Abstract
PURPOSE. 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. METHODS. 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. RESULTS. 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. CONCLUSIONS. Amelioration of mitochondrial oxidative stress by SOD2 gene delivery may be a therapeutic strategy for suppressing neurodegeneration in optic neuritis.
| Original language | English |
|---|---|
| Pages (from-to) | 681-691 |
| Number of pages | 11 |
| Journal | Investigative Ophthalmology and Visual Science |
| Volume | 48 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 1 2007 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Ophthalmology
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Suppression of mitochondrial oxidative stress provides long-term neuroprotection in experimental optic neuritis. / Qi, Xiaoping; Lewin, Alfred S.; Sun, Liang; Hauswirth, William W.; Guy, John.
In: Investigative Ophthalmology and Visual Science, Vol. 48, No. 2, 01.02.2007, p. 681-691.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Suppression of mitochondrial oxidative stress provides long-term neuroprotection in experimental optic neuritis
AU - Qi, Xiaoping
AU - Lewin, Alfred S.
AU - Sun, Liang
AU - Hauswirth, William W.
AU - Guy, John
PY - 2007/2/1
Y1 - 2007/2/1
N2 - PURPOSE. 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. METHODS. 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. RESULTS. 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. CONCLUSIONS. Amelioration of mitochondrial oxidative stress by SOD2 gene delivery may be a therapeutic strategy for suppressing neurodegeneration in optic neuritis.
AB - PURPOSE. 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. METHODS. 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. RESULTS. 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. CONCLUSIONS. Amelioration of mitochondrial oxidative stress by SOD2 gene delivery may be a therapeutic strategy for suppressing neurodegeneration in optic neuritis.
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UR - http://www.scopus.com/inward/citedby.url?scp=33847701239&partnerID=8YFLogxK
U2 - 10.1167/iovs.06-0553
DO - 10.1167/iovs.06-0553
M3 - Article
C2 - 17251466
AN - SCOPUS:33847701239
VL - 48
SP - 681
EP - 691
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
SN - 0146-0404
IS - 2
ER -