Dr Nicholas Young
BSc(Hons) BOptom PhD(Med) GradCertOcTher
Director, The Dry Eye Centre Heathmont VIC
In the quest for human immortality, some notable contributions are well documented. Of particular interest is the free radical theory of ageing proposed by physicist Denham Harman in 1956.1 Harmon’s theory was that cumulative cell damage leads to cell death and the ageing of an organism, due to unstable free-radical molecules.
At a molecular level, free radicals are atoms or molecules with unpaired valence electrons. Consequently, they are unstable and reactive. In cells, free radicals are produced primarily by the enzyme-mediated conversion of O2 to superoxide (O2-) and hydrogen peroxide (H2O2).2 The effects of their instability can be observed by these reactive substances ‘stealing’ electrons from other chemical entities. While this can be harmless, damage will occur if the ‘theft’ is from a chemical entity that cannot function without its stolen electron.3
Free radicals are sometimes referred to as reactive oxygen species (ROS) and their consequences on biological systems are now well-documented in numerous disease states. Oxidative stress describes the extent to which a biological system can withstand the effects of ROS with antioxidative measures.
Mitochondrial theory of ageing
In modified form, Harman’s theory further proposes that critical destructive effects of ROS occur within mitochondria. The mitochondrial theory of ageing proposes that ROS mutation of mDNA and protein and lipid damage leads to further ROS accumulation, increased oxidative stress and eventual destruction of the mitochondrial unit.4
Critics of the theory point out that ROS are also involved in positive effects on mitochondria, such as signal transduction/processing functions critical for maintaining cellular health.5,6 Therefore, this aspect of cell homeostasis can be somewhat oversimplified as a balance between toxic and beneficial effects of oxidative stress and the cell’s ability to recover from any damage sustained.
Studies of mitochondrial-delivered antioxidants have shown mixed but overall positive effects on tissue and organ structures from various species of animal models and humans. While the effects of supplementing our diets with foods and pills that might increase our lifespans continues to be explored, a more specific target of ROS research—dry eye—is also now showing promise.
Depending on one’s reading of the existing literature on the topic, the SKQ1 molecule is everything from a potential cure of various ailments to the elixir of immortality. Before the reader switches off and moves to the next article, it may be worth paying some serious attention to SKQ1.
SK, short for ‘Skulachev’, is a patented organic cation containing a phosphorus atom, with three hydrophobic phenyl residues that can penetrate the lipid bilayer of the mitochondrial membrane. Given the negatively-charged state of the mitochondrial interior, the cation concentration readily accumulates up to 1,000-fold higher than in the extracellular space. Attached to the SK molecule is an augmented plastoquinone (an electron carrying antioxidant): plastoquinonyl-decyl-triphenyl-phosphonium, designated ‘Q’. The combined molecule is called SKQ1 and was invented by Skulachev and colleagues.7
The scientists behind the compound have produced volumes of peer-reviewed studies supportive of the remissive and life-prolonging effects of their molecule. Vladamir Skulachev, who is credited with the invention of SKQ1, is a scientific icon in Eastern Europe and has a significant following elsewhere.
Dry eye and SKQ1
Notable diseases of SKQ1 inquiry with promising results include Alzheimer’s, Parkinson’s and other neuro-degenerative diseases, thymus disease, dermal wound healing, acute pyelonephritis and kidney disease, ischaemia-induced heart arrhythmia and tissue damage in myocardial infarction and stroke.8,9 However, perhaps the most interesting area of inquiry is the role of SKQ1 in dry eye disease.
Dry eye specialists know all too well the refractory nature of the condition. Skulachev and colleagues chose to investigate the effects of SKQ1 on dry eye for this reason.
Investigation of SKQ1 in dry eye has progressed remarkably quickly in Russia, from a novel chemical entity to a registered topical treatment in just a few years. The ophthalmic formulation of SKQ1 is called ‘Visomitin.’ Preclinical studies found the drug to be safe at the likely therapeutic dosages.10
In the initial human clinical trial, SKQ1 was compared with Tears Naturale (Alcon) in a group of dry eye patients over 21 days. SKQ1 produced a significantly greater reduction in conjunctival hyperaemia and oedema, corneal micro-erosions and improved vision compared with Tears Naturale. In most cases, the ocular signs of dry eye almost completely resolved in the SKQ1 group (Figure 1).10,11
Figure 1. Comparison of efficacy of SKQ1-based eye-drops Visomitin and Tears Naturale (Alcon) in clinical trials on patients suffering from dry eye syndrome. Percentage of successful cases is indicated p < 0.001. A case was considered successful if the dry eye symptoms disappeared completely.
As mentioned, the Anglicised name for the topical SKQ1 eye-drop now marketed in Russia is Visomitin. A Luxemberg-based pharmaceutical company, Mitotech, has the US rights for Visomitin and is also now conducting clinical trials for the US Food and Drug Administration. Mitotech presented data of the Phase 1 safety and Phase 2 safety and efficacy studies at ARVO in Denver, USA earlier this year. A conjunctival cell culture model was used to investigate whether SKQ1 could down-regulate an inflammatory response of surface epithelial cells. SKQ1 proved effective and non-toxic at therapeutic dose levels below 300 nM.12
In the Phase 2 single-centre randomised, double-masked, placebo-controlled study, a controlled adverse environment (CAE) was created for 91 dry eye subjects. Key eligibility criteria included scores of > 2, > 0.5 and > 2 for fluorescein corneal staining (FCS), inferior region FCS, and one symptom from a four-symptom questionnaire, respectively. A positive response to CAE exposure on two visits with exacerbation of FCS and ocular discomfort were also required. Eligible subjects were dosed bid with 1.55 µg/mL SKQ1, 0.155 µg/mL SKQ1 or placebo for 28 days and recorded their symptoms in diaries. Efficacy was assessed as the amount of inferior region FCS pre-CAE and at day 28 as well as diary data for the 28-day period.
Differences were observed for total FCS scores in the intention-to-treat group when compared pre and post CAE at day 28 (p = 0.0452). Differences in dry eye symptom scores were also observed for ‘ocular discomfort’ when day 28 and baseline scores were compared (p = 0.0068). SKQ1 was also safe and well tolerated with no significant differences in adverse events between treatment groups and controls.13
Ocular SKQ1 studies are not limited to dry eye disease. In 2008, a series of laboratory and veterinary animal based experiments were published involving SKQ1 treatment in a range of ocular conditions. Notably, SKQ1 reversed cataract and retinopathies in 3-12-month-old, but not in 24-month-old, OXYS (senescence accelerated) rats.
Laboratory-induced uveitis and glaucoma were found to be prevented or reversed by instillation of SKQ1 drops in rabbits. In 271 veterinary based animals (dogs, cats, and horses) with retinopathies, uveitis, conjunctivitis and corneal diseases, the ocular health of 242 animals improved with SKQ1. Of the 89 animals blind on presentation, vision returned to 67 after treatment. Ex vivo studies of cultivated posterior retina sector showed a reduction of macrophage transformation of the retinal pigmented epithelial following 20 nM SKQ114 Studies now continue in earnest in glaucoma, light-induced retinal degeneration, non-exudative macular disease, cataract and uveitis.
Hope for dry eye?
This article is intended to provide a snapshot rather than a comprehensive review of mitochondrial antioxidants. As the evidence mounts, researchers are moving away from early claims of SKQ1’s anti-ageing benefits. According to the data currently available, SKQ1 does at least appear to hold the promise of symptom remission for many dry eye patients.
SKQ1’s potential role in various other ocular and systemic diseases is also of great interest. Of course, eye-care professionals and dry-eye patients know all about false hope. While it is important to keep perspective, it is hard not to get just a little excited about the possibilities for SKQ1.
- Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol 1956; 11: 3: 298-300.
- Skulachev VP. Mitochondrial physiology and pathology; concepts of programmed death of organelles, cells and organisms. Mol Aspects Med 1999; 20: 139-184.
- Hang C, Kong Y, Zhang H. Oxidative stress, mitochondrial dysfunction, and aging. J Signal Transduction 2012; 1-13.
- Harman D. Origin and evolution of the free radical theory of aging: a brief personal history, 1954-2009. Biogerontology 2009; 10: 6: 773-781.
- Brink TC, Demetrius L, Lehrach H et al. Age-related transcriptional changes in gene expression in different organs of mice support the metabolic stability theory of aging. Biogerontology 2009; 10: 5: 549-564.
- Yee C, Yang W, Hekimi S. The intrinsic apoptosis pathway mediates the pro-longevity response to mitochondrial ROS in C elegans. Cell 2014; 157: 897-909.
- Skulachev VP. A biochemical approach to the problem of aging: ‘megaproject’ on membrane-penetrating ions. The Biochemistry (Mosc) 2007; 72: 12: 1385-1396.
- Egor Y, Plotnikov MA, Morosanova IB et al. Protective effect of mitochondria-targeted antioxidants in an acute bacterial infection. Proc Natl Acad Sci (USA) 2013; 110: 33. E3100–E3108. Published online 2013 July 29.
- Skulachev VP, Anisimov VN, Antonenko YN et al. An attempt to prevent senescence: a mitochondrial approach. Biochim Biophys Acta 2009; 1787: 5: 437-461.
- Yani EV, Katargina LA, Chesnokova NB et al. The first experience of using the drug Visomitin in the treatment of ‘dry eyes’ Pract Med 2012; 4: 134-137. (Russ) Translation available on request.
- Osiewacz HD. Progress in molecular biology and translational science. The mitochondrion in aging and disease. Academic Press: 2014; 127.
- Wei Y, Asbell PA, Perekhvatova N et al. Role of SKQ1 on inflammatory responses associated with ocular surface disease: a cell culture model. Invest Ophthalmol Vis Sci 2015; 56: 7: 1184. (Meeting abstract)
- Perekhvatova N, Petrov A, Friedhoff L et al. Evaluation of anti-oxidant SKQ1 as a treatment for the signs and symptoms of dry eye. Invest Ophthalmol Vis Sci 2015; 56: 7: 4481. (Meeting abstract)
- Neroev VV, Archipova MM, Bakeeva LE et al. 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) 2008; 73: 12: 1317-1328.