Generation of reactive oxygen species in the anterior eye segment. Synergistic codrugs of N-acetylcarnosine lubricant eye drops and mitochondria-targeted antioxidant act as a powerful therapeutic platform for the treatment of cataracts and primary open-angle glaucoma

Abstract

Senile cataract is a clouding of the lens in the aging eye leading to a decrease in vision. Symptoms may include faded colors, blurry vision, halos around light, trouble with bright lights, and trouble seeing at night. This may result in trouble driving, reading, or recognizing faces. Cataracts are the cause of half of blindness and 33% of visual impairment worldwide. Cataracts result from the deposition of aggregated proteins in the eye lens and lens fiber cells plasma membrane damage which causes clouding of the lens, light scattering, and obstruction of vision. ROS induced damage in the lens cell may consist of oxidation of proteins, DNA damage and/or lipid peroxidation, all of which have been implicated in cataractogenesis. The inner eye pressure (also called intraocular pressure or IOP) rises because the correct amount of fluid can't drain out of the eye. With primary open-angle glaucoma, the entrances to the drainage canals are clear and should be working correctly. The clogging problem occurs further inside the drainage canals, similar to a clogged pipe below the drain in a sink.

The excessive oxidative damage is a major factor of the ocular diseases because the mitochondrial respiratory chain in mitochondria of the vital cells is a significant source of the damaging reactive oxygen species superoxide and hydrogen peroxide. However, despite the clinical importance of mitochondrial oxidative damage, antioxidants have been of limited therapeutic success. This may be because the antioxidants are not selectively taken up by mitochondria, but instead are dispersed throughout the body, ocular tissues and fluids' moieties.

This work is an attempt to integrate how mitochondrial reactive oxygen species (ROS) are altered in the aging eye, along with those protective and repair therapeutic systems believed to regulate ROS levels in ocular tissues and how damage to these systems contributes to age-onset eye disease and cataract formation.

Mitochondria-targeted antioxidants might be used to effectively prevent ROS-induced oxidation of lipids and proteins in the inner mitochondrial membrane in vivo. The authors developed and patented the new ophthalmic compositions including N-acetylcarnosine acting as a prodrug of naturally targeted to mitochondria l-carnosine endowed with pluripotent antioxidant activities, combined with mitochondria-targeted rechargeable antioxidant (either MitoVit E, Mito Q or SkQs) as a potent medicine to treat ocular diseases. Such specificity is explained by the fact that developed compositions might be used to effectively prevent ROS-induced oxidation of lipids and proteins in the inner mitochondrial membrane in vivo and outside mitochondria in the cellular and tissue structures of the lens and eye compartments.

Mitochondrial targeting of compounds with universal types of antioxidant activity represents a promising approach for treating a number of ROS-related ocular diseases of the aging eye and can be implicated in the management of cataracts and primary open-angle glaucoma.