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Y. Han, S. N. M. Reid, K. B. Phan, N. O. Tsivkovskaia, T. V. Bui, N. L. Mata; Development of Topically Applied Modulators of Ocular Oxidative Stress. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4546. doi: https://doi.org/.
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Reactive oxygen species (ROS), which includes oxygen ions, free radicals and peroxides, form as a natural byproduct of the normal metabolism of oxygen. During periods of excessive cellular stress, ROS levels can increase dramatically causing damage to cell structures and a condition known as oxidative stress. Damage from oxidative stress plays a prominent role in the pathogenesis of various retinal diseases. Thus, ROS scavengers and antioxidants would be expected to provide a therapeutic benefit. Presently, we have developed a new class of highly soluble and cell-permeant chemical modulators, which incorporate a ROS chelator as a functional group. The ability of these compounds to suppress oxidative stress was examined in vitro and in vivo.
The new chemical entities (NCEs) were synthesized as prodrugs by covalently linking the ROS chelating functional group to various side chain moieties. All NCEs were formulated for topical delivery to the anterior portion of the eye. In vitro analyses included i) evaluation of anti-oxidative potency; ii) susceptibility to hydrolysis by corneal esterases; and iii) determination of potential lens and liver (cytochrome P450 inhibition) toxicity. Therapeutic efficacy was determined using an ex vivo model of light-mediated oxidative stress and in the superoxide dismutase 1 (SOD1) deficient mouse.
In vitro screening showed that each of the NCEs possessed the desired mechanism of action and significant anti-oxidant activity. Neither lens toxicity nor inhibition of key drug-metabolizing enzymes was demonstrated by the NCEs. Data from ex vivo assays indicated that the NCEs profoundly reduce the oxidation of fatty acids and lipids. In SOD1 mutant mice, daily application of a test NCE suppressed the development of oxidative stress biomarkers (e.g., lipid hydroperoxides and conjugates of malondialdehyde and nitrotyrosine). Additionally, SOD1 mutant mice treated with the test NCE showed improved integrity of retinal vessels. No deleterious alterations in tissue structure or morphology were observed.
A new class of topically applied small molecules to treat oxidative stress has been developed. The anti-oxidative potency of these compounds has been demonstrated in vitro and in an animal model of oxidative stress. Importantly, there is no evidence of either systemic or local toxicity following chronic and/or acute exposure to these compounds. These findings provide the impetus for further development of topically applied anti-oxidants as a potential therapy for ocular diseases which are characterized by oxidative stress.
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