Beneficial Effects ofN-Acetylcysteine and Ebselen on Renal Ischemia/Reperfusion Injury
Murat KızılgünYavuz PoyrazoğluYeşim ÖztaşHalıl YamanErdinç ÇakırTuncer ÇaycıÖzgür AkgülYasemin Gülcan KurtHakan YarenZeki Ilker KunakEnis MacitEsin ÖzkanMine Yavuz TaşlıpınarTürker TürkerAyhan Özcan
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Introduction: It has been demonstrated that peroxynitrite accompanies acute renal ischemia and contributes to the pathophysiology of renal damage. Therefore, we aimed to investigate the roles of N-acetylcysteine (NAC), a well-known powerful antioxidant, and ebselen (E), a scavenger of peroxynitrite, on renal injury induced by renal ischemia/reperfusion injury (IRI) of rat kidney. Materials and methods: Forty male Sprague–Dawley rats were divided into five groups: sham, renal IRI, renal IRI+NAC, renal IRI+E, and renal IRI+NAC+E. IR injury was induced by 60 min of bilateral renal ischemia followed by 6 h of reperfusion. After reperfusion, kidneys and blood samples were obtained for histopathological and biochemical evaluations. Results: Renal IR resulted in increased malondialdehyde and nitrite/nitrate levels suggesting increased lipid peroxidation and peroxynitrite production and decreased superoxide dismutase and glutathione peroxidase activities. Both NAC and E alone significantly decreased malondialdehyde and nitrite/nitrate levels and increased superoxide dismutase and glutathione peroxidase activities. Additionally in the renal IRI+NAC+E group, all biochemical results were quite close to those of sham group. Histopathologically, the kidney injury in rats treated with combination of NAC and E was found significantly less than the other groups. Conclusions: Both NAC and E are able to ameliorate IRI of the kidney by decreasing oxidative and nitrosative stresses and increasing free radical scavenger properties. Additionally, combination of NAC and E prevents kidney damage more than when each drug is used alone, suggesting that scavenging peroxynitrite nearby antioxidant activity is important in preventing renal IRI.Keywords:
Malondialdehyde
Renal ischemia
Ebselen
Ebselen, 2-phenyl-1,2-benzisoselenazol-3(2H)-one, rapidly reacts with peroxynitrite, the rate constant being of the order of 106 M-1 s-1; the reaction yields the selenoxide of the parent molecule, 2-phenyl-1,2-benzisoselenazol-3(2H)-one 1-oxide, as the sole selenium-containing product; a stoichiometry of 1 mol of ebselen reacted and of the selenoxide formed per mole of peroxynitrite was observed. The reaction was studied in detail at neutral and alkaline pH (pH 10−11). It also proceeds at acidic pH where peroxynitrous acid (ONOOH) is predominant, the yield of the selenoxide being lower because peroxynitrous acid (pKa = 6.8) decays rapidly. Reduction of the selenoxide in cells to regenerate ebselen would allow for a sustained defense against peroxynitrite. This novel reaction constitutes a potential cellular defense line against peroxynitrite, one of the important reactive species in inflammatory processes.
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Peroxynitrous acid
Stoichiometry
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Excess production of superoxide (O2−) and nitric oxide (NO) in blood vessel walls may occur early in atherogenesis leading to the formation of peroxynitrite, a strong oxidant and nitrating agent. This study was designed to determine the effect of diphenyl diselenide (PhSe)2, a synthetic organoselenium compound, in comparison with ebselen, on peroxynitrite-mediated endothelial damage. Experimental results showed that pre-incubation of BAEC (24 h) with low concentrations of (PhSe)2 (0.5 and 1 μM) protected the cells from peroxynitrite-dependent apoptosis and protein tyrosine nitration. The intracellular levels of GSH were almost completely depleted by peroxynitrite and, although the compounds did not restore its normal levels, (PhSe)2 per se significantly increased GSH in a concentration-dependent manner. Moreover, (PhSe)2, which was about two times more active as a GPx mimic than ebselen, induced a significantly higher increase in both cellular GPx expression and activity. Taking into account the kinetics of the reaction between peroxynitrite and (PhSe)2, our data indicate that (PhSe)2 protects BAEC against peroxynitrite-mediated cell damage not by a direct reaction, but rather by increasing cellular GPx expression as a consequence of enhanced nuclear translocation of Nrf-2, which together with the increase in intracellular GSH, may work catalytically to reduce peroxynitrite to nitrite.
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Diphenyl diselenide
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Ebselen
Senescence
Nitrotyrosine
Reactive nitrogen species
Endothelial Dysfunction
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Peroxynitrite (0.5–50 μM) induced dose-dependent cytotoxic effects in rat pancreatic acinar AR4–2J cells. Glutathione (2 mM) and ebselen (10 μM) partially reduced the cytotoxicity caused by 1–10 μM concentrations of peroxynitrite. Higher concentrations (10–50 μM) of peroxynitrite induced DNA smear suggestive of necrosis, while lower concentrations (2–5 μM) induced DNA fragmentations suggestive of apoptosis. The effects of peroxynitrite on [Ca2+]ishowed a similar dose dependency. Peroxynitrite concentrations >10 μM rapidly increased [Ca2+]i in a dose-dependent manner, while concentrations <5 μM did not affect [Ca2+]i. In contrast, the presentation of wild-type P53 was accelerated at lower concentrations of peroxynitrite (≤10 μM) but not at higher concentrations (50 μM). The present study suggests that peroxynitrite at lower concentrations (2–5 μM) induces wild-type P53 and apoptosis, which is potentially a protective response toward the DNA damage caused by peroxynitrite. On the other hand, higher concentrations of peroxynitrite (10–50 μM) rapidly increase [Ca2+]i and eventually induce necrosis.
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Abstract Many selenoorganic compounds play an important role in biochemical processes and act as antioxidants, enzyme inhibitors or drugs. The effects of a new selenocompound — bis(2-aminophenyl)-diselenide on oxidative/nitrative changes in human plasma proteins induced by peroxynitrite (ONOO−) were studied in vitro and compared with the those of ebselen, a well-known antioxidant. We also studied the role of the tested selenocompounds in peroxynitrite-induced plasma lipid peroxidation. Exposure of the plasma to peroxynitrite (0.1 mM) resulted in an increase in the level of carbonyl groups and nitrotyrosine residues in plasma proteins (estimated using the ELISA method and Western blot analysis). In the presence of different concentrations (0.025–0.1 mM) of the tested selenocompounds, 0.1 mM peroxynitrite caused a distinct decrease in the level of carbonyl group formation and tyrosine nitration in plasma proteins. Moreover, these selenocompounds also inhibited plasma lipid peroxidation induced by ONOO−1 (0.1 mM). The obtained results indicate that in vitro bis(2-aminophenyl)-diselenide and ebselen have very similar protective effects against peroxynitrite-induced oxidative/nitrative damage to human plasma proteins and lipids.
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Diphenyl diselenide
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Peroxynitrous acid
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Selenoprotein
Glutathione reductase
GPX1
Selenoprotein P
Phospholipid-hydroperoxide glutathione peroxidase
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Cellular defense against excessive peroxynitrite generation is required to protect against DNA strand-breaks and mutations and against interference with protein tyrosine-based signaling and other protein functions due to formation of 3-nitrotyrosine. We recently demonstrated a role of selenium-containing enzymes catalyzing peroxynitrite reduction. Glutathione peroxidase (GPx) protected against the oxidation of dihydrorhodamine 123 (DHR) by peroxynitrite more effectively than ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), a selenoorganic compound exhibiting a high second-order rate constant for the reaction with peroxynitrite, 2 x 10(6) M-1s-1. The maintenance of protection by GPx against peroxynitrite requires GSH as reductant. Similarly, selenomethionine but not selenomethionine oxide exhibited inhibition of rhodamine 123 formation from DHR caused by peroxynitrite. In steady-state experiments, in which peroxynitrite was infused to maintain a 0.2 microM concentration, GPx in the presence of GSH, but neither GPx nor GSH alone, effectively inhibited the hydroxylation of benzoate by peroxynitrite. Under these steady-state conditions peroxynitrite did not cause loss of 'classical' GPx activity. GPx, like selenomethionine, protected against protein 3-nitrotyrosine formation in human fibroblast lysates, shown in Western blots. The formation of nitrite rather than nitrate from peroxynitrite was enhanced by GPx, ebselen or selenomethionine. The selenoxides can be effectively reduced by glutathione, establishing a biological line of defense against peroxynitrite. The novel function of GPx as a peroxynitrite reductase may extend to other selenoproteins containing selenocysteine or selenomethionine. Recent work on organotellurium compounds revealed peroxynitrite reductase activity as well. Inhibition of dihydrorhodamine 123 oxidation correlated well with the GPx-like activity of a variety of diaryl tellurides.
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Phospholipid-hydroperoxide glutathione peroxidase
Glutathione reductase
Nitrotyrosine
GPX1
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The second-order rate constant for the reaction of ebselen with peroxynitrite (ONOO-) is (2.0+/-0.1) X 10(6) M(-1) s(-1) at pH > or = 8 and 25 degrees C, 3-4 orders of magnitude higher than the rate constants observed for cysteine, ascorbate, or methionine. The activation energy is relatively low, 12.8 kJ/mol. This is the fastest reaction of peroxynitrite observed so far. It may allow Se-containing compounds to play a novel role in the defense against peroxynitrite, one of the important reactive species generated during inflammatory processes.
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Peroxynitrous acid
Reaction rate
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