Optic neuritis is an inflammatory demyelinating disease of the optic nerve that occurs in association with the central nervous system (CNS) demyelinating disease multiple sclerosis (MS) and leads to permanent visual loss in up to 40% of patients. Axonal damage and neuronal loss in optic neuritis and MS patients, including loss of retinal ganglion cell (RGC) axons, correlates with permanent neurological dysfunction. Identifying novel therapies that prevent neuronal loss following an acute episode of optic neuritis therefore has tremendous potential for preventing permanent visual loss, and may prevent loss of retinal neurons in other eye diseases and loss of CNS neurons in MS as well if the therapy targets a common mechanism of neuronal damage. One mechanism of cellular damage, oxidative stress induced by generation of reactive oxygen species (ROS), has been shown to contribute to RGC loss in experimental optic neuritis. SIRT1 is an NAD+-dependent deacetylase involved in cellular stress responses and cell survival that may reduce oxidative stress by promoting mitochondrial function or reducing inflammation induced ROS generation. A number of molecules have been identified that increase the deacetylase activity of SIRT1 for its protein substrates. Resveratrol, the most widely studied SIRT1 activator, promotes neuronal survival in animal models of Huntington's Disease and Amyotrophic Lateral Sclerosis. In preliminary studies, we found that resveratrol attenuates RGC loss during optic neuritis in experimental autoimmune encephalomyelitis (EAE) mice, an animal model of MS. However, the molecular mechanisms that mediate this neuroprotective effect are not known. Because mitochondrial oxidative stress plays a role in RGC loss in experimental optic neuritis, and SIRT1 can promote mitochondrial function, reducing oxidative stress, we hypothesize that the mechanism of SIRT1 activator-mediated neuroprotection of RGCs occurs through reduction of mitochondrial oxidative stress. To test this hypothesis we propose three specific aims: 1) Evaluate the neuroprotective effects of resveratrol on RGC survival in experimental optic neuritis and examine the role of SIRT1 activation and immunomodulation as underlying mechanisms mediating these effects;2) Examine whether the mechanism of neuroprotection by SIRT1 activators in optic neuritis occurs through promoting mitochondria and reducing oxidative stress with suppression of RGC apoptosis;3) Determine whether SIRT1 activators can reduce oxidative stress and apoptosis, conferring neuroprotection to retinal ganglion cells damaged by different insults. Mechanisms of neuroprotection in optic neuritis will be addressed using EAE mice. EAE mice have a high incidence of optic neuritis resulting in significant loss of RGCs. Mice will be treated with SIRT1 activators, and RGC loss will be measured in control and EAE animals. Generation of ROS that induce oxidative stress will be examined, and mitochondrial numbers and function will be assessed to determine whether RGC survival is promoted by reducing oxidative stress.

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 permanent visual loss in up to 40% 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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY019014-04
Application #
8443419
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Chin, Hemin R
Project Start
2010-04-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
4
Fiscal Year
2013
Total Cost
$364,800
Indirect Cost
$136,800
Name
University of Pennsylvania
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
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
Testa, Francesco; Maguire, Albert M; Rossi, Settimio et al. (2013) Three-year follow-up after unilateral subretinal delivery of adeno-associated virus in patients with Leber congenital Amaurosis type 2. Ophthalmology 120:1283-91
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
Bennett, Jean; Ashtari, Manzar; Wellman, Jennifer et al. (2012) AAV2 gene therapy readministration in three adults with congenital blindness. Sci Transl Med 4:120ra15
Quinn, Thomas A; Dutt, Mahasweta; Shindler, Kenneth S (2011) Optic neuritis and retinal ganglion cell loss in a chronic murine model of multiple sclerosis. Front Neurol 2:50
Ashtari, Manzar; Cyckowski, Laura L; Monroe, Justin F et al. (2011) The human visual cortex responds to gene therapy-mediated recovery of retinal function. J Clin Invest 121:2160-8
Shindler, Kenneth S; Chatterjee, Dhriti; Biswas, Kaushiki et al. (2011) Macrophage-mediated optic neuritis induced by retrograde axonal transport of spike gene recombinant mouse hepatitis virus. J Neuropathol Exp Neurol 70:470-80
Shindler, Kenneth S; Ventura, Elvira; Dutt, Mahasweta et al. (2010) Oral resveratrol reduces neuronal damage in a model of multiple sclerosis. J Neuroophthalmol 30:328-39