Suppression of Mitochondrial Oxidative Stress Provides Long-term Neuroprotection in Experimental Optic Neuritis

Axonal loss is thought to contribute to the persistence of visual loss in optic neuritis and multiple sclerosis (MS). The mechanisms of injury are poorly understood. The authors investigated the contribution of mitochondrial oxidative stress and the effects of modulating mitochondrial antioxidant ge...

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Bibliographic Details
Published in:Investigative ophthalmology & visual science 2007-02, Vol.48 (2), p.681-691
Main Authors: Qi, Xiaoping, Lewin, Alfred S, Sun, Liang, Hauswirth, William W, Guy, John
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cell Culture Techniques
Dependovirus - genetics
Diseases of visual field, optic nerve, optic chiasma and optic tracts
Encephalomyelitis, Autoimmune, Experimental - enzymology
Encephalomyelitis, Autoimmune, Experimental - pathology
Encephalomyelitis, Autoimmune, Experimental - prevention & control
Eye and associated structures. Visual pathways and centers. Vision
Fluorescent Antibody Technique, Indirect
Fluorescent Dyes
Fundamental and applied biological sciences. Psychology
Genetic Therapy
Magnetic Resonance Imaging
Medical sciences
Mice
Mice, Inbred DBA
Mitochondria - enzymology
Myelin Sheath - pathology
Ophthalmology
Optic Nerve - enzymology
Optic Nerve - pathology
Optic Neuritis - enzymology
Optic Neuritis - pathology
Optic Neuritis - prevention & control
Oxidative Stress
Reactive Oxygen Species - metabolism
Retinal Ganglion Cells - enzymology
Retinal Ganglion Cells - pathology
RNA, Catalytic - genetics
Superoxide Dismutase - genetics
Superoxide Dismutase - metabolism
Transfection
Vertebrates: nervous system and sense organs
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Summary:Axonal loss is thought to contribute to the persistence of visual loss in optic neuritis and multiple sclerosis (MS). The mechanisms of injury are poorly understood. The authors investigated the contribution of mitochondrial oxidative stress and the effects of modulating mitochondrial antioxidant gene expression in the optic nerves of mice induced with experimental allergic encephalomyelitis (EAE), with a focus on long-term neuroprotection. Optic nerves from mice with EAE were probed for reactive oxygen species (ROS) with the use of dichlorofluorescein diacetate (DCFDA), dihydroethidium, and cerium chloride. To modulate mitochondrial oxidative stress, recombinant AAV containing the human SOD2 gene or a ribozyme targeting murine SOD2 was injected into the vitreous. Control eyes received the recombinant virus without a therapeutic gene. Mice were sensitized for EAE and were monitored by serial contrast-enhanced MRI. The effects of SOD2 modulation on the EAE optic nerve were gauged by computerized analysis of optic nerve volume, myelin fiber area, and retinal ganglion cell loss at 1, 3, and 12 months after sensitization for EAE. ROS were detected in the EAE optic nerve as early as 3 days after antigenic sensitization. Colocalization suggested mitochondria as the source of ROS activity in the absence of inflammation. The ribozyme suppressing SOD2 gene expression increased myelin fiber injury by 27%. Increasing SOD2 levels twofold in the optic nerve by virally mediated gene transfer ameliorated myelin fiber injury by 51% and RGC loss fourfold, limiting it to 7% in EAE at 1 year. Amelioration of mitochondrial oxidative stress by SOD2 gene delivery may be a therapeutic strategy for suppressing neurodegeneration in optic neuritis.
ISSN:0146-0404
1552-5783
1552-5783
DOI:10.1167/iovs.06-0553