Antioxidant nitroxides protect hepatic cells from oxidative stress-induced cell death.

Oxidative stress causes cell death and induces many kinds of disease, including liver disease. Nitroxides are known to react catalytically with free radicals. In this study, the cell protective activities of nitroxides were compared with those of other antioxidants. Nitroxides showed much greater inhibition of hydrogen peroxide-induced cell death than other antioxidants in a hepatic cell line and in primary hepatocytes. The intracellular oxidative stress level at 24 h after hydrogen peroxide stimulation was significantly decreased by nitroxides, but not by other antioxidants. To clarify the mechanism of cell protection by nitroxides, we investigated whether nitroxides inhibited DNA damage and mitogen-activated protein kinase pathway activation. We found that nitroxides reduced caspase-3 activation and may have ultimately inhibited cell death. In conclusion, nitroxides are very useful for attenuating cell damage due to oxidative stress. Nitroxides are thus a potential therapeutic agent for oxidative stress-related diseases.

Construction of a screening system for lipid-derived radical inhibitors and validation of hit compounds to target retinal and cerebrovascular diseases.

Recent studies have highlighted the indispensable role of oxidized lipids in inflammatory responses, cell death, and disease pathogenesis. Consequently, inhibitors targeting oxidized lipids, particularly lipid-derived radicals critical in lipid peroxidation, which are known as radical-trapping antioxidants (RTAs), have been actively pursued. We focused our investigation on nitroxide compounds that have rapid second-order reaction rate constants for reaction with lipid-derived radicals. A novel screening system was developed by employing competitive reactions between library compounds and a newly developed profluorescence nitroxide probe with lipid-derived radicals to identify RTA compounds. A PubMed search of the top hit compounds revealed their wide application as repositioned drugs. Notably, the inhibitory efficacy of methyldopa, selected from these compounds, against retinal damage and bilateral common carotid artery stenosis was confirmed in animal models. These findings underscore the efficacy of our screening system and suggest that it is an effective approach for the discovery of RTA compounds.

Lipid radicals cause light-induced retinal degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness worldwide. Although the cause of AMD remains unknown, lipid peroxidation (LPO) end-products are critical molecules for its development. Herein, we report the imaging of lipid radicals, which are key factors in the LPO reaction, and therapeutic information using animal models.