Ebselen prevents excitotoxicity provoked by glutamate in rat cerebellar granule neurons

Porciúncula, Lisiane O.; Rocha, João Batista Teixeira da; Boeck, Carina Rodrigues; Vendite, Deusa; Souza, Diogo O.

doi:10.1016/s0304-3940(01)01519-1

Cited by 104 publications

(47 citation statements)

References 19 publications

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“…In addition, several studies have shown that ebselen is neuroprotective in different animal and cellular models of neurodegenerative diseases (e.g. Parkinson disease (72)(73)(74)) and glutamate-induced neurotoxicity (74). Our findings that ebselen modifications occurs at the Se-S bond is consistent with previous studies, which have documented that ebselen inhibition of several enzymes and receptors is mediated by directly reacting with thiol groups resulting in a modification of their oxidation state and/or conformational properties.…”

Section: Discussionsupporting

confidence: 92%

Identification and Characterization of Novel Classes of Macrophage Migration Inhibitory Factor (MIF) Inhibitors with Distinct Mechanisms of Action

Ouertatani-Sakouhi

El-Turk

Fauvet

et al. 2010

Journal of Biological Chemistry

123

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Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, is considered an attractive therapeutic target in multiple inflammatory and autoimmune disorders. In addition to its known biologic activities, MIF can also function as a tautomerase. Several small molecules have been reported to be effective inhibitors of MIF tautomerase activity in vitro. Herein we employed a robust activity-based assay to identify different classes of novel inhibitors of the catalytic and biological activities of MIF. Several novel chemical classes of inhibitors of the catalytic activity of MIF with IC 50 values in the range of 0.2-15.5 M were identified and validated. The interaction site and mechanism of action of these inhibitors were defined using structure-activity studies and a battery of biochemical and biophysical methods. MIF inhibitors emerging from these studies could be divided into three categories based on their mechanism of action: 1) molecules that covalently modify the catalytic site at the N-terminal proline residue, Pro 1 ; 2) a novel class of catalytic site inhibitors; and finally 3) molecules that disrupt the trimeric structure of MIF. Importantly, all inhibitors demonstrated total inhibition of MIF-mediated glucocorticoid overriding and AKT phosphorylation, whereas ebselen, a trimer-disrupting inhibitor, additionally acted as a potent hyperagonist in MIF-mediated chemotactic migration. The identification of biologically active compounds with known toxicity, pharmacokinetic properties, and biological activities in vivo should accelerate the development of clinically relevant MIF inhibitors. Furthermore, the diversity of chemical structures and mechanisms of action of our inhibitors makes them ideal mechanistic probes for elucidating the structurefunction relationships of MIF and to further determine the role of the oligomerization state and catalytic activity of MIF in regulating the function(s) of MIF in health and disease. Macrophage migration inhibitory factor (MIF)2 was discovered in the 1960's as a T-lymphocyte product that inhibits the random migration of macrophages during delayed-type hypersensitivity responses (1, 2). Two decades later, a human MIF gene was cloned (3). Yet, the biological activity of MIF remained ambiguous until the production of bioactive MIF and anti-MIF antibodies (4). Various biological activities have been attributed to MIF, which is recognized as a major regulator of inflammation and a central upstream mediator of innate immune responses (5, 6). MIF has broad regulatory properties and is considered as a critical mediator of multiple disorders including inflammatory and autoimmune diseases such as rheumatoid arthritis (7, 8), glomerulonephritis (9, 10), diabetes (11), atherosclerosis (12), sepsis (13-15), asthma (16,17), and acute respiratory distress syndrome (18). Furthermore, recent studies have highlighted a role for MIF in tumorigenesis. Human cancer tissues, including skin, brain, breast, colon, prostate, and lung-derived tumors were observed to overexpress MIF, ...

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Section: Discussionsupporting

confidence: 92%

Identification and Characterization of Novel Classes of Macrophage Migration Inhibitory Factor (MIF) Inhibitors with Distinct Mechanisms of Action

Ouertatani-Sakouhi

El-Turk

Fauvet

et al. 2010

Journal of Biological Chemistry

123

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“…2 Additionally, ebselen neutralizes free radicals produced by NMDA receptor stimulation 7 and reduces lipoperoxidation mediated by glutamate-induced excitotoxicity. 8 This represents an important property of ebselen because free radicals, particularly reactive oxygen species, can accumulate to such a degree as to cause a biochemical chain of events that ultimately lead to cell death. 9 Preliminary clinical trials have shown that ebselen may be useful in the treatment of acute ischemic stroke.…”

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confidence: 99%

Ebselen, a Seleno-Organic Antioxidant, Is Neuroprotective After Embolic Strokes in Rabbits

Lapchak

Zivin

2003

Stroke

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Background and Purpose-It has been proposed that antioxidants and spin-trap agents may be neuroprotective after acute ischemia stroke. Although the antioxidant ebselen is currently in clinical trials, little is known about the effectiveness of ebselen, which has glutathione peroxidase-like and anti-inflammatory properties in embolic stroke models. Therefore, we determined the effects of ebselen when administered alone or with the thrombolytic tissue plasminogen activator (tPA), the only Food and Drug Administration-approved pharmacological agent for the treatment of stroke. Methods-Male New Zealand White rabbits were embolized by injection of a suspension of small blood clots into the middle cerebral artery via a catheter. Five minutes after embolization, ebselen (10 to 50 mg/kg) was infused intravenously. Control rabbits received infusions of the vehicle required to solubilize ebselen. In additional rabbits, ebselen (20 mg/kg) was administered 60 minutes after embolization, either alone or in combination with tPA (0.9 or 3.3 mg/kg tPA). Behavioral analysis was conducted 24 hours after embolization, allowing determination of the effective stroke dose (P 50 ) or clot amount (mg) that produces neurological deficits in 50% of the rabbits. Results-A drug is considered neuroprotective if it significantly increases the P 50 compared with the vehicle-treated control group. The P 50 of controls 24 hours after embolization was 1.35Ϯ0.30 mg. Rabbits treated 5 minutes after embolization with 10, 20, or 50 mg/kg ebselen had P 50 values of 2.12Ϯ0.56, 2.82Ϯ0.75 (PϽ0.05), and 0.49Ϯ0.54 mg, respectively. A significant neuroprotective effect was observed with the 20-mg/kg dose, but not if there was a 60-minute delay before administration (P 50 ϭ1.69Ϯ0.32 mg). When tPA (3.3 mg/kg) was infused 60 minutes after embolization and ebselen (20 mg/kg) was injected at either 5 (P 50 ϭ2.98Ϯ0.18 mg) or 60 (P 50 ϭ3.60Ϯ0.79 mg) minutes, there was no additional neuroprotective effect compared with tPA alone (P 50 ϭ3.38Ϯ0.55 mg). However, if ebselen (20 mg/kg) was administered concomitantly with low-dose tPA (0.9 mg/kg) 60 minutes after embolization, the P 50 was 3.52Ϯ0.73 mg (PϽ0.05), indicating a synergistic effect of the drug combination because neither alone was effective (P 50 ϭ1.69Ϯ0.32 and 1.54Ϯ0.36 mg, respectively). Conclusions-This study indicates that ebselen may be neuroprotective when administered shortly after an embolic stroke, but the time-and dose-response analyses suggest that it has a narrow therapeutic window. Nevertheless, ebselen may be beneficial if administered concomitantly with a thrombolytic because it significantly enhanced the neuroprotective activity of low-dose tPA.

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“…Итак, физиологиче-ское поступление селена признано защитным фактором в борьбе с инсультом. Ионы Se активи-руют окислительно-восстановительные ферменты митохондрий и микросом, глутатионредуктазу, глутатионпероксидазу, цитохром Р 450 , участвуют в синтезе гликогена, АТФ, в передаче электронов от гемоглобина к кислороду, поддерживают об-мен цистеина, потенцируют работу α-токоферола, являются антидотом против тяжелых металлов в мозге (ртути, серебра, кадмия, в меньшей степени − свинца, никеля (Parnham et al, 2000;Porciúncula et al, 2001;Голубкина и др. 2002;Reisinger et al, 2009;Mehta et al, 2012;Chan et al, 2012;Клименко и др., 2014).…”

Section: Introductionunclassified

The Role of Selenium in the Multivariate Etiopathogenesis of Ischemic Stroke

Klimenko¹,

Skalny²,

Turna³

et al. 2015

TEM (Moscow)

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1 Институт химической физики им. Н.Н. Семенова РАН, Москва, Россия 2 АНО «Центр биотической медицины», Москва, Россия 3 Институт повышения квалификации ФМБА России, Москва, Россия 4 Вычислительный центр им. А.А. Дородницына РАН, Москва, Россия 5 Клиническая больница № 123 ФМБА России, Одинцово, Моск. обл., Россия 6 Институт биохимической физики им. Н.М. Эмануэля РАН, Москва, Россия РЕЗЮМЕ. Проанализирована роль селена в многофакторном этиопатогенезе ишемического инсуль-та. В клинических условиях у пациентов с диагнозом «ишемический инсульт» определены показатели биомаркеров дисциркуляторной патологии. Методом атомно-эмиссионной спектрометрии с индуктивно связанной аргоновой плазмой определена концентрация селена в сыворотке крови. Методом иммуно-ферментного анализа в сыворотке крови определена концентрация нейроспецифического белка AT к NR2 (нг/мл), являющегося строгим предиктором ишемического инсульта и характеризующего степень повреждения ишемизированной мозговой ткани. Неинвазивным нейрофизиологическим методом про-ведена регистрация уровня постоянных потенциалов головного мозга (УПП, мВ) в разных возрастных группах. Методом Манна−Уитни показано достоверно более низкое значение концентрации селена в старшей возрастной группе (больше 60 лет), что свидетельствует об истощении глутатионовых антиок-сидантных ферментов в позднем возрасте. Выявлена сопряженность концентраций селена и AT к NR2: более высокому значению селена соответствует более низкая концентрация AT к NR2 и наоборот. Дан-ный факт подтверждает взаимозависимость антиоксидантной защиты, показателем которой является селен, и нейроспецифического белка AT к NR2 − показателя повреждения ишемизированной мозговой ткани. Корреляционный анализ выявил достоверную связь между концентрацией селена и УПП в раз-личных областях мозга и между концентрациями селена и AT к NR2, что свидетельствует о возможно-сти использования этих показателей в качестве биомаркеров ишемии мозга с целью обеспечения мак-симальной сохранности мозговой ткани при дисциркуляционных расстройствах.КЛЮЧЕВЫЕ СЛОВА: ишемический инсульт, селен, AT к NR2, энергетический метаболизм мозга, уровень постоянного потенциала, макроэлементы, микроэлементы.

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Ebselen prevents excitotoxicity provoked by glutamate in rat cerebellar granule neurons

Cited by 104 publications

References 19 publications

Identification and Characterization of Novel Classes of Macrophage Migration Inhibitory Factor (MIF) Inhibitors with Distinct Mechanisms of Action

Identification and Characterization of Novel Classes of Macrophage Migration Inhibitory Factor (MIF) Inhibitors with Distinct Mechanisms of Action

Ebselen, a Seleno-Organic Antioxidant, Is Neuroprotective After Embolic Strokes in Rabbits

The Role of Selenium in the Multivariate Etiopathogenesis of Ischemic Stroke

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