ubiquinone and Retinal-Degeneration

Topics: Animals; Antioxidants; Apoptosis; Astrocytes; bcl-2-Associated X Protein; bcl-Associated Death Protein; bcl-X Protein; Caspase 3; Cell Survival; Disease Models, Animal; Female; Gene Expression Regulation; Intraocular Pressure; Mice; Mice, Inbred C57BL; Microglia; Oxidative Stress; Phosphorylation; Reactive Oxygen Species; Reperfusion Injury; Retinal Degeneration; Retinal Ganglion Cells; Signal Transduction; Ubiquinone

To test whether a diet supplemented with coenzyme Q10 (CoQ10) ameliorates glutamate excitotoxicity and oxidative stress-mediated retinal ganglion cell (RGC) degeneration by preventing mitochondrial alterations in the retina of glaucomatous DBA/2J mice.. Preglaucomatous DBA/2J and age-matched control DBA/2J-Gpnmb(+) mice were fed with CoQ10 (1%) or a control diet daily for 6 months. The RGC survival and axon preservation were measured by Brn3a and neurofilament immunohistochemistry and by conventional transmission electron microscopy. Glial fibrillary acidic protein (GFAP), superoxide dismutase-2 (SOD2), heme oxygenase-1 (HO1), N-methyl-d-aspartate receptor (NR) 1 and 2A, and Bax and phosphorylated Bad (pBad) protein expression was measured by Western blot analysis. Apoptotic cell death was assessed by TUNEL staining. Mitochondrial DNA (mtDNA) content and mitochondrial transcription factor A (Tfam)/oxidative phosphorylation (OXPHOS) complex IV protein expression were measured by real-time PCR and Western blot analysis.. Coenzyme Q10 promoted RGC survival by approximately 29% and preserved the axons in the optic nerve head (ONH), as well as inhibited astroglial activation by decreasing GFAP expression in the retina and ONH of glaucomatous DBA/2J mice. Intriguingly, CoQ10 significantly blocked the upregulation of NR1 and NR2A, as well as of SOD2 and HO1 protein expression in the retina of glaucomatous DBA/2J mice. In addition, CoQ10 significantly prevented apoptotic cell death by decreasing Bax protein expression or by increasing pBad protein expression. More importantly, CoQ10 preserved mtDNA content and Tfam/OXPHOS complex IV protein expression in the retina of glaucomatous DBA/2J mice.. Our findings suggest that CoQ10 may be a promising therapeutic strategy for ameliorating glutamate excitotoxicity and oxidative stress in glaucomatous neurodegeneration.

Topics: Animals; Axons; bcl-Associated Death Protein; Blotting, Western; Disease Models, Animal; Female; Glaucoma; Glial Fibrillary Acidic Protein; Glutamic Acid; Heme Oxygenase-1; In Situ Nick-End Labeling; Membrane Proteins; Mice; Mice, Inbred DBA; Mitochondria; Nerve Tissue Proteins; Oxidative Stress; Real-Time Polymerase Chain Reaction; Receptors, N-Methyl-D-Aspartate; Retinal Degeneration; Retinal Ganglion Cells; Superoxide Dismutase; Ubiquinone; Vitamins

The role of oxidative stress within photoreceptors (PRs) in inherited photoreceptor degeneration (IPD) is unclear. We investigated this question using four IPD mouse models (Pde6b(rd1/rd1), Pde6b(atrd1/atrd1), Rho(-/-) and Prph2(rds/rds)) and compared the abundance of reduced glutathione (GSH) and the activity of mitochondrial NADH:ubiquinone oxidoreductase (complex I), which is oxidative stress sensitive, as indirect measures of redox status, in the retinas of wild type and IPD mice. All four IPD mutants had significantly reduced retinal complex I activities (14-29% of wild type) and two showed reduced GSH, at a stage prior to the occurrence of significant cell death, whereas mitochondrial citrate synthase, which is oxidative stress insensitive, was unchanged. We orally administered the mitochondrially targeted anti oxidant MitoQ in order to reduce oxidative stress but without any improvement in retinal complex I activity, GSH or rates of PR degeneration. One possible source of oxidative stress in IPDs is oxygen toxicity in the outer retina due to reduced consumption by PR mitochondria. We therefore asked whether a reduction in the ambient O(2) concentration might improve PR survival in Pde6b(rd1/rd1) retinal explants either directly, by reducing reactive oxygen species formation, or indirectly by a neuroprotective mechanism. Pde6b(rd1/rd1) retinal explants cultured in 6% O(2) showed 31% less PR death than normoxic explants. We conclude that (i) mitochondrial oxidative stress is a significant early feature of IPDs; (ii) the ineffectiveness of MitoQ may indicate its inability to reduce some mediators of oxidative stress, such as hydrogen peroxide; and (iii) elucidation of the mechanisms by which hypoxia protects mutant PRs may identify novel neuroprotective pathways in the retina.

Topics: Animals; Antioxidants; Cell Hypoxia; Cell Survival; Disease Models, Animal; Electron Transport Complex I; Glutathione; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred DBA; Mitochondria; Organophosphorus Compounds; Oxidative Stress; Photoreceptor Cells; Retinal Degeneration; Superoxide Dismutase; Ubiquinone