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Tomomi Kohara, Tomoko Umemoto, Masaaki Sasaoka, Takashi Ota, Masaaki Kageyama; Rotenone Induces Degeneration of Retinal Ganglion Cells and Amacrine Cells in the Rat Retina via Oxidative Stress and Glutamate Excitotoxicity. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1365.
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© ARVO (1962-2015); The Authors (2016-present)
The aims of this study on rats, were to clarify the morphological changes occurring after intravitreal injection of rotenone and to investigate the mechanism responsible for rotenone-induced retinal neurodegeneration.
Adult Sprague-Dawley rats were intravitreously injected with rotenone (2 nmol/eye). Morphological changes after intravitreal injection of rotenone were evaluated by counting the cell number in the ganglion cell layer (GCL) and by transmission electron microscope (TEM) analysis. The mRNA expression levels of retinal cell-specific markers were quantified by real-time PCR. In addition, we evaluated the effects of compounds related to either excitotoxicity or oxidative stress on the rotenone-induced neurodegeneration.
Intravitreal injection of 2 nmol of rotenone caused time-dependent retinal neurodegeneration, especially in the inner retinal layer. TEM revealed pyknotic nuclei, enlarged granular endoplasmic reticula, and vacuolation of nerve fibers in GCL in such rotenone-treated eyes. Pyknotic nuclei were also observed in a subset of neuronal cells of the inner nuclear layer. No marked changes were observed in Müller cells or in other neuronal cells of the inner and outer retinal layer. The mRNA expression levels of a retinal ganglion-cell marker (neurofilament light-chain [NF-L]) and amacrine-cell markers (parvalbumin [PVA], tyrosine hydroxylase) were reduced by rotenone injection in a time- and dose-dependent manner. In contrast, the mRNA expression levels of bipolar-cell markers (metabotropic glutamate receptor 6 and protein kinase C alpha) and a rod-photoreceptor cell marker (rhodopsin) were not reduced. Co-injection of compounds related to excitotoxicity or oxidative stress with rotenone led to significant prevention of the rotenone-induced reductions in NF-L and PVA mRNA expression levels.
This study reveals that intravitreal injection of rotenone affected retinal ganglion cells and a subset of amacrine cells in the inner nuclear layer. Furthermore, our data suggest that oxidative stress and excitotoxicity are causal co-factors in this neurodegeneration. Rotenone is used in a model of Leber’s hereditary optic neuropathy, while both excitotoxicity and oxidative stress are thought to be involved in other neurodegenerative diseases (such as glaucoma or ischemic neuropathy). Therefore, rotenone-induced retinal neurodegeneration might be a useful model for research into these optic neuropathies.
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