Characterization of the Radical Trapping Activity of a Novel Series of Cyclic Nitrone Spin Traps

Abstract

␣-Phenyl-tert-butyl nitrone (PBN) is a nitrone spin trap, which has shown efficacy in animal models of oxidative stress, including stroke, aging, sepsis, and myocardial ischemia/reperfusion injury. We have prepared a series of novel cyclic variants of PBN and evaluated them for radical trapping activity in vitro. The cyclic nitrones were shown to trap ⅐ OH with MDL 101,002 being 20 -25 times more active than PBN as assessed using 2-deoxyribose and p-nitrosodimethylaniline as substrates, respectively. Trapping of ⅐ OH by MDL 101,002 was also examined by using ESR spectroscopy. When Fenton's reagent was used, the ⅐ OH adduct of MDL 101,002 yielded a six-line spectrum with hyperfine coupling constants distinct from that of PBN. Importantly, the half-life of the adduct was nearly 5 min, while that of PBN is less than 1 min at physiologic pH. MDL 101,002 also trapped the O 2 . radical to yield a six-line spectrum with coupling constants very distinct from that of the ⅐ OH adduct. In mice, the cyclic nitrones ameliorated the damaging effects of oxidative stress induced by ferrous iron injection into brain tissue. Similar protection was not afforded by the lipid peroxidation inhibitor U74006F, thus implicating radical trapping as a unique feature in the prevention of cell injury. Together, the in vivo activity, the stability of the nitroxide adducts, and the ability to distinguish between trapping of ⅐ OH and O 2 . suggest the cyclic nitrones to be ideal reagents for the study of oxidative cell injury.

Effects of the Spin Trap Agent Disodium- [tert-butylimino)methyl]benzene-1,3-disulfonate N -Oxide (Generic NXY-059) on Intracerebral Hemorrhage in a Rabbit Large Clot Embolic Stroke Model

“…9 Moreover, Asahi et al 39 reported that PBN effectively decreased tPA-induced hemorrhage in a rat embolic focal cerebral ischemia model. Hu et al 40 also showed that MDL 101,002, a conformationally constrained cyclic analogue of PBN, 41 reduced hemorrhage rate in rabbits after an embolism.…”

Ethanol and Arachidonic Acid Increase α2(I) Collagen Expression in Rat Hepatic Stellate Cells Overexpressing Cytochrome P450 2E1

“…, a spin-trapping reagent that reacts with many radicals, including superoxide, hydroxyl, lipid, and 1-hydroxyethyl radicals (33), produced a concentrationdependent decrease in COL1A2 mRNA levels in the E5 cells and completely prevented the increase by AA (Fig. 3C).…”

Inibidores de fosfodiesterases: novas perspectivas de uma antiga terapia na asma?

“…Ao mesmo tempo, vem sendo avaliado o valor terapêutico de citocinas com efeitos antiinflamató-rios (IL-10, IL-12 e interferon-gama (IFN-γ)). Também vêm sendo estudados: inibidores de fatores de transcrição, (11)(12)(13) inibidores da proteína ativada pela mitógene-quinase, (14) bloqueadores de adesão celular, inibidores de prostaglandinas, (15)(16)(17) antagonistas do fator ativador de plaquetas, (18,19) inibidores de fosfolipases, (20,21) antagonistas da bradicinina, (22)(23)(24) antioxidantes, (25,26) antagonistas de adenosina, (27)(28)(29) inibidores da NO-sintase, (30,31) antagonistas da endotelina, (32) inibidor da proteína básica do eosinófilo (33)(34)(35) e inibidores de enzimas inflamatórias. (36)(37)(38) .…”