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 (O(2)(-)) and H(2)O(2). 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 (H(2)O(2), 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 NO(2) and also oxidize nitrite (NO(2)(-) to nitrate (NO(2)(-)). Thus these Mn-Salens have the potential to ameliorate cellular damage caused by both oxidative and nitrosative stresses, by the catalytic breakdown of O(2)(-), H(2)O(2), ONOO(-) and NO to benign species: O(2), H(2)O, NO(2)(-) and NO(3)(-).

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

“…If one does the calculation per molar basis, assuming the MW of the enzyme to be 250,000, and considering its tetramer structure (MW ¼ 62,500), and the MW ¼ 357 for EUK-8, EUK-8 has 7Â10 À5 % of catalase activity (171). In agreement with these calculations, Sharpe et al (284) considered Mn salens to be poor catalysts of H 2 O 2 breakdown (284). Although SOD-like activity is reportedly not dependent on the structure, the structure-activity relationship has been established for catalase-like activity (93,94).…”

“…Besides O 2 ·À -and H 2 O 2 -related activity, Sharpe et al (284) reported the reactivity of EUK-8 and EUK-134 toward OCl À and ONOO À , in which Mn(V) oxo species were formed by a two-electron process, thus giving rise to the benign species, H 2 O, O 2 , and NO 2 ·À . The Mn(V) oxo species can react with · NO, giving rise to · NO 2 , which will combine with · NO, giving rise to N 2 O 3 , which, with water, will produce HNO 2 .…”

Reduction of paraquat-induced renal cytotoxicity by manganese and copper complexes of EGTA and EHPG

“…Furthermore, SOD can have pro-oxidant activities at higher concentrations, e.g., Cu/ZnSOD can promote the generation of hydroxyl radicals [16] and [48] and inhibit the ability of superoxide to regulate lipid peroxidation [19] and [49]. This has generated much interest in SODm, leading to the development of agents including macrocyclics, manganese salens, nitroxides, porphyrins, and many other catalytic antioxidants [15], [20], [50], [51], [52], [53], [54] and [55]. However, many of these have also suffered problems ranging from cytotoxicity to poor stability [23] and [56].…”

Islet transplantation and antioxidant management: A comprehensive review

“…N (G)-monomethyl-L-arginine (NMA) (a reversible inhibitor of NO synthase) prevented the dysfunction or destruction of cultured islets and markedly decreased the time needed to restore euglycemia after intraportal transplantation of islets in diabetic rats [64] . Direct antioxidants such as vitamin E and salen-manganese compounds can prevent NO and nitrite radicals as well as ROS [65,66] thus may play a protective role.…”