Mitochondria-targeted antioxidant SkQ1 reverses glaucomatous lesions in rabbits

Original article is published in: Frontiers in Bioscience, Landmark, 20, 892–901, January 1, 2015

Glaucoma is the main cause of irreversible blindness worldwide. This disease is characterized by apoptosis of retinal ganglion cells (RGC) and visual field loss that seems to be related to elevated intraocular pressure (IOP). Several lines of evidences have implicated the crucial role of mitochondrial dysfunction in the pathogenesis of glaucoma. Increased mitochondrial oxidative stress in RGC may underlie or contribute to susceptibility of RGC to apoptosis. In our work we (i) designed a rabbit model of chronic, moderately elevated IOP for studying glaucoma and (ii) demonstrated efficacy of mitochondria-targeted antioxidant SkQ1 as a tool to reverse several traits of experimental glaucoma induced by a series of injections of hydroxypropylmethylcellulose (HPMC) to the anterior chamber of the rabbit eye. It is shown that 6 months instillations of drops of 0.2.5–5 µM solution of SkQ1 normalize IOP and eye hydrodynamics and abolish an increase in lens thickness that accompanies glaucoma.

1. Quigley HA, AT Broman: The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 90, 262-267 (2006) DOI: 10.1136/bjo.2005.081224

2. Quigley HA: Glaucoma: macrocosm to microcosm the Friedenwald lecture. Invest Ophthalmol Vis Sci 46, 2662-2670 (2005) DOI: 10.1167/iovs.04-1070

3. Leske MC, A Heijl, L Hyman, B Bengtsson, L Dong, Z Yang: Predictors of long-term progression in the early manifest glaucoma trial. Ophthalmology 114, 1965-1972 (2007) DOI: 10.1016/j.ophtha.2007.03.016

4. Tezel G, MB Wax: Hypoxia-inducible factor 1alpha in the glaucomatous retina and optic nerve head. Arch Ophthalmol 122, 1348-1356 (2004) DOI: 10.1001/archopht.122.9.1348

5. He Z, AJ Vingrys, JA Armitage, J. BV Bui: The role of blood pressure in glaucoma. Clin Exp Optom 94, 133-149 (2011) DOI: 10.1111/j.1444-0938.2010.00564.x

6. Cioffi GA: Three common assumptions about ocular blood flow and glaucoma. Surv Ophthalmol 45, S325-S331 (2001) DOI: 10.1016/S0039-6257(01)00199-0

7. Osborne NN, J Melena, G Chidlow, JPM Wood: A hypothesis to explain ganglion cell death caused by vascular insults at the optic nerve head: possible implication for the treatment of glaucoma. Br J Ophthalmol 85, 1252-1259 (2001) DOI: 10.1136/bjo.85.10.1252

8. Lafuente MP, MP Villegas-Perez, I Selles-Navarro, S Mayor-Torroglosa, JM De Imperial, M Vidal-Sanz: Retinal ganglion cell death after acute retinal ischemia is an ongoing process whose severity and duration depends on the duration of the insult. Neuroscience 109, 157-168 (2002) DOI: 10.1016/S0306-4522(01)00458-4

9. Adachi M, K Takahashi, M Nishikawa, H Miki, M Uyama: High intraocular pressure-induced ischemia and reperfusion injury in the optic nerve and retina in rats. Graefes Arch Clin Exp Ophthalmol 234, 445- 451 (1996) DOI: 10.1007/BF02539411

10. Bouhenni RA, J Dunmire, A Sewell, DP Edward: Animal Models of Glaucoma. J Biomed Biotech 2012, 692609 (2012) DOI: 10.1155/2012/692609

11. Urcola JH, M Hernandez, E Vecino: Three experimental glaucoma models in rats: Comparison of the effects of intraocular pressure elevation on retinal ganglion cell size and death. Exp Eye Res 83, 429-437 (2006) DOI: 10.1016/j.exer.2006.01.025

12. Benozzi J, LP Nahum, JL Campanelli, RE Rosenstein: Effect of hyaluronic acid on intraocular pressure in rats. Invest Ophthalmol Vis Sci 43, 2196-2200 (2002)

13. Moreno MC, J Campanelli, P Sande, DA Saenz, MISK Sarmiento, RE Rosenstein: Retinal oxidative stress induced by high intraocular pressure. Free Rad Biol Med 37, 803-812 (2004) DOI: 10.1016/j.freeradbiomed.2004.06.001

14. York M, W Steiling: A critical review of the assessment of eye irritation potential using the Draize rabbit eye test. J Appl Toxicol 18, 233-240 (1998) DOI: 10.1002/(SICI)1099-1263(199807/08)18:43.0.CO;2-Y

15. Abu-Amero KK, J Morales, TM Bosley: Mitochondrial abnormalities in patients with primary open-angle glaucoma. Invest Ophthalmol Vis Sci 47, 2533-2541 (2006) DOI: 10.1167/iovs.05-1639

16. Chrysostomou V, F Rezania, IA Trounce, JG Crowston: Oxidative stress and mitochondrial dysfunction in glaucoma. Curr Opin Pharmacol 13, 12-15 (2013) DOI: 10.1016/j.coph.2012.09.008

17. Lee D, KY Kim, YH Noh, S Chai, JD Lindsey, MH Ellisman, RN Weinreb, WK Ju: Brimonidine Blocks Glutamate Excitotoxicity-Induced Oxidative Stress and Preserves Mitochondrial Transcription Factor A in Ischemic Retinal Injury. PLoS One 7, e47098 (2012) DOI: 10.1371/journal.pone.0047098

18. Skulachev VP: Functions of mitochondria: from intracellular power stations to mediators of a senescence program. Cell Mol Life Sci 66, 1785-1793 (2009) DOI: 10.1007/s00018-009-9183-6

19. Skulachev VP: Mitochondrial physiology and pathology; concepts of programmed death of organelles, cells and organisms. Mol Aspects Med 20, 139-184 (1999) DOI: 10.1016/S0098-2997(99)00008-4

20. Korshunov SS, VP Skulachev, AA Starkov: High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett 416, 15-18 (1997) DOI: 10.1016/S0014-5793(97)01159-9

21. Izzotti A, SC Sacca, B Di Marco, S Penco, AM Bassi: Antioxidant activity of timolol on endothelial cells and its relevance for glaucoma course. Eye (Lond) 22, 445-453 (2008) DOI: 10.1038/sj.eye.6702737

22. Kelso GF, CM Porteous, CV Coulter, G Hughes, WK Porteous, EC Ledgerwood, RA Smith, MP Murphy: Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. J Biol Chem 276, 4588-4596 (2001) DOI: 10.1074/jbc.M009093200

23. Skulachev VP: Cationic antioxidants as a powerful tool against mitochondrial oxidative stress. Biochem Biophys Res Commun 441, 275-279 (2013) DOI: 10.1016/j.bbrc.2013.10.063

24. Antonenko YN, AV Avetisyan, LE Bakeeva, BV Chernyak, VA Chertkov, LV Domnina, OY Ivanova, DS Izyumov, LS Khailova, SS Klishin, GA Korshunova, KG Lyamzaev, MS Muntyan, OK Nepryakhina, AA Pashkovskaya, OY Pletjushkina, AV Pustovidko, VA Roginsky, TI Rokitskaya, EK Ruuge, VB Saprunova, II Severina, RA Simonyan, IV Skulachev, MV Skulachev, NV Sumbatyan, IV Sviryaeva, VN Tashlitsky, JM Vassiliev, MY Vyssokikh, LS Yaguzhinsky, AA Zamyatnin Jr, VP Skulachev: Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 1. Cationic plastoquinone derivatives: synthesis and in vitro studies. Biochemistry (Mosc) 73, 1273-1287 (2008) DOI: 10.1134/S0006297908120018

25. Skulachev VP, VN Anisimov, YN Antonenko, LE Bakeeva, BV Chernyak, VP Erichev, OF Filenko, NI Kalinina, VI Kapelko, NG Kolosova, BP Kopnin, GA Korshunova, MR Lichinitser, LA Obukhova, EG Pasyukova, OI Pisarenko, VA Roginsky, EK Ruuge, II Senin, II Severina, MV Skulachev, IM Spivak, VN Tashlitsky, VA Tkachuk, MY Vyssokikh, LS Yaguzhinsky, DB Zorov: An attempt to prevent senescence: a mitochondrial approach. Biochim Biophys Acta 1787, 437-461 (2009) DOI: 10.1016/j.bbabio.2008.12.008

26. Skulachev MV, YN Antonenko, VN Anisimov, BV Chernyak, DA Cherepanov, VA Chistyakov, MV Egorov, NG Kolosova, GA Korshunova, KG Lyamzaev, EY Plotnikov, VA Roginsky, AY Savchenko, II Severina, FF Severin, TP Shkurat, VN Tashlitsky, KM Shidlovsky, MY Vyssokikh, AA Zamyatnin Jr, DB Zorov, VP Skulachev: Mitochondrial-targeted plastoquinone derivatives. Effect on senescence and acute age-related pathologies. Curr Drug Targets 12, 800-826 (2011) DOI: 10.2174/138945011795528859

27. Plotnikov EY, MA Morosanova, IB Pevzner, LD Zorova, VN Manskikh, NV Pulkova, SI Galkina, VP Skulachev, DB Zorov: Protective effect of mitochondria-targeted antioxidants in an acute bacterial infection. Proc Natl Acad Sci USA 110, E3100-E3108 (2013) DOI: 10.1073/pnas.1307096110

28. Neroev VV, MM Archipova, LE Bakeeva, A Fursova, EN Grigorian, AY Grishanova, EN Iomdina, ZN Ivashchenko, LA Katargina, IP Khoroshilova-Maslova, OV Kilina, NG Kolosova, EP Kopenkin, SS Korshunov, NA Kovaleva, YP Novikova, PP Philippov, DI Pilipenko, OV Robustova, VB Saprunova, II Senin, MV Skulachev, LF Sotnikova, NA Stefanova, NK Tikhomirova, IV Tsapenko, AI Shchipanova, RA Zinovkin, VP Skulachev: Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 4. Age-related eye disease. SkQ1 returns vision to blind animals. Biochemistry (Mosc) 73, 1317- 1328 (2008) DOI: 10.1134/S0006297908120043

29. Sasaoka M, T Taniguchi, M Shimazawa, N Ishida, A Shimazaki, H Hara: Intravitreal injection of endothelin-1 caused optic nerve damage following to ocular hypoperfusion in rabbits. Exp Eye Res 83, 629-637 (2006) DOI: 10.1016/j.exer.2006.03.007

30. Barron BA, M Busin, C Page, DR Bergsma, HE Kaufman: Comparison of the effects of Viscoat and Healon on postoperative intraocular pressure. Am J Ophthalmol 100, 377-384 (1985)

31. Liesegang TJ, WM Bourne, DM Ilstrup: The use of hydroxypropyl methylcellulose in extracapsular cataract extraction with intraocular lens implantation. Am J Ophthalmol 102, 723-726 (1986)

32. Zhu MD, FY Cai: Development of experimental chronic intraocular hypertension in the rabbit. Aust N Z J Ophthalmol 20, 225-234 (1992) DOI: 10.1111/j.1442-9071.1992.tb00944.x

33. Ju WK, KY Kim, JD Lindsey, M Angert, KX Duong-Polk, RT Scott, JJ Kim, I Kukhmazov, MH Ellisman, GA Perkins, RN Weinreb: Intraocular pressure elevation induces mitochondrial fission and triggers OPA1 release in glaucomatous optic nerve. Invest Ophthalmol Vis Sci 49, 4903-4911 (2008) DOI: 10.1167/iovs.07-1661

34. Patten DA, VN Lafleur, GA Robitaille, DA Chan, AJ Giaccia, DE Richard: Hypoxia-inducible factor-1 activation in nonhypoxic conditions: the essential role of mitochondrial-derived reactive oxygen species. Mol Biol Cell 21, 3247-3257 (2010) DOI: 10.1091/mbc.E10-01-0025

35. Guo L, TE Salt, V Luong, N Wood, W Cheung, A Maass, G Ferrari, F Russo-Marie, AM Sillito, ME Cheetham, SE Moss, FW Fitzke, MF Cordeiro: Targeting amyloid-beta in glaucoma treatment. Proc Natl Acad Sci USA 104, 13444-13449 (2007) DOI: 10.1073/pnas.0703707104

36. Li J, Z Dong, B Liu, Y Zhuo, X Sun, Z Yang, J Ge, Z Tan: Hypoxia induces beta-amyloid in association with death of RGC-5 cells in culture. Biochem Biophys Res Commun 410, 40-44 (2011) DOI: 10.1016/j.bbrc.2011.05.101

37. Stefanova NA, NA Muraleva, VP Skulachev, NG Kolosova: Alzheimer’s disease-like pathology in senescence-accelerated OXYS rats can be partially retarded with mitochondria-targeted antioxidant SkQ1. J Alzheimers Dis 38, 681-694 (2014) DOI: 10.3233/JAD-131034

38. Kapay NA, OV Popova, NK Isaev, EV Stelmashook, RV Kondratenko, DB Zorov, VG Skrebitsky, VP Skulachev: Mitochondria-targeted plastoquinone antioxidant SkQ1 prevents amyloid-beta-induced impairment of long-term potentiation in rat hippocampal slices. J Alzheimers Dis 36, 377-383 (2013) DOI: 10.3233/JAD-122428