依布硒啉对心肌缺血再灌注损伤大鼠心功能的保护作用及其机制

目的探讨依布硒啉(Ebs)对心肌缺血再灌注损伤大鼠心功能的保护作用及其机制。方法取24只雄性大鼠,结扎其冠状动脉左前降支30 min、灌注90 min制作心肌缺血再灌注损伤模型,观察Ebs对大鼠心功能、心肌酶学和脂质过氧化的影响。结果Ebs能够对抗心肌缺血再灌注引起的左心室内压(LVSP)、左心室内压最大上升与下降速率(±dp/dtmax)、动脉血压下降,并能够稳定心肌组织Na -K -ATPase和Ca2 -Mg2 -AT-Pase活性,降低丙二醛(MDA)含量和增高SOD活性。结论提示依布硒啉(Ebs)对大鼠心肌缺血再灌注引起的心功能减弱具有明显的保护作用,其机制可能为改善能量代谢障碍,抑制自由基生成或清除氧自由基。     

依布硒啉对急性肺损伤大鼠氧化应激的影响

目的 观察依布硒啉对内毒素性急性肺损伤的保护作用.方法 健康雄性SD大鼠,随机分成6组:正常对照组、模型组、依布硒啉高剂量组、中剂量组、低剂量组和地塞米松对照组.通过尾静脉注射LPS(5 mg/kg)建立模型,治疗组于造模前30 min,大鼠腹腔注射依布硒啉(7.5 mg/kg、15 mg/kg、30 mg/kg),对照组和模型组分别注入等量溶剂.造模后6h,麻醉放血处死动物,并取肺组织,测定肺湿质量/干质量.采用硫代巴比妥酸和黄嘌呤氧化法分别检测肺组织中超氧化物歧化酶SOD活性和丙二醛MDA及髓过氧化物酶(MPO)含量.光镜下观察肺组织病理学改变.结果 依布硒啉治疗组与模型组相比,肺湿质量/干质量降低,肺组织SOD的活性明显增高,MDA和MPO含量显著降低(P＜0.05),病理改善明显.结论 依布硒啉对内毒素性急性肺损伤有一定保护作用,其机制可能与提高抗氧化能力有关.     

The seleno-organic compound ebselen impairs mitochondrial physiology and induces cell death in AR42J cells

Ebselen is a seleno-organic compound that causes cell death in several cancer cell types. The mechanisms underlying its deleterious effects have not been fully elucidated. In this study, the effects of ebselen (1 μM–40 μM) on AR42J tumor cells have been examined. Cell viability was studied using AlamarBlue^® test. Cell cycle phase determination was carried out by flow cytometry. Changes in intracellular free Ca²⁺ concentration were followed by fluorimetry analysis of fura-2-loaded cells. Distribution of mitochondria, mitochondrial Ca²⁺ concentration and mitochondrial membrane potential were monitored by confocal microscopy of cells loaded with Mitotracker Green™ FM, rhod-2 or TMRM respectively. Caspase-3 activity was calculated following the luorogenic substrate ACDEVD-AMC signal with a spectrofluorimeter. Results show that cell viability decreased in the presence of ebselen. An increase in the number of cells in the S-phase of the cell cycle was observed. Ebselen induced a concentration-dependent mobilization of Ca²⁺ from agonist- and thapsigargin-sensitive Ca²⁺ pools. Ebselen induced also a transient increase in mitochondrial Ca²⁺ concentration, a progressive decrease of the mitochondrial membrane potential and a disruption of the mitochondrial network. Finally, a concentration-dependent increase in caspase-3 activity was detected. We conclude that ebselen exerts deleterious actions on the cells that involve the impairment of mitochondrial physiology and the activation of caspase-3-mediated apoptotic pathway.     

Design and Synthesis of a Mitochondria-Targeted Mimic of Glutathione Peroxidase,MitoEbselen-2, as a Radiation Mitigator

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Diphenyl diselenide protects rat hippocampal slices submitted to oxygen-glucose deprivation and diminishes inducible nitric oxide synthase immunocontent

Diphenyl diselenide (PhSe)2 is an organic selenium compound that has been little studied. In this study we investigated the effects of (PhSe)2 (0.1-3 microM) in a classical model of in vitro brain ischemia, which consists of exposing rat hippocampal slices to oxygen-glucose deprivation (OGD). Hippocampal slices were exposed for 60 min to OGD and the cellular viability (performed by MTT assay) as well as the immunocontent of nitric oxide synthase inducible (iNOS) were evaluated after 180 min of a recovery period. OGD decreased cellular viability by 50% and increased more than twice the immunocontent of iNOS of hippocampal slices. (PhSe)2 (1 and 3 microM) added during OGD and the recovery period abolished both effects. These results demonstrate for the first time the neuroprotective effects of (PhSe)2. Although the selenium analog--ebselen--has been widely used in ischemia models, our results suggest that other selenoorganic compounds could be investigated as pharmacological tools against brain disorders.     

The antioxidant ebselen prevents neurotoxicity and clinical symptoms in a primate model of Parkinson's disease

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), via its major metabolite 1-methyl-4-phenylpyridinium (MPP(+)), produces in primates including humans clinical, biochemical, and neuropathological changes similar to those which occur in idiopathic Parkinson's disease. Ebselen is an antioxidant drug with glutathione peroxidase-like activity and a proven neuroprotective action in stroke patients. Here we show that Ebselen, when administered before, during, and after MPTP injections, prevents both neuronal loss and clinical symptoms in a primate MPTP model of Parkinson's disease. Ebselen also prevents peroxide radical overproduction induced by serum withdrawal in cultured PC12 cells and hydroxyl radical generation induced by the mitochondrial toxin, MPP(+), in vivo in rat brain. Moreover, Ebselen inhibits MPP(+)-induced toxicity in PC12 cells, without interacting with the dopamine uptake system. Our results demonstrate that compounds which prevent mitochondrial dysfunction and free radical production may be useful as preventive treatment of Parkinson's disease.     

Ebselen对阿霉素致的心肌亚急性毒性损伤的保护作用

以小鼠为模型，模拟阿霉素临床用药方式，观察了Ｅｂｓｅｌｅｎ对阿霉素致的心脏毒性作用的保护效果。结果显示Ｅｂｓｅｌｅｎ能够降低阿霉素所致的心肌脂质过氧化物（ＬＰＯ）形成，提高机体的抗氧化能力，即提高ＳｅＧＳＨＰｘ／ＬＰＯ比值。血清肌酸磷酸激酶（ＣＰＫ）和谷草转氨酶（ＡＳＴ）活性测定及心肌组织病理切片均表明Ｅｂｓｅｌｅｎ能减轻和防止阿霉素对心肌组织的亚急性、广泛性损伤。     

Ethanol inhibits δ-aminolevulinate dehydratase and glutathione peroxidase activities in mice liver: Protective effects of ebselen and N-acetylcysteine

Changes in sulfhydryl status have been shown to be involved with the ethanol-induced hepatotoxicity. In addition, evidence shows the importance of replenishing thiols in patients with alcoholic liver disease. This study was undertaken to examine the possible beneficial effects of the individual and simultaneous treatments with two antioxidant drugs (N-acetylcysteine and ebselen) against ethanol-induced changes in thiol status, as well as on the activities of δ-aminolevulinate dehydratase (δ-ALA-D) and glutathione peroxidase (GPx) in mice liver. Daily ethanol administrations (3 g ethanol/kg, by gavage) decreased liver nonprotein thiols (NPSH) concentration after 30 days of treatment and N-acetylcysteine (300 mg/kg once a day, i.p.) or ebselen (5 mg/kg once a day, subcutaneously) treatment restored this variable to control levels. However, additive beneficial effects concerning NPSH levels were not observed after the simultaneous administration with both drugs. While liver GPx and δ-ALA-D activities were inhibited by ethanol exposure and these inhibitions were significantly blunted by N-acetylcysteine or ebselen treatment, the simultaneous administration with both drugs did not show additive beneficial effects in relation to the enzymes’ activities. NPSH levels were positively correlated with GPx and δ-ALA-D activities. The results presented herein show that ebselen and N-acetylcysteine alone are able to restore ethanol-induced thiols as well as the inhibition of hepatic enzymes whose catalytic functions depend on their thiol (δ-ALA-D) and selenol (GPx) groups.     

Organoselenium compounds prevent hyperphosphorylation of cytoskeletal proteins induced by the neurotoxic agent diphenyl ditelluride in cerebral cortex of young rats

In this work we investigated the protective ability of the selenium compounds ebselen and diphenyl diselenide against the effect of diphenyl ditelluride on the in vitro incorporation of ³²P into intermediate filament (IF) proteins from slices of cerebral cortex of 17-day-old rats. We observed that ditelluride in the concentrations of 1, 15 and 50 μM induced hyperphosphorylation of the high-salt Triton insoluble neurofilament subunits (NF-M and NF-L), glial fibrillary acidic protein (GFAP) and vimentin, without altering the immunocontent of these proteins. Concerning the selenium compounds, diselenide (1, 15 and 50 μM) did not induce alteration of the in vitro phosphorylation of the IF proteins. Otherwise, ebselen induced an altered in vitro phosphorylation of the cytoskeletal proteins in a dose-dependent manner. At intermediate concentrations (15 and 30 μM) it increased the in vitro phosphorylation even though, at low (5 μM) or high (50 and 100 μM) concentrations this compound was ineffective in altering the activity of the cytoskeletal-associated phosphorylating system. In addition, 15 μM diselenide and 5 μM ebselen, presented a protective effect against the action of ditelluride, on the phosphorylation of the proteins studied. Considering that hyperphosphorylation of cytoskeletal proteins is associated with neuronal dysfunction and neurodegeneration, it is probable that the effects of ditelluride could be related to the remarkable neurotoxicity of this organic form of tellurium. Furthermore the neuroprotective action of selenium compounds against tellurium effects could be a promising route to be exploited for a possible treatment of organic tellurium poisoning.