Mitochondrial Antioxidant SkQ1 as a Treatment for Age-Related Dry Eye Syndrome

The mitochondrially targeted antioxidant SkQ1 and other compounds in its family have moved into commercial development in Europe. Over the past decade these plastoquinone derivatives have been shown to modestly slow aging in flies and mice, but the greatest and most reliable effects involve reduction of inflammation and effective treatment of inflammatory eye conditions. Thus clinical development has focused on diseases such as dry eye syndrome, an unpleasant condition caused by age-related dysfunction of the lacrimal gland responsible for tear secretion. Aging eventually causes problems in every bodily system, including those that we tend to take for granted, not realizing that we will be greatly pained and inconvenienced by their failure.

Dry eye syndrome (DES) is a frequent eye disorder affecting many people worldwide, especially at an old age. DES is a multifactorial disorder of the ocular surface unit and results in eye discomfort, visual disturbances, and tear film instability with potential damage to the ocular surface and often poor quality of life. Current therapies for DES are only palliative, focusing on replacement of tear fluid to reduce the symptoms. Thus, there is a need for drugs that directly address the causes of DES. Clinical and basic studies have shown that the age-related decline of lacrimal-gland functions decreases the ability to synthesize and secrete proteins. These alterations may cause aqueous tear deficiency in DES. Approximately 80% of the lacrimal gland is acinar cells: highly differentiated epithelial cells specialized for the synthesis, storage, and secretion of tear fluid components, such as water, proteins, glycoproteins, and electrolytes. During aging, the synthesis and secretion of proteins decrease in lacrimal glands, and acinar cells start to produce and secrete a mucous product. The latter causes aberrations in the tear film of the eyes.

Researchers have compared ultrastructure of mitochondria in acinar cells of 6- and 12-month-old ad libitum fed Fischer 344 rats and uncovered occasional mitochondrial swelling, disorientation, shortening, and disorganization of cristae in the 12-month-old animals. Mitochondria, when dysregulated, are a major source and target of oxidative stress. Mitochondrial dysfunction strongly promotes aging and the pathogenesis of age-related diseases including eye diseases. Some authors demonstrated a connection of age-related alterations in the lacrimal gland with oxidative stress. Other authors showed the possibility of interventions (e.g., calorie restriction) aimed at reducing excessive production of reactive oxygen species (ROS) to prevent disturbances in the mitochondrial ultrastructure of acinar cells in the lacrimal gland. Changes in signaling pathways associated with age-related upregulation of oxidative stress have been detected in the aging lacrimal gland. Increased oxidative stress can result from reductions in insulin secretion and parasympathetic signaling accompanied by an increase in hormone resistance and by accumulation of advanced glycation end products in the aging lacrimal gland.

Thus, an increasing body of evidence suggests that prevention of upregulation of mitochondrial ROS is important for possible therapeutic strategies to delay age-associated alterations and to prevent age-related disorders in humans. Despite the disappointing effects of antioxidants in clinical trials, there is growing evidence of beneficial effects of mitochondria-targeted antioxidants during aging and in age-related diseases. Previously, we showed that mitochondria-targeted antioxidant 10-(6′-plastoquinonyl) decyltriphenyl phosphonium cation (SkQ1) ameliorates the signs of aging and inhibits the development of such age-related diseases as cataract, age-related macular degeneration, and glaucoma in rats. SkQ1 (under the brand name Visomitin) in the form of eye drops is already manufactured and has been successfully used since 2012 for treatment of DES in Russia. Nevertheless, the link between SkQ1's effects and its suppression of age-related aberrations in the lacrimal gland has not been explored. The aim of this study was to examine the effects of long-term dietary supplementation with SkQ1 on age-related deterioration of lacrimal-gland ultrastructure Wistar rats.

Here we demonstrated that dietary supplementation with SkQ1 (250 nmol/[kg body weight] daily) starting at age 1.5 months significantly alleviated the pathological changes in lacrimal glands of Wistar rats by age 24 months. By this age, lacrimal glands underwent dramatic deterioration of the ultrastructure that was indicative of irreversible disturbances in these glands' functioning. In contrast, in SkQ1-treated rats, the ultrastructure of the lacrimal gland was similar to that in much younger rats. Morphometric analysis of electron-microscopic specimens of lacrimal glands revealed the presence of numerous secretory granules in acinar cells and a significant increase in the number of operating intercalary ducts. Our results confirm that dietary supplementation with SkQ1 is a promising approach to healthy ageing and to prevention of aberrations in the lacrimal gland that underlie dry eye syndrome.



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