A randomized, placebo-controlled trial of the benzoquinone idebenone in a mouse model of OPA1-related dominant optic atrophy reveals a limited therapeutic effect on retinal ganglion cell dendropathy and visual function

Neuroscience
Terence Gordon SmithM Votruba

Abstract

Dominant optic atrophy (DOA) arises from mutations in the OPA1 gene that promotes fusion of the inner mitochondrial membrane and plays a role in maintaining ATP levels. Patients display optic disc pallor, retinal ganglion cell (RGC) loss and bilaterally reduced vision. We report a randomized, placebo-controlled trial of idebenone at 2000 mg/kg/day in 56 Opa1 mutant mice (B6;C3-Opa1(Q285STOP)), with RGC dendropathy and visual loss, and 63 wildtype mice. We assessed cellular responses in the retina, brain and liver and RGC morphology, by diolistic labeling, Sholl analysis and quantification of dendritic morphometric features. Vision was assessed by optokinetic responses. ATP levels were raised by 0.57 nmol/mg (97.73%, p=0.035) in brain from idebenone-treated Opa1 mutant mice, but in the liver there was an 80.35% (p=0.011) increase in oxidative damage. NQO1 expression in Opa1 mutant mice was reduced in the brain (to 30.5%, p=0.002) but not in retina, and neither expression level was induced by idebenone. ON-center RGCs failed to show major recovery, other than improvements in secondary dendritic length (by 53.89%, p=0.052) and dendritic territory (by 2.22 × 10(4) μm(2) or 90.24%, p=0.074). An improvement in optokinetic response wa...Continue Reading

References

Jun 1, 1984·Japanese Journal of Pharmacology·M Suno, A Nagaoka
Jun 1, 1994·Human Molecular Genetics·H EibergT Rosenberg
Mar 26, 1998·Archives of Ophthalmology·M VotrubaA T Moore
Oct 23, 1998·Journal of Medical Genetics·M VotrubaS S Bhattacharya
Dec 5, 1998·Naunyn-Schmiedeberg's Archives of Pharmacology·K HiraiM Miyamoto
Nov 10, 2004·Eye·N J Newman, V Biousse
May 26, 2005·Investigative Ophthalmology & Visual Science·Alistair J BarberSarah K Bronson
Mar 28, 2006·Experimental Eye Research·Vanessa Davies, Marcela Votruba
Apr 22, 2006·Neuroscience·J CoombsL M Chalupa
Dec 15, 2006·Journal of Cellular Physiology·Aurélien OlichonPascale Belenguer
Feb 23, 2007·Brain : a Journal of Neurology·Marcel V AlaviBernd Wissinger
Jun 15, 2007·Archives of Neurology·Nicholas A Di ProsperoJ Paul Taylor
Jan 7, 2009·European Journal of Clinical Pharmacology·Michael BodmerJürgen Drewe
Apr 11, 2009·Journal of Neurology·Klaus KutzPierre Vankan
Feb 17, 2010·Brain : a Journal of Neurology·P Yu-Wai-ManP F Chinnery
Sep 8, 2010·Brain : a Journal of Neurology·Pete A WilliamsMarcela Votruba
Oct 20, 2010·Expert Opinion on Drug Metabolism & Toxicology·Claudia BeckerJuergen Drewe
Oct 27, 2010·Genome Research·Ghizlane ElachouriGuy Lenaers
May 10, 2011·Molecular Biology of the Cell·Zhongyan ZhangHiromi Sesaki
Jul 27, 2011·Brain : a Journal of Neurology·Thomas KlopstockPatrick F Chinnery
Aug 2, 2011·Experimental Eye Research·Alun R BarnardRobert E MacLaren
Aug 4, 2011·Brain : a Journal of Neurology·Valerio CarelliPiero Barboni
Nov 17, 2011·Biochimica Et Biophysica Acta·Valentina GiorgioPaolo Bernardi
Feb 4, 2012·Brain : a Journal of Neurology·Pete A WilliamsMarcela Votruba
Jul 11, 2012·Orphanet Journal of Rare Diseases·Guy LenaersDan Milea
Dec 20, 2012·Brain : a Journal of Neurology·Emmanuelle SarziGuy Lenaers
Feb 8, 2013·Brain : a Journal of Neurology·Piero BarboniValerio Carelli
Jul 23, 2013·Journal of Neuroimmunology·Sebastian M FiebigerCarmen Infante-Duarte
Nov 1, 2013·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Luca Della SantinaRachel O L Wong
Feb 8, 2014·Journal of Neuroscience Methods·Luis Miguel Garcia-Segura, Julio Perez-Marquez

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Citations

Jul 17, 2018·Asia-Pacific Journal of Ophthalmology·Ungsoo Samuel KimPatrick Yu-Wai-Man
Feb 6, 2020·International Journal of Molecular Sciences·Piergiorgio La RosaFiorella Piemonte
Nov 8, 2020·Drugs·Giulia AmoreChiara La Morgia
Nov 25, 2020·Human Molecular Genetics·Serena J AleoClaudia Zanna
Dec 20, 2020·Progress in Retinal and Eye Research·Guy LenaersBernd Wissinger
Feb 20, 2018·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Valentina Del DottoClaudia Zanna
Jul 19, 2017·Mitochondrion·Leonardo CaporaliValerio Carelli

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