Year: 2005
Type: dissertation
Abstract: Neurodegenerative diseases have been closely linked to dysfunction of \nmitochondria. For example, Leber's hereditary optic neuropathy is associated with \nmutations in mitochondrial complex I. To create an in vivo animal model of \nneurodegeneration for studying the mechanisms and treatments of neurodegenerative \ndiseases, the mouse eye was injected with the pesticide rotenone, a specific \nmitochondrial complex I inhibitor. Then, the neurotoxicity of rotenone on the retina \nwas characterized at the cellular level. Finally, a therapeutic intervention was tested \nusing the model. A dose of methylene blue was found to effectively prevent the \nneurodegeneration caused by rotenone. \nFollowing intravitreal injection of rotenone, the retinal ganglion cell layer \n(GCL) and the retinal nerve fiber layer (RNFL) showed degeneration as indicated by \nviii \nthe reduction of their thicknesses. The maximum reduction in the GCL and RNFL \nthickness in complex I staining was around 40% and 89% respectively at 24 h. The \nGCL thickness reduction was also verified with cresyl violet staining. The number of \nGCL cells was reduced by 21% (cell profile counts) and 23% (unbiased stereological \ncell counts) in rotenone-treated eyes. There was a preferential reduction in the \nproportion of larger cells, while no overall cellular morphometric changes (soma area, \nperimeter, and diameter) were observed. Therefore, the reduction in GCL thickness 24 \nh after rotenone microinjection could be accounted for by cell loss and nerve fiber \nshrinkage, but not by overall soma size change. \nThis optic neuropathy model was used to test the hypothesis that methylene \nblue, a reduction–oxidation agent that can act as a powerful antioxidant, may be \nprotective against rotenone. Rotenone-induced neurodegeneration in the retinal \nganglion cell layer 24 h after injection was completely prevented by the injection of \nmethylene blue along with rotenone, as indicated by both the GCL thickness and cell \nnumbers. \nThis is the first animal model of optic neuropathy resulting from mitochondrial \ndysfunction, and our studies suggest that it could be used as a convenient means to test \nnew treatments to prevent neurodegeneration. It was concluded that methylene blue \nmay be a promising therapeutic agent in optic neuropathy and perhaps other \nneurodegenerative diseases caused by mitochondrial dysfunction
Author: Xian Zhang
Language: English
Subfield: Ophthalmology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1929743279