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First Author: D.Lee SOUTH KOREA
Co Author(s): Y. Kim M. Ahn N. Cho W. Ju
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Glutamate excitotoxicity and/or oxidative stress has been linked to mitochondrial dysfunction in optic neuropathies including glaucoma. We recently reported that acute IOP elevation triggered glutamate excitotoxicity-?induced oxidative stress and upregulated mitochondrial transcription factor A (Tfam)/oxidative phosphorylation (OXPHOS) complex protein expression in ischemic rat retina. Coenzyme Q10 (CoQ10) acts by scavenging reactive oxygen species for protecting neuronal cells against oxidative stress in neurodegenerative diseases including Parkinsons and Huntington diseases. Here, we tested whether CoQ10 diet ameliorates glutamate excitotoxicity-? and/or oxidative stress-? mediated retinal ganglion cell (RGC) degeneration, as well as preserves mitochondrial DNA (mtDNA) content and Tfam/OXPHOS complex protein expression in the retina of a mouse model of glaucoma.
Pre-?glaucomatous DBA/2J and age-?matched non-? glaucomatous control DBA/2J- Gpnmb+ (D2 ?Gpnmb+) mice were fed with CoQ10 (1%) or control diet daily for 6 month.
Intraocular pressure (IOP) in the mice was measured monthly. To count retinal ganglion cell(RGC), immunohistochemistry of whole mounted retina was used with Brn3a antibody. The retinas were used for western blot analysis GFAP, Tfam, OXPHOS and NMDA receptors expression change was obseved.
CoQ10 diet promoted about 30% of RGC survival and inhibited astroglial activation by deceasing GFAP expression compared with control diet-?treated glaucomatous DBA/2J mouse retina. Intriguingly, CoQ10 diet significantly blocked the upregulations of N- methyl- D ?aspartate receptors 1 and 2B, as well as superoxide dismutase 2 and hemeoxygenase-?1 protein expression in the retinas of glaucomatous DBA/2J mice. In addition, CoQ10 diet significantly prevented apoptotic pathway by decreasing Bax and by increasing phosphorylated Bad protein expression. More importantly, CoQ10 diet preserved mtDNA content and Tfam/OXPHOS complex protein expression in the retinas of glaucomatous DBA/2J mice. Our results conclusively demonstrate that CoQ10 promotes RGC survival by inhibiting glutamate excitotoxicity, oxidative stress and Bax/Bad-?mediated apoptotic pathway, as well as by preserving mtDNA content and Tfam/OXPHOS complex protein expression in the retinas of glaucomatous DBA/2J mice.
We propose a vicious cycle involved in glaucomatous neurodegeneration that includes glutamate exicitotoxicity, oxidative stress, mtDNA alteration and mitochondrial dysfunction. Therefore, our findings suggest that CoQ10 may provide a promising therapeutic strategy for ameliorating glutamate excitotoxicity-and/or oxidative stress-?mediated mitochondrial dysfunction in glaucomatous neurodegeneration.