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M. F. Cordeiro, S. Nizari, W. Cheung, L. Guo; Mitochondrial Mechanisms in RGC Apoptosis in Glaucoma. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4046.
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Changes in mitochondrial activity and the mitochondrial permeability transition pore complex (MPTP) are increasingly implicated in neurodegenerative disease, where they often precede neuronal apoptosis. However the role of Cytochrome C Oxidase (COX), a marker of neuronal mitochondrial energetic metabolism, and constituents of the MPTP (VDAC, ANT, Hexokinase II (Hexo) and Cycophilin D (CypD)), have not previously been studied together in glaucoma. In this study, we investigated changes in MPTP markers and COX activity, in relation to RGC apoptosis in an OHT rat model, and treatment with the neuroprotective agent CoEnzyme Q10 (CoQ10).
Using our established chronic ocular hypertension (OHT) rat model, IOP was induced in 24 animals, with DARC imaging performed at 3 and 12 weeks after IOP elevation. Animals were randomly assigned to no treatment (untreated OHT) or CoQ10 0.1% eyedrops (Visufarma srl, Italy) 30 minutes before, and 1 hour and 1, 3 & 6 weeks after IOP elevation (treated OHT), and unoperated, opposite eyes were used as controls (controls). Immunohistological analysis of VDAC, Hexo II, COX, ANT and Cyp D expression was performed on sequential 5 µm thick paraffin sections from enucleated eyes (n=6 per treatment group) at 3 & 12 weeks.
DARC imaging recorded showed that CoQ10 0.1% significantly inhibited the development of RGC apoptosis in OHT eyes at 3 weeks (95.6% reduction RGC apoptosis treated OHT compared to untreated OHT, p<0.05) though not at 12 weeks. Immunohistological assessment showed at 3 weeks significant elevation of CypD in RGC layer in all OHT eyes compared to control (p<0.05), and this was significantly greater in treated OHT eyes (p<0.05). VDAC was significantly increased in all OHT eyes (p<0.05) compared to control but with no difference between treatment groups at 3 weeks. Finally, levels of COX were significantly (p<0.05) increased in treated OHT eyes compared to control (p<0.05) at 3 weeks only.
Changes in the mitochondrial markers predictablyhave a similar profile to the development of RGC apoptosis in this experimental model of glaucoma. Mitochondrial activity is maximal at the time of peak RGC apoptosis activity (3 weeks). The effects of CoQ10 being neuroprotective appear to be mediated through the mitochondria, although further work needs to be done with respect to its effect on CypD, which is known to be a repressor of apoptosis. We suggest that the targeting of mitochondrial activity, and delineation of its relationship with RGC apoptosis could have great potential in the management of glaucoma.
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