Nitroxides attenuate carrageenan-induced inflammation in rat paws by reducing neutrophil infiltration and the resulting myeloperoxidase-mediated damage

Abstract

Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) and other cyclic nitroxides have been shown to inhibit the chlorinating activity of myeloperoxidase (MPO) in vitro and in cells. To examine whether nitroxides inhibit MPO activity in vivo we selected acute carrageenan-induced inflammation on the rat paw as a model. Tempol and three more hydrophobic 4-substituted derivatives (4-azido, 4-benzenesulfonyl, and 4-(4-phenyl-1H-1,2,3-triazol-1-yl)) were synthesized, and their ability to inhibit the in vitro chlorinating activity of MPO and carrageenan-induced inflammation in rat paws was evaluated. All of the tested nitroxides inhibited the chlorinating activity of MPO in vitro with similar IC(50) values (between 1.5 and 1.8 μM). In vivo, the attenuation of carrageenan-induced inflammation showed some correlation with the lipophilicity of the nitroxide at early time points but the differences in the effects were small (<2-fold) compared with the differences in lipophilicity (>200-fold). No inhibition of MPO activity in vivo was evident because the levels of MPO activity in rat paws correlated with the levels of MPO protein. Likewise, paw edema, levels of nitrated and oxidized proteins, and levels of plasma exudation correlated with the levels of MPO protein in the paws of the animals that were untreated or treated with the nitroxides. The effects of the nitroxides in vivo were compared with those of 4-aminobenzoic hydrazide and of colchicine. Taken together, the results indicate that nitroxides attenuate carrageenan-induced inflammation mainly by reducing neutrophil migration and the resulting MPO-mediated damage. Accordingly, tempol was shown to inhibit rat neutrophil migration in vitro.

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

“…This possibility should be further evaluated in the future, although the participation of oxidative processes in the production of non-native hSOD1 forms in ALS disease remains to be unambiguously demonstrated [12][13][14][15][16][17][18]25,28]. Overall, the present study further supports the view that tempol and related cyclic nitroxides are protective against protein oxidation and the ensuing consequences [1][2][3][4][5][6]47,50]. …”

Chemical Compounds and Biological Activity of an Extract From Bougainvillea X Buttiana (Var. Rose) Holttum and Standl

“…The kinnins correspond to the continuity between the two phases [25]. The second phase, from 2.3 to 6 h, is mediated by prostaglandins and cyclooxygenase [25]. The present study clearly demonstrated that BxbREE at doses of 4 and 40 mg/kg significantly reduced the oedema formation induced by carrageenan at all assessment time periods.…”

“…The first phase, at 1 hour after carrageenan injection, is characterised by the liberation of histamine and serotonin. The kinnins correspond to the continuity between the two phases [25]. The second phase, from 2.3 to 6 h, is mediated by prostaglandins and cyclooxygenase [25].…”

“…They have also been highlighted for their contribution towards lowering the risks of diverse diseases, especially for coronary heart and pulmonary diseases as well as for different cancer types [22][23][24][25]. With respect to tannins, they can antagonise the effects of permeability in rats and inhibit the migration of leucocytes to an inflamed site.…”

Crystal structure of (S)-2-(2,2′-diethoxy-[1,1′-binaphthalen]-6-yl)-4,4,5,5-tetra-methyl-2-imidazoline-1-oxyle, C31H33N2O3

“…Recent studies showed that nitroxide radicals also exhibited interesting biological activities such as anticancer, antiradiation, anti-oxidation properties [3][4][5]. We here report the crystal structure of (S)-2-(2,2′-diethoxy-[1,1′-binaphthalen]-6-yl)-4,4,5,5-tetramethyl-2-imidazoline-1-oxyle, a strong intramolecular quencher of the uorescence from uorophores [1].…”