS), affects over 1/1000 people in the United States and leads to some level of permanent visual loss in up to 60% of patients. There are over 400,000 patients in the United States with MS, a leading cause of neurological disability in young adults, and damage of nerve cells in optic neuritis and MS patients correlates with permanent visual and other neurological dysfunction. Identifying novel therapies that prevent nerve damage following an acute episode of optic neuritis therefore has tremendous potential for preventing permanent visual loss, and may prevent vision loss in other optic nerve diseases and neurological disability in MS as well if the therapy targets a common mechanism of nerve damage.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Diseases and Pathophysiology of the Visual System Study Section (DPVS)
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Liberman, Ellen S
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University of Pennsylvania
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Khan, Reas S; Dine, Kimberly; Geisler, John G et al. (2017) Mitochondrial Uncoupler Prodrug of 2,4-Dinitrophenol, MP201, Prevents Neuronal Damage and Preserves Vision in Experimental Optic Neuritis. Oxid Med Cell Longev 2017:7180632
Huang, Haoliang; Miao, Linqing; Liang, Feisi et al. (2017) Neuroprotection by eIF2?-CHOP inhibition and XBP-1 activation in EAE/optic neuritiss. Cell Death Dis 8:e2936
Khan, Reas S; Dine, Kimberly; Bauman, Bailey et al. (2017) Intranasal Delivery of A Novel Amnion Cell Secretome Prevents Neuronal Damage and Preserves Function In A Mouse Multiple Sclerosis Model. Sci Rep 7:41768
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Chatterjee, Dhriti; Addya, Sankar; Khan, Reas S et al. (2014) Mouse hepatitis virus infection upregulates genes involved in innate immune responses. PLoS One 9:e111351
Khan, Reas S; Dine, Kimberly; Luna, Esteban et al. (2014) HE3286 reduces axonal loss and preserves retinal ganglion cell function in experimental optic neuritis. Invest Ophthalmol Vis Sci 55:5744-51
Khan, Reas S; Dine, Kimberly; Das Sarma, Jayasri et al. (2014) SIRT1 activating compounds reduce oxidative stress mediated neuronal loss in viral induced CNS demyelinating disease. Acta Neuropathol Commun 2:3
Zuo, Ling; Khan, Reas S; Lee, Vivian et al. (2013) SIRT1 promotes RGC survival and delays loss of function following optic nerve crush. Invest Ophthalmol Vis Sci 54:5097-102
Chen, Yong; Khan, Reas S; Cwanger, Alyssa et al. (2013) Dexras1, a small GTPase, is required for glutamate-NMDA neurotoxicity. J Neurosci 33:3582-7
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