Cyclic nitroxides inhibit the toxicity of nitric oxide-derived oxidants: mechanisms and implications

Abstract

The substantial therapeutic potential of tempol (4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy) and related cyclic nitroxides as antioxidants has stimulated innumerous studies of their reactions with reactive oxygen species. In comparison, reactions of nitroxides with nitric oxide-derived oxidants have been less frequently investigated. Nevertheless, this is relevant because tempol has also been shown to protect animals from injuries associated with inflammatory conditions, which are characterized by the increased production of nitric oxide and its derived oxidants. Here, we review recent studies addressing the mechanisms by which cyclic nitroxides attenuate the toxicity of nitric oxidederived oxidants. As an example, we present data showing that tempol protects mice from acetaminophen-induced hepatotoxicity and discuss the possible protection mechanism. In view of the summarized studies, it is proposed that nitroxides attenuate tissue injury under inflammatory conditions mainly because of their ability to react rapidly with nitrogen dioxide and carbonate radical. In the process the nitroxides are oxidized to the corresponding oxammonium cation, which, in turn, can be recycled back to the nitroxides by reacting with upstream species, such as peroxynitrite and hydrogen peroxide, or with cellular reductants. An auxiliary protection mechanism may be down-regulation of inducible nitric oxide synthase expression. The possible therapeutic implications of these mechanisms are addressed.

Oxidative Stress Increases Blood–Brain Barrier Permeability and Induces Alterations in Occludin during Hypoxia–Reoxygenation

“…(Saito et al, 2003), nitrogen dioxide (NO 2 . ), and the carbonate radical (CO 3 .À ) (Augusto et al, 2008). Tempol readily crosses the BBB (Zhelev et al, 2009), and has previously been shown to provide neuroprotection as a free radical scavenger in several models of brain injury and ischemia (Kwon et al, 2003;Deng-Bryant et al, 2008;Rak et al, 2000;Cuzzocrea et al, 2000).…”

The carbonylation and covalent dimerization of human superoxide dismutase 1 caused by its bicarbonate-dependent peroxidase activity is inhibited by the radical scavenger tempol

“…Cyclic nitroxides are stable free radicals that are potential therapeutic agents because of their pronounced antioxidant properties and low toxicity [1][2][3][4][5][6]. In vivo, the most investigated nitroxide is tempol (4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl), which reduces tissue injury in diverse animal models of oxidative stress and inflammation [7].…”

Connecting the Chemical and Biological Properties of Nitric Oxide

“…On the contrary, the routes responsible for transforming NO • into reactive oxidants provide new targets to explore pharmacological interventions aiming to handle the harmful effects of chronic inflammatory conditions. 18,81,82,165 …”