Oxidation of nitric oxide by oxomanganese–salen complexes: a new mechanism for cellular protection by superoxide dismutase/catalase mimetics

Abstract

Manganese—salen complexes (Mn-Salen), including EUK-8 [manganese N,N′-bis(salicylidene)ethylenediamine chloride] and EUK-134 [manganese 3-methoxy N,N′-bis(salicylidene)ethylenediamine chloride], have been reported to possess combined superoxide dismutase (SOD) and catalase mimetic functions. Because of this SOD/catalase mimicry, EUK-8 and EUK-134 have been investigated as possible therapeutic agents in neurological disorders resulting from oxidative stress, including Alzheimer's disease, Parkinson's disease, stroke and multiple sclerosis. These actions have been explained by the ability of the Mn-Salen to remove deleterious superoxide (O2−) and H2O2. However, in addition to oxidative stress, cells in models for neurodegenerative diseases may also be subjected to damage from reactive nitrogen oxides (nitrosative stress), resulting from elevated levels of NO and sister compounds, including peroxynitrite (ONOO−). We have been examining the interaction of EUK-8 and EUK-134 with NO and ONOO−. We find that in the presence of a per-species (H2O2, ONOO−, peracetate and persulphate), the Mn-Salen complexes are oxidized to the corresponding oxo-species (oxoMn-Salen). OxoMn-Salens are potent oxidants, and we demonstrate that they can rapidly oxidize NO to NO2 and also oxidize nitrite (NO2− to nitrate (NO2−). Thus these Mn-Salens have the potential to ameliorate cellular damage caused by both oxidative and nitrosative stresses, by the catalytic breakdown of O2−, H2O2, ONOO− and NO to benign species: O2, H2O, NO2− and NO3−.