Neurodegeneration caused by mitochondrial complex I dysfunction in the mouse retina

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2005

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Zhang, Xian

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Neurodegenerative diseases have been closely linked to dysfunction of mitochondria. For example, Leber's hereditary optic neuropathy is associated with mutations in mitochondrial complex I. To create an in vivo animal model of neurodegeneration for studying the mechanisms and treatments of neurodegenerative diseases, the mouse eye was injected with the pesticide rotenone, a specific mitochondrial complex I inhibitor. Then, the neurotoxicity of rotenone on the retina was characterized at the cellular level. Finally, a therapeutic intervention was tested using the model. A dose of methylene blue was found to effectively prevent the neurodegeneration caused by rotenone. Following intravitreal injection of rotenone, the retinal ganglion cell layer (GCL) and the retinal nerve fiber layer (RNFL) showed degeneration as indicated by viii the reduction of their thicknesses. The maximum reduction in the GCL and RNFL thickness in complex I staining was around 40% and 89% respectively at 24 h. The GCL thickness reduction was also verified with cresyl violet staining. The number of GCL cells was reduced by 21% (cell profile counts) and 23% (unbiased stereological cell counts) in rotenone-treated eyes. There was a preferential reduction in the proportion of larger cells, while no overall cellular morphometric changes (soma area, perimeter, and diameter) were observed. Therefore, the reduction in GCL thickness 24 h after rotenone microinjection could be accounted for by cell loss and nerve fiber shrinkage, but not by overall soma size change. This optic neuropathy model was used to test the hypothesis that methylene blue, a reduction–oxidation agent that can act as a powerful antioxidant, may be protective against rotenone. Rotenone-induced neurodegeneration in the retinal ganglion cell layer 24 h after injection was completely prevented by the injection of methylene blue along with rotenone, as indicated by both the GCL thickness and cell numbers. This is the first animal model of optic neuropathy resulting from mitochondrial dysfunction, and our studies suggest that it could be used as a convenient means to test new treatments to prevent neurodegeneration. It was concluded that methylene blue may be a promising therapeutic agent in optic neuropathy and perhaps other neurodegenerative diseases caused by mitochondrial dysfunction

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