Coenzyme Q10 inhibits glutamate excitotoxicity and oxidative stress-mediated mitochondrial alteration in a mouse model of glaucoma.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
Our findings suggest that CoQ10 may be a promising therapeutic strategy for ameliorating glutamate excitotoxicity and oxidative stress in glaucomatous neurodegeneration.
Laboratory for Optic Nerve Biology, Hamilton Glaucoma Center and Department of Ophthalmology, University of California, San Diego, La Jolla, California.
Dongwook
D
Lee
Myoung Sup
MS
Shim
Keun-Young
KY
Kim
You Hyun
YH
Noh
Heemin
H
Kim
Sang Yeop
SY
Kim
Robert N
RN
Weinreb
Won-Kyu
WK
Ju
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology; D015153:Blotting, Western; D004195:Disease Models, Animal; D005260:Female; D005901:Glaucoma / Q000188:drug therapy* / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein; D018698:Glutamic Acid / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D060888:Real-Time Polymerase Chain Reaction; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012162:Retinal Degeneration / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000473:pathology; D013482:Superoxide Dismutase / Q000378:metabolism; D014451:Ubiquinone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014815:Vitamins / Q000008:administration & dosage / Q000627:therapeutic use*; D051025:bcl-Associated Death Protein / Q000378:metabolism; D000099156:Superoxide Dismutase 2
D005904:Glial Fibrillary Acidic Protein; D018698:Glutamic Acid; D051547:Heme Oxygenase-1; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D013482:Superoxide Dismutase; D014451:Ubiquinone; D014815:Vitamins; D051025:bcl-Associated Death Protein; D000099156:Superoxide Dismutase 2; C494820:Bad protein, mouse; C528900:glial fibrillary astrocytic protein, mouse; C496542:Hmox1 protein, mouse; C024989:coenzyme Q10
coenzyme Q10; excitotoxicity; glaucoma; mitochondrial alteration; oxidative stress