4-hydroxy-2-nonenal and ebselen

The metabolic role of aldehydes, hydroperoxides, and quinones was investigated with emphasis on oxidative transitions involving oxygen free radicals and associated with enzymatic activities. The oxidative metabolism of aldehydes (originating either from ethanol oxidation, or monoamine oxidase activity, or oxidative breakdown of lipid hydroperoxides during lipid peroxidation) is a source of alkane production and low-level chemiluminescence. Since both parameters reflect cellular oxidative conditions, it can be inferred that side-products of aldehyde oxidase activity might participate in the link between the initial enzymatic oxidation of aldehyde and the occurrence of oxidizing species leading to chemiluminescence and alkane production. The metabolism of hydroperoxides was considered under two different aspects: first, the hydroperoxide reduction, within the frame of a detoxication mechanism, as mediated by a selenoorganic compound PZ-51 that displays glutathione peroxidase-like activity and an antioxidant activity; second, the enzyme-catalyzed disproportionation of hydroperoxides as a source of a potent oxidizing equivalent, singlet molecular oxygen. The cytotoxicity of quinones, utilized in therapeutic agents such as anticancer drugs, is believed to be related to oxidative stress due to the formation of the superoxide radical and subsequent more reactive oxygen species. The enzyme-catalyzed one-electron reduction of menadione seems to play a substantial role in the development of cytotoxic effects, at variance with the 2-electron reduction of the quinone. The observation of low-level chemiluminescence under conditions which favor the one-electron reduction process or which diminished the two-electron reduction process indicates the practicability of low-level chemiluminescence measurements in monitoring changes in quinone metabolism and related cytotoxic effects.

Topics: Aldehydes; Animals; Azoles; Cell Survival; Electron Transport; Ethanol; Free Radicals; Isoindoles; Lipid Metabolism; Organoselenium Compounds; Oxidation-Reduction; Oxygen; Pargyline; Peroxides; Quinones; Selenium

Intracochlear electrical stimulation (ES) generated by cochlear implants (CIs) is used to activate auditory nerves to restore hearing perception in deaf subjects and those with residual hearing who use electroacoustic stimulation (EAS) technology. Approximately 1/3 of EAS recipients experience loss of residual hearing a few months after ES activation, but the underlying mechanism is unknown. Clinical evidence indicates that the loss is related to the previous history of noise-induced hearing loss (NIHL). In this report, we investigated the impact of intracochlear ES on oxidative stress levels and synaptic counts in inner hair cells (IHCs) of the apical, middle and basal regions of guinea pigs with normal hearing (NH) and NIHL. Our results demonstrated that intracochlear ES with an intensity of 6 dB above the thresholds of electrically evoked compound action potentials (ECAPs) could induce the elevation of oxidative stress levels, resulting in a loss of IHC synapses near the electrodes in the basal and middle regions of the NH cochleae. Furthermore, the apical region of cochleae with NIHL were more susceptible to synaptic loss induced by relatively low-intensity ES than that of NH cochleae, resulting from the additional elevation of oxidative stress levels and the reduced antioxidant capability throughout the whole cochlea.

Topics: Action Potentials; Aldehydes; Animals; Antioxidants; Cochlea; Cochlear Implants; Electric Stimulation; Evoked Potentials, Auditory, Brain Stem; Fatty Acids, Unsaturated; Guinea Pigs; Hair Cells, Auditory, Inner; Hearing Loss, Noise-Induced; Hydroxy Acids; Isoindoles; Organoselenium Compounds; Oxidative Stress; Severity of Illness Index; Synapses; Tyrosine

To investigate the effect of the GPx1-mimetic ebselen on diabetes-associated atherosclerosis and renal injury in a model of increased oxidative stress.. The study was performed using diabetic apolipoprotein E/GPx1 (ApoE(-/-)GPx1(-/-))-double knockout (dKO) mice, a model combining hyperlipidemia and hyperglycemia with increased oxidative stress. Mice were randomized into two groups, one injected with streptozotocin, the other with vehicle, at 8 weeks of age. Groups were further randomized to receive either ebselen or no treatment for 20 weeks.. Ebselen reduced diabetes-associated atherosclerosis in most aortic regions, with the exception of the aortic sinus, and protected dKO mice from renal structural and functional injury. The protective effects of ebselen were associated with a reduction in oxidative stress (hydroperoxides in plasma, 8-isoprostane in urine, nitrotyrosine in the kidney, and 4-hydroxynonenal in the aorta) as well as a reduction in VEGF, CTGF, VCAM-1, MCP-1, and Nox2 after 10 weeks of diabetes in the dKO aorta. Ebselen also significantly reduced the expression of proteins implicated in fibrosis and inflammation in the kidney as well as reducing related key intracellular signaling pathways.. Ebselen has an antiatherosclerotic and renoprotective effect in a model of accelerated diabetic complications in the setting of enhanced oxidative stress. Our data suggest that ebselen effectively repletes the lack of GPx1, and indicate that ebselen may be an effective therapeutic for the treatment of diabetes-related atherosclerosis and nephropathy. Furthermore, this study highlights the feasibility of addressing two diabetic complications with one treatment regimen through the unifying approach of targeted antioxidant therapy.

Topics: Aldehydes; Animals; Antioxidants; Apolipoproteins E; Atherosclerosis; Azoles; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Diabetic Nephropathies; Glutathione Peroxidase; Glutathione Peroxidase GPX1; Isoindoles; Kidney; Male; Mice; Mice, Knockout; Organoselenium Compounds; Reactive Oxygen Species; Tyrosine; Vascular Cell Adhesion Molecule-1

4-Hydroxynonenal (HNE), an aldehydic product of membrane lipid peroxidation, has been shown to induce neurotoxicity in various types of neurons. To clarify the mechanisms underlying HNE-induced neurotoxicity, the effects of antioxidants (N-acetylcysteine (NAC) and ebselen with or without NAC pretreatment) and Ca(2+)-related reagents were examined in cerebellar granule neurons. The decreases in neuronal survival and mitochondrial membrane potential induced by HNE were suppressed by pretreatment with NAC at concentrations of 500 and 1000 microM. HNE-induced protein modification and reactive oxygen species generation were also suppressed by pretreatment with NAC at 1000 microM. Although simultaneous application of ebselen (10 microM) did not protect against HNE-induced neurotoxicity, it completely suppressed HNE-induced injury after pretreatment with NAC at 300 microM. HNE increased [Ca(2+)](i) levels, and this increase was significantly attenuated by simultaneous application of nifedipine (10 microM) or EGTA (1000 microM), but not by MK-801 or CNQX. However, none of these Ca(2+)-related reagents was able to prevent HNE-induced neuronal death or mitochondrial injury. These results suggest that pretreatment with a low concentration of NAC dramatically potentiates the neuroprotective activity of ebselen, and that HNE-induced increase in [Ca(2+)](i) is not involved in HNE-induced neuronal death in cerebellar granule neurons.

Topics: Acetylcysteine; Aldehydes; Animals; Animals, Newborn; Azoles; Calcium; Cell Death; Cells, Cultured; Cerebellum; Cysteine Proteinase Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Glutathione; Isoindoles; Membrane Potential, Mitochondrial; Neurons; Neuroprotective Agents; Nifedipine; Organoselenium Compounds; Rats; Rats, Wistar; Reactive Oxygen Species; Time Factors

Oxidants have been shown to be involved in alcohol-induced liver injury. Moreover, 2-phenyl-1,2-benzisoselenazole-3(2H)-one (ebselen), an organoselenium compound and glutathione peroxidase mimic, decreases oxidative stress and protects against stroke clinically. This study was designed to test the hypothesis that ebselen protects against early alcohol-induced liver injury in rats. Male Wistar rats were fed high-fat liquid diets with or without ethanol (10-16 g/kg/d) continuously for up to 4 weeks using the intragastric enteral feeding protocol developed by Tsukamoto and French. Ebselen (50 mg/kg twice daily, intragastrically) or vehicle (1% tylose) was administered throughout the experiment. Mean urine ethanol concentrations were not significantly different between treatment groups, and ebselen did not affect body weight gains or cyclic patterns of ethanol concentrations in urine. After 4 weeks, serum ALT levels were increased significantly about 4-fold over control values (37 +/- 5 IU/l) by enteral ethanol (112 +/- 7 IU/l); ebselen blunted this increase significantly (61 +/- 8 IU/l). Enteral ethanol also caused severe fatty accumulation, mild inflammation, and necrosis in the liver (pathology score: 4.3 +/- 0.3). In contrast, these pathological changes were blunted significantly by ebselen (pathology score: 2.5 +/- 0.4). While there were no significant effects of either ethanol or ebselen on glutathione peroxidase activity in serum or liver tissue, ebselen blocked the increase in serum nitrate/nitrite caused by ethanol. Furthermore, ethanol increased the activity of NF-kappaB over 5-fold, the number of infiltrating neutrophils 4-fold, and the accumulation of 4-hydroxynonenal over 5-fold. Ebselen blunted all of these effects significantly. These results indicate that ebselen prevents early alcohol-induced liver injury, most likely by preventing oxidative stress, which decreases inflammation.

Topics: Alanine Transaminase; Aldehydes; Animals; Antioxidants; Azoles; Body Weight; Enteral Nutrition; Ethanol; Glutathione Peroxidase; Hepatitis, Alcoholic; Inflammation; Isoindoles; Liver; Male; NF-kappa B; Organoselenium Compounds; Oxidative Stress; Oxidoreductases; Rats; Rats, Wistar

Primary spinal cord trauma can trigger a cascade of secondary processes leading to delayed and amplified injury to spinal cord neurons. Release of fatty acids, in particular arachidonic acid, from cell membranes is believed to contribute significantly to these events. Mechanisms of fatty acid-induced injury to spinal cord neurons may include lipid peroxidation. One of the major biologically active products of arachidonic acid peroxidation is 4-hydroxynonenal (HNE). The levels of HNE-protein conjugates in cultured spinal cord neurons increased in a dose-dependent manner after a 24-h exposure to arachidonic acid. To study cellular effects of HNE, spinal cord neurons were treated with different doses of HNE, and cellular oxidative stress, intracellular calcium, and cell viability were determined. A 3-h exposure to 10 microM HNE caused approximately 80% increase in oxidative stress and 30% elevation of intracellular calcium. Exposure of spinal cord neurons to HNE caused a dramatic loss of cellular viability, indicated by a dose-dependent decrease in MTS [3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-s ulfophenyl)- 2H-tetrazolium, inner salt] conversion. The cytotoxic effect of HNE was diminished by pretreating neurons with ebselen or N-acetylcysteine. These data support the hypothesis that formation of HNE may be responsible, at least in part, for the cytotoxic effects of membrane-released arachidonic acid to spinal cord neurons.

Topics: Acetylcysteine; Aldehydes; Animals; Antioxidants; Apoptosis; Arachidonic Acid; Azoles; Calcium; Cell Survival; Cells, Cultured; Cysteine Proteinase Inhibitors; DNA Fragmentation; Fetus; Isoindoles; Lipid Peroxidation; Mice; Neurons; Organoselenium Compounds; Oxidative Stress; Spinal Cord