Drug Design of Mitochondria-Targeted Antioxidants, Action, Metabolism and Perspectives for Ophthalmic Therapeutics: N-acetylcarnosine Codrug Treatment Platform

Maintaining the redox balance within the mitochondria is critical for cellular homeostasis in the eye since the mitochondria host the energy producing systems of the cell and it is widely recognized that damage to the mitochondria plays a key role in sight threatening age-related eye disorders, including retinopathies (maculodystrophy, retinitis pigmentosa , hereditary optic neuropathy), as well as glaucoma, cataract, and autoimmune uveitis. Reactive oxygen species (ROS) are generated as by-products of cellular metabolism, primarily in the mitochondria. Although ROS are essential participants in cell signaling and regulation, when their cellular production overwhelms the intrinsic antioxidant capacity, damage to cellular macromolecules such as DNA, proteins, and lipids ensues. Oxidized phospholipids play an important role in execution of the mitochondrial stage of apoptosis and clearance of apoptotic cells. During the lipid peroxidation (LPO) reaction, lipid hydroperoxides are formed as primary products. Several lines of evidence suggest that lipid hydroperoxides can trigger cell death in many cell types, which may be mediated by mitochondria dysfunction pathway. Recently, there was a breakthrough in mitochondrial targeting of antioxidants. Mitochondrial function can be manipulated selectively by targeting bioactive compounds to mitochondria in living cells. Lipophylic antioxidants were covalently coupled to a triphenylphosphonium cation, and these compounds were preferentially taken up by mitochondria. In this work we proposed the combined use of mitochondria-targeted antioxidant mito Vit E and N-acetylcarnosine, an ophthalmic prodrug of L-carnosine in patented formulation of eye drops including the mucoadhesive compound carboxymethylcellulose to help elucidate the role of mitochondrial oxidative damage in apoptotic cell death. We suggest that mitochondrial oxidative damage plays an important role in ROS-induced apoptosis. Further work using these and other mitochondrially targeted compounds to dissect out the role of mitochondrial oxidative changes in peroxide-induced apoptosis is ongoing. The findings reported demonstrate that mitochondrially targeted antioxidants such as mito vit E + N-acetylcarnosine in the eye drop formulation with carboxymethylcellulose can be used to investigate the role of mitochondrial oxidative stress in retinal neuronal cells (RGCs) death and may represent a new pharmacologic tool to mitigate complex ocular pathology for the treatment of sight-threatening eye diseases and, especially, neurodegeneration originating from an oxidative injury and glaucomatous neurodegeneration. This strategy also has potential for unraveling the contribution of oxidative stress to other ocular pathologies involving mitochondrial dysfunction