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Molecular Biology Reports

, Volume 41, Issue 8, pp 4865–4879 | Cite as

Ebselen, a promising antioxidant drug: mechanisms of action and targets of biological pathways

  • Gajendra Kumar Azad
  • Raghuvir S. Tomar
Article

Abstract

Ebselen, an organoselenium compound, mimics glutathione peroxidase activity. It is a multifunctional compound, which catalyzes several essential reactions for the protection of cellular components from oxidative and free radical damage. Based on a number of in vitro and in vivo studies, various mechanisms are proposed to understand the biomedical actions of ebselen in health and diseases. It modulates metallo-proteins, enzymatic cofactors, gene expression, epigenetics, antioxidant defenses and immune systems. Owing to these properties, ebselen is currently under clinical trials for the prevention and treatment of various disorders such as cardiovascular diseases, arthritis, stroke, atherosclerosis, and cancer. A few ebselen-based pharmaceutical agents are under extensive investigation. As ebselen has been shown to have significant cellular toxicity, appropriate studies are needed to redesign the ebselen-based therapy for clinical trials. This review summarizes current understanding of the biochemical and molecular properties, and pharmacological applications of ebselen and future directions in this area of research.

Keywords

Ebselen Organoselenium compounds Redox biology Antioxidant Enzyme mimic 

Notes

Acknowledgments

We apologize to the authors whose work is not cited due to space limitation. Council of Scientific and Industrial Research (CSIR), Govt. of India is acknowledged for fellowship support to GKA. This work was financially supported by the fund from Council of Scientific and Industrial Research (CSIR), Govt. of India to RST. Members of the Laboratory of Chromatin Biology are acknowledged for helpful discussions throughout the preparation of this manuscript.

References

  1. 1.
    Sakurai T, Kanayama M, Shibata T, Itoh K, Kobayashi A, Yamamoto M, Uchida K (2006) Ebselen, a seleno-organic antioxidant, as an electrophile. Chem Res Toxicol 19(9):1196–1204. doi: 10.1021/tx0601105 PubMedGoogle Scholar
  2. 2.
    Ullrich V, Weber P, Meisch F, von Appen F (1996) Ebselen-binding equilibria between plasma and target proteins. Biochem Pharmacol 52(1):15–19PubMedGoogle Scholar
  3. 3.
    Zhao R, Masayasu H, Holmgren A (2002) Ebselen: a substrate for human thioredoxin reductase strongly stimulating its hydroperoxide reductase activity and a superfast thioredoxin oxidant. Proc Natl Acad Sci USA 99(13):8579–8584. doi: 10.1073/pnas.122061399 PubMedCentralPubMedGoogle Scholar
  4. 4.
    Antony S, Bayse CA (2011) Modeling the mechanism of the glutathione peroxidase mimic ebselen. Inorg Chem 50(23):12075–12084. doi: 10.1021/ic201603v PubMedGoogle Scholar
  5. 5.
    Sies H, Sharov VS, Klotz LO, Briviba K (1997) Glutathione peroxidase protects against peroxynitrite-mediated oxidations. A new function for selenoproteins as peroxynitrite reductase. J Biol Chem 272(44):27812–27817PubMedGoogle Scholar
  6. 6.
    Zhao R, Holmgren A (2004) Ebselen is a dehydroascorbate reductase mimic, facilitating the recycling of ascorbate via mammalian thioredoxin systems. Antioxid Redox Signal 6(1):99–104. doi: 10.1089/152308604771978390 PubMedGoogle Scholar
  7. 7.
    Nakamura Y, Feng Q, Kumagai T, Torikai K, Ohigashi H, Osawa T, Noguchi N, Niki E, Uchida K (2002) Ebselen, a glutathione peroxidase mimetic seleno-organic compound, as a multifunctional antioxidant. Implication for inflammation-associated carcinogenesis. J Biol Chem 277(4):2687–2694. doi: 10.1074/jbc.M109641200 PubMedGoogle Scholar
  8. 8.
    Imai H, Masayasu H, Dewar D, Graham DI, Macrae IM (2001) Ebselen protects both gray model of focal and white matter in a rodent cerebral ischemia. Stroke 32(9):2149–2156. doi: 10.1161/hs0901.095725 PubMedGoogle Scholar
  9. 9.
    Noguchi N, Yoshida Y, Kaneda H, Yamamoto Y, Niki E (1992) Action of ebselen as an antioxidant against lipid peroxidation. Biochem Pharmacol 44(1):39–44PubMedGoogle Scholar
  10. 10.
    Schewe T (1995) Molecular actions of ebselen—an antiinflammatory antioxidant. Gen Pharmacol 26(6):1153–1169PubMedGoogle Scholar
  11. 11.
    Chew P, Yuen DY, Stefanovic N, Pete J, Coughlan MT, Jandeleit-Dahm KA, Thomas MC, Rosenfeldt F, Cooper ME, de Haan JB (2010) Antiatherosclerotic and renoprotective effects of ebselen in the diabetic apolipoprotein E/GPx1-double knockout mouse. Diabetes 59(12):3198–3207. doi: 10.2337/db10-0195 PubMedCentralPubMedGoogle Scholar
  12. 12.
    Lindenblatt N, Schareck W, Belusa L, Nickels RM, Menger MD, Vollmar B (2003) Anti-oxidant ebselen delays microvascular thrombus formation in the rat cremaster muscle by inhibiting platelet P-selectin expression. Thromb Haemost 90(5):882–892. doi: 10.1267/THRO03050882 PubMedGoogle Scholar
  13. 13.
    Nogueira CW, Rotta LN, Zeni G, Souza DO, Rocha JB (2002) Exposure to ebselen changes glutamate uptake and release by rat brain synaptosomes. Neurochem Res 27(4):283–288PubMedGoogle Scholar
  14. 14.
    Kasraee B, Nikolic DS, Salomon D, Carraux P, Fontao L, Piguet V, Omrani GR, Sorg O, Saurat JH (2012) Ebselen is a new skin depigmenting agent that inhibits melanin biosynthesis and melanosomal transfer. Exp Dermatol 21(1):19–24. doi: 10.1111/j.1600-0625.2011.01394.x PubMedGoogle Scholar
  15. 15.
    Morin D, Zini R, Ligeret H, Neckameyer W, Labidalle S, Tillement JP (2003) Dual effect of ebselen on mitochondrial permeability transition. Biochem Pharmacol 65(10):1643–1651PubMedGoogle Scholar
  16. 16.
    Batna A, Fuchs C, Spiteller G (1997) Lipid peroxidation in presence of ebselen. Chem Phys Lipids 87(2):149–158PubMedGoogle Scholar
  17. 17.
    Chan PH (1996) Role of oxidants in ischemic brain damage. Stroke 27(6):1124–1129PubMedGoogle Scholar
  18. 18.
    Muller A, Cadenas E, Graf P, Sies H (1984) A novel biologically active seleno-organic compound-I. Glutathione peroxidase-like activity in vitro and antioxidant capacity of PZ 51 (Ebselen). Biochem Pharmacol 33(20):3235–3239PubMedGoogle Scholar
  19. 19.
    Sies H (1993) Ebselen, a selenoorganic compound as glutathione peroxidase mimic. Free Radical Biol Med 14(3):313–323Google Scholar
  20. 20.
    Sies H, de Groot H (1992) Role of reactive oxygen species in cell toxicity. Toxicol Lett 64–65:547–551PubMedGoogle Scholar
  21. 21.
    Masumoto H, Sies H (1996) The reaction of ebselen with peroxynitrite. Chem Res Toxicol 9(1):262–267. doi: 10.1021/tx950115u PubMedGoogle Scholar
  22. 22.
    Briviba K, Roussyn I, Sharov VS, Sies H (1996) Attenuation of oxidation and nitration reactions of peroxynitrite by selenomethionine, selenocystine and ebselen. Biochem J 319(Pt 1):13–15PubMedCentralPubMedGoogle Scholar
  23. 23.
    Masumoto H, Kissner R, Koppenol WH, Sies H (1996) Kinetic study of the reaction of ebselen with peroxynitrite. FEBS Lett 398(2–3):179–182PubMedGoogle Scholar
  24. 24.
    Seo JY, Lee CH, Cho JH, Choi JH, Yoo KY, Kim DW, Park OK, Li H, Choi SY, Hwang IK, Won MH (2009) Neuroprotection of ebselen against ischemia/reperfusion injury involves GABA shunt enzymes. J Neurol Sci 285(1–2):88–94. doi: 10.1016/j.jns.2009.05.029 PubMedGoogle Scholar
  25. 25.
    Gabryel B, Malecki A (2006) Ebselen attenuates oxidative stress in ischemic astrocytes depleted of glutathione. Comparison with glutathione precursors. Pharmacol Rep 58(3):381–392PubMedGoogle Scholar
  26. 26.
    Hamacher J, Stammberger U, Weber E, Lucas R, Wendel A (2009) Ebselen improves ischemia-reperfusion injury after rat lung transplantation. Lung 187(2):98–103. doi: 10.1007/s00408-009-9134-x PubMedGoogle Scholar
  27. 27.
    Pawlas N, Malecki A (2007) Effects of ebselen on glutathione level in neurons exposed to arachidonic acid and 4-hydroxynonenal during simulated ischemia in vitro. Pharmacol Rep 59(6):708–714PubMedGoogle Scholar
  28. 28.
    Namura S, Nagata I, Takami S, Masayasu H, Kikuchi H (2001) Ebselen reduces cytochrome c release from mitochondria and subsequent DNA fragmentation after transient focal cerebral ischemia in mice. Stroke 32(8):1906–1911PubMedGoogle Scholar
  29. 29.
    Ishii Y, Hashimoto K, Hirano K, Morishima Y, Mochizuki M, Masuyama K, Nomura A, Sakamoto T, Uchida Y, Sagai M, Sekizawa K (2000) Ebselen decreases ozone-induced pulmonary inflammation in rats. Lung 178(4):225–234PubMedGoogle Scholar
  30. 30.
    Pratta MA, Ackerman NR, Arner EC (1998) Effect of ebselen on IL-1-induced alterations in cartilage metabolism. Inflamm Res 47(3):115–121PubMedGoogle Scholar
  31. 31.
    Johnsen-Soriano S, Genoves JM, Romero B, Garcia-Delpech S, Muriach M, Sancho-Tello M, Bosch-Morell F, Romero FJ (2007) Chronic ethanol feeding induces oxidative stress in the rat retina: treatment with the antioxidant ebselen. Arch Soc Esp Oftalmol 82(12):757–762PubMedGoogle Scholar
  32. 32.
    Zhang M, Nomura A, Uchida Y, Iijima H, Sakamoto T, Iishii Y, Morishima Y, Mochizuki M, Masuyama K, Hirano K, Sekizawa K (2002) Ebselen suppresses late airway responses and airway inflammation in guinea pigs. Free Radical Biol Med 32(5):454–464Google Scholar
  33. 33.
    Gogvadze V, Klein SD, Shigenaga M, Ames BN, Richter C (2000) Effect of ebselen on Ca2+ transport in mitochondria. Redox Rep 5(6):359–363. doi: 10.1179/135100000101535924 PubMedGoogle Scholar
  34. 34.
    Yang CF, Shen HM, Ong CN (2000) Intracellular thiol depletion causes mitochondrial permeability transition in ebselen-induced apoptosis. Arch Biochem Biophys 380(2):319–330. doi: 10.1006/abbi.2000.1939 PubMedGoogle Scholar
  35. 35.
    Guerin PJ, Gauthier ER (2003) Induction of cellular necrosis by the glutathione peroxidase mimetic ebselen. J Cell Biochem 89(1):203–211. doi: 10.1002/jcb.10500 PubMedGoogle Scholar
  36. 36.
    Miorelli ST, Rosa RM, Moura DJ, Rocha JC, Lobo LA, Henriques JA, Saffi J (2008) Antioxidant and anti-mutagenic effects of ebselen in yeast and in cultured mammalian V79 cells. Mutagenesis 23(2):93–99. doi: 10.1093/mutage/gem048 PubMedGoogle Scholar
  37. 37.
    Yang CF, Shen HM, Ong CN (2000) Ebselen induces apoptosis in HepG(2) cells through rapid depletion of intracellular thiols. Arch Biochem Biophys 374(2):142–152. doi: 10.1006/abbi.1999.1574 PubMedGoogle Scholar
  38. 38.
    Azad GK, Balkrishna SJ, Sathish N, Kumar S, Tomar RS (2012) Multifunctional Ebselen drug functions through the activation of DNA damage response and alterations in nuclear proteins. Biochem Pharmacol 83(2):296–303. doi: 10.1016/j.bcp.2011.10.011 PubMedGoogle Scholar
  39. 39.
    Larabee JL, Hocker JR, Hanas JS (2009) Mechanisms of inhibition of zinc-finger transcription factors by selenium compounds ebselen and selenite. J Inorg Biochem 103(3):419–426. doi: 10.1016/j.jinorgbio.2008.12.007 PubMedGoogle Scholar
  40. 40.
    Jacob C, Maret W, Vallee BL (1998) Ebselen, a selenium-containing redox drug, releases zinc from metallothionein. Biochem Biophys Res Commun 248(3):569–573. doi: 10.1006/bbrc.1998.9026 PubMedGoogle Scholar
  41. 41.
    Wagner G, Schuch G, Akerboom TP, Sies H (1994) Transport of ebselen in plasma and its transfer to binding sites in the hepatocyte. Biochem Pharmacol 48(6):1137–1144PubMedGoogle Scholar
  42. 42.
    Christison J, Sies H, Stocker R (1994) Human blood cells support the reduction of low-density-lipoprotein-associated cholesteryl ester hydroperoxides by albumin-bound ebselen. Biochem J 304(Pt 2):341–345PubMedCentralPubMedGoogle Scholar
  43. 43.
    Aitken JB, Lay PA, Duong TT, Aran R, Witting PK, Harris HH, Lai B, Vogt S, Giles GI (2012) Synchrotron radiation induced X-ray emission studies of the antioxidant mechanism of the organoselenium drug ebselen. J Biol Inorg Chem 17(4):589–598. doi: 10.1007/s00775-012-0879-y PubMedGoogle Scholar
  44. 44.
    Boireau A, Marechal PM, Meunier M, Dubedat P, Moussaoui S (2000) The anti-oxidant ebselen antagonizes the release of the apoptogenic factor cytochrome c induced by Fe2+/citrate in rat liver mitochondria. Neurosci Lett 289(2):95–98PubMedGoogle Scholar
  45. 45.
    Tiano L, Fedeli D, Santoni G, Davies I, Wakabayashi T, Falcioni G (2003) Ebselen prevents mitochondrial ageing due to oxidative stress: in vitro study of fish erythrocytes. Mitochondrion 2(6):428–436. doi: 10.1016/S1567-7249(03)00032-1 PubMedGoogle Scholar
  46. 46.
    Moussaoui S, Obinu MC, Daniel N, Reibaud M, Blanchard V, Imperato A (2000) The antioxidant ebselen prevents neurotoxicity and clinical symptoms in a primate model of Parkinson’s disease. Exp Neurol 166(2):235–245. doi: 10.1006/exnr.2000.7516 PubMedGoogle Scholar
  47. 47.
    Nagi MN, Laguna JC, Cook L, Cinti DL (1989) Disruption of rat hepatic microsomal electron transport chains by the selenium-containing anti-inflammatory agent Ebselen. Arch Biochem Biophys 269(1):264–271PubMedGoogle Scholar
  48. 48.
    Narayanaswami V, Sies H (1990) Oxidative damage to mitochondria and protection by ebselen and other antioxidants. Biochem Pharmacol 40(7):1623–1629PubMedGoogle Scholar
  49. 49.
    Santofimia-Castano P, Salido GM, Gonzalez A (2013) Ebselen alters mitochondrial physiology and reduces viability of rat hippocampal astrocytes. DNA Cell Biol 32(4):147–155. doi: 10.1089/dna.2012.1939 PubMedCentralPubMedGoogle Scholar
  50. 50.
    Xu KH, Zhang Y, Tang B, Laskin J, Roach PJ, Chen H (2010) Study of highly selective and efficient thiol derivatization using selenium reagents by mass spectrometry. Anal Chem 82(16):6926–6932. doi: 10.1021/Ac1011602 PubMedGoogle Scholar
  51. 51.
    Schewe C, Schewe T, Wendel A (1994) Strong inhibition of mammalian lipoxygenases by the antiinflammatory seleno-organic compound ebselen in the absence of glutathione. Biochem Pharmacol 48(1):65–74PubMedGoogle Scholar
  52. 52.
    Walther M, Holzhutter HG, Kuban RJ, Wiesner R, Rathmann J, Kuhn H (1999) The inhibition of mammalian 15-lipoxygenases by the anti-inflammatory drug ebselen: dual-type mechanism involving covalent linkage and alteration of the iron ligand sphere. Mol Pharmacol 56(1):196–203PubMedGoogle Scholar
  53. 53.
    Hattori R, Yui Y, Shinoda E, Inoue R, Aoyama T, Masayasu H, Kawai C, Sasayama S (1996) Effect of ebselen on bovine and rat nitric oxide synthase activity is modified by thiols. Jpn J Pharmacol 72(2):191–193PubMedGoogle Scholar
  54. 54.
    Smith SM, Min J, Ganesh T, Diebold B, Kawahara T, Zhu Y, McCoy J, Sun A, Snyder JP, Fu H, Du Y, Lewis I, Lambeth JD (2012) Ebselen and congeners inhibit NADPH oxidase 2-dependent superoxide generation by interrupting the binding of regulatory subunits. Chem Biol 19(6):752–763. doi: 10.1016/j.chembiol.2012.04.015 PubMedCentralPubMedGoogle Scholar
  55. 55.
    Tabuchi Y, Ogasawara T, Furuhama K (1994) Mechanism of the inhibition of hog gastric H+, K(+)-ATPase by the seleno-organic compound ebselen. Arzneimittelforschung 44(1):51–54PubMedGoogle Scholar
  56. 56.
    Mishra B, Priyadarsini KI, Mohan H, Mugesh G (2006) Horseradish peroxidase inhibition and antioxidant activity of ebselen and related organoselenium compounds. Bioorg Med Chem Lett 16(20):5334–5338. doi: 10.1016/j.bmcl.2006.07.085 PubMedGoogle Scholar
  57. 57.
    Azad GK, Singh V, Mandal P, Singh P, Golla U, Baranwal S, Chauhan S, Tomar RS (2014) Ebselen induces reactive oxygen species (ROS)-mediated cytotoxicity in Saccharomyces cerevisiae with inhibition of glutamate dehydrogenase being a target. FEBS Open Bio 4:77–89. doi: 10.1016/j.fob.2014.01.002 PubMedCentralPubMedGoogle Scholar
  58. 58.
    Lugokenski TH, Muller LG, Taube PS, Rocha JB, Pereira ME (2011) Inhibitory effect of ebselen on lactate dehydrogenase activity from mammals: a comparative study with diphenyl diselenide and diphenyl ditelluride. Drug Chem Toxicol 34(1):66–76. doi: 10.3109/01480541003782294 PubMedGoogle Scholar
  59. 59.
    Borges VC, Rocha JB, Nogueira CW (2005) Effect of diphenyl diselenide, diphenyl ditelluride and ebselen on cerebral Na(+), K(+)-ATPase activity in rats. Toxicology 215(3):191–197. doi: 10.1016/j.tox.2005.07.002 PubMedGoogle Scholar
  60. 60.
    Terentis AC, Freewan M, Sempertegui Plaza TS, Raftery MJ, Stocker R, Thomas SR (2010) The selenazal drug ebselen potently inhibits indoleamine 2,3-dioxygenase by targeting enzyme cysteine residues. Biochemistry 49(3):591–600. doi: 10.1021/bi901546e PubMedGoogle Scholar
  61. 61.
    Xia R, Ganther HE, Egge A, Abramson JJ (2004) Selenium compounds modulate the calcium release channel/ryanodine receptor of rabbit skeletal muscle by oxidizing functional thiols. Biochem Pharmacol 67(11):2071–2079. doi: 10.1016/j.bcp.2004.02.018 PubMedGoogle Scholar
  62. 62.
    Klug A (2010) The discovery of zinc fingers and their applications in gene regulation and genome manipulation. Annu Rev Biochem 79:213–231. doi: 10.1146/annurev-biochem-010909-095056 PubMedGoogle Scholar
  63. 63.
    Laity JH, Lee BM, Wright PE (2001) Zinc finger proteins: new insights into structural and functional diversity. Curr Opin Struc Biol 11(1):39–46. doi: 10.1016/S0959-440x(00)00167-6 Google Scholar
  64. 64.
    Antony S, Bayse CA (2013) Density functional theory study of the attack of ebselen on a zinc-finger model. Inorg Chem. doi: 10.1021/ic401429z PubMedGoogle Scholar
  65. 65.
    Sekirnik R, Rose NR, Thalhammer A, Seden PT, Mecinovic J, Schofield CJ (2009) Inhibition of the histone lysine demethylase JMJD2A by ejection of structural Zn(II). Chem Commun (Camb) 42:6376–6378. doi: 10.1039/b916357c Google Scholar
  66. 66.
    Blessing H, Kraus S, Heindl P, Bal W, Hartwig A (2004) Interaction of selenium compounds with zinc finger proteins involved in DNA repair. Eur J Biochem/FEBS 271(15):3190–3199. doi: 10.1111/j.1432-1033.2004.04251.x Google Scholar
  67. 67.
    Wood-Allum CA, Barber SC, Kirby J, Heath P, Holden H, Mead R, Higginbottom A, Allen S, Beaujeux T, Alexson SE, Ince PG, Shaw PJ (2006) Impairment of mitochondrial anti-oxidant defence in SOD1-related motor neuron injury and amelioration by ebselen. Brain 129(Pt 7):1693–1709. doi: 10.1093/brain/awl118 PubMedGoogle Scholar
  68. 68.
    Kim SJ, Park C, Han AL, Youn MJ, Lee JH, Kim Y, Kim ES, Kim HJ, Kim JK, Lee HK, Chung SY, So H, Park R (2009) Ebselen attenuates cisplatin-induced ROS generation through Nrf2 activation in auditory cells. Hear Res 251(1–2):70–82. doi: 10.1016/j.heares.2009.03.003 PubMedGoogle Scholar
  69. 69.
    Tamasi V, Jeffries JM, Arteel GE, Falkner KC (2004) Ebselen augments its peroxidase activity by inducing nrf-2-dependent transcription. Arch Biochem Biophys 431(2):161–168. doi: 10.1016/j.abb.2004.07.030 PubMedGoogle Scholar
  70. 70.
    Meier P, Finch A, Evan G (2000) Apoptosis in development. Nature 407(6805):796–801. doi: 10.1038/35037734 PubMedGoogle Scholar
  71. 71.
    Milleron RS, Bratton SB (2006) Heat shock induces apoptosis independently of any known initiator caspase-activating complex. J Biol Chem 281(25):16991–17000. doi: 10.1074/jbc.M512754200 PubMedGoogle Scholar
  72. 72.
    Verheij M, Bartelink H (2000) Radiation-induced apoptosis. Cell Tissue Res 301(1):133–142PubMedGoogle Scholar
  73. 73.
    Maulik N, Yoshida T (2000) Oxidative stress developed during open heart surgery induces apoptosis: reduction of apoptotic cell death by ebselen, a glutathione peroxidase mimic. J Cardiovasc Pharmacol 36(5):601–608PubMedGoogle Scholar
  74. 74.
    Koizumi H, Fujisawa H, Suehiro E, Shirao S, Suzuki M (2011) Neuroprotective effects of ebselen following forebrain ischemia: involvement of glutamate and nitric oxide. Neurol Med Chir 51(5):337–343Google Scholar
  75. 75.
    Yamaguchi T, Sano K, Takakura K, Saito I, Shinohara Y, Asano T, Yasuhara H, Grp ES (1998) Ebselen in acute ischemic stroke—a placebo-controlled, double-blind clinical trial. Stroke 29(1):12–17PubMedGoogle Scholar
  76. 76.
    Parnham M, Sies H (2000) Ebselen: prospective therapy for cerebral ischaemia. Expert Opin Investig Drugs 9(3):607–619. doi: 10.1517/13543784.9.3.607 PubMedGoogle Scholar
  77. 77.
    Holl V, Coelho D, Silbernagel L, Keyser JF, Waltzinger C, Dufour P, Bischoff PL (2000) Prevention of nitrogen mustard-induced apoptosis in normal and transformed lymphocytes by ebselen. Biochem Pharmacol 60(11):1565–1577PubMedGoogle Scholar
  78. 78.
    Tak JK, Park JW (2009) The use of ebselen for radioprotection in cultured cells and mice. Free Radical Biol Med 46(8):1177–1185. doi: 10.1016/j.freeradbiomed.2009.01.023 Google Scholar
  79. 79.
    Ramakrishnan N, Kalinich JF, McClain DE (1996) Ebselen inhibition of apoptosis by reduction of peroxides. Biochem Pharmacol 51(11):1443–1451PubMedGoogle Scholar
  80. 80.
    Yoshizumi M, Kogame T, Suzaki Y, Fujita Y, Kyaw M, Kirima K, Ishizawa K, Tsuchiya K, Kagami S, Tamaki T (2002) Ebselen attenuates oxidative stress-induced apoptosis via the inhibition of the c-Jun N-terminal kinase and activator protein-1 signalling pathway in PC12 cells. Br J Pharmacol 136(7):1023–1032. doi: 10.1038/sj.bjp.0704808 PubMedCentralPubMedGoogle Scholar
  81. 81.
    Ali N, Yoshizumi M, Tsuchiya K, Kyaw M, Fujita Y, Izawa Y, Abe S, Kanematsu Y, Kagami S, Tamaki T (2004) Ebselen inhibits p38 mitogen-activated protein kinase-mediated endothelial cell death by hydrogen peroxide. Eur J Pharmacol 485(1–3):127–135PubMedGoogle Scholar
  82. 82.
    Sarker KP, Biswas KK, Rosales JL, Yamaji K, Hashiguchi T, Lee KY, Maruyama I (2003) Ebselen inhibits NO-induced apoptosis of differentiated PC12 cells via inhibition of ASK1-p38 MAPK-p53 and JNK signaling and activation of p44/42 MAPK and Bcl-2. J Neurochem 87(6):1345–1353PubMedGoogle Scholar
  83. 83.
    Xu JH, Hu HT, Liu Y, Qian YH, Liu ZH, Tan QR, Zhang ZJ (2006) Neuroprotective effects of ebselen are associated with the regulation of Bcl-2 and Bax proteins in cultured mouse cortical neurons. Neurosci Lett 399(3):210–214. doi: 10.1016/j.neulet.2006.02.024 PubMedGoogle Scholar
  84. 84.
    Yoshizumi M, Fujita Y, Izawa Y, Suzaki Y, Kyaw M, Ali N, Tsuchiya K, Kagami S, Yano S, Sone S, Tamaki T (2004) Ebselen inhibits tumor necrosis factor-alpha-induced c-Jun N-terminal kinase activation and adhesion molecule expression in endothelial cells. Exp Cell Res 292(1):1–10PubMedGoogle Scholar
  85. 85.
    Cooke MS, Evans MD, Dizdaroglu M, Lunec J (2003) Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J 17(10):1195–1214. doi: 10.1096/fj.02-0752rev PubMedGoogle Scholar
  86. 86.
    Wiseman H, Halliwell B (1996) Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer. Biochem J 313(Pt 1):17–29PubMedCentralPubMedGoogle Scholar
  87. 87.
    Yang CF, Shen HM, Ong CN (1999) Protective effect of ebselen against hydrogen peroxide-induced cytotoxicity and DNA damage in HepG2 cells. Biochem Pharmacol 57(3):273–279PubMedGoogle Scholar
  88. 88.
    Li J, Chen JJ, Zhang F, Zhang C (2000) Ebselen protection against hydrogen peroxide-induced cytotoxicity and DNA damage in HL-60 cells. Acta Pharmacol Sin 21(5):455–459PubMedGoogle Scholar
  89. 89.
    Roussyn I, Briviba K, Masumoto H, Sies H (1996) Selenium-containing compounds protect DNA from single-strand breaks caused by peroxynitrite. Arch Biochem Biophys 330(1):216–218. doi: 10.1006/abbi.1996.0245 PubMedGoogle Scholar
  90. 90.
    Li Y, Cao Z (2002) The neuroprotectant ebselen inhibits oxidative DNA damage induced by dopamine in the presence of copper ions. Neurosci Lett 330(1):69–73PubMedGoogle Scholar
  91. 91.
    Tripathi DN, Jena GB (2008) Ebselen attenuates cyclophosphamide-induced oxidative stress and DNA damage in mice. Free Radical Res 42(11–12):966–977. doi: 10.1080/10715760802566558 Google Scholar
  92. 92.
    Yang CF, Liu J, Wasser S, Shen HM, Tan CE, Ong CN (2000) Inhibition of ebselen on aflatoxin B(1)-induced hepatocarcinogenesis in Fischer 344 rats. Carcinogenesis 21(12):2237–2243PubMedGoogle Scholar
  93. 93.
    Balkrishna SJ, Kumar S, Azad GK, Bhakuni BS, Panini P, Ahalawat N, Tomar RS, Detty MR (2014) An ebselen like catalyst with enhanced GPx activity via a selenol intermediate. Org Biomol Chem 12(8):1215–1219. doi: 10.1039/c4ob00027g PubMedGoogle Scholar
  94. 94.
    Zhao XL, Chabes A, Domkin V, Thelander L, Rothstein R (2001) The ribonucleotide reductase inhibitor Sml1 is a new target of the Mec1/Rad53 kinase cascade during growth and in response to DNA damage. EMBO J 20(13):3544–3553. doi: 10.1093/emboj/20.13.3544 PubMedCentralPubMedGoogle Scholar
  95. 95.
    Inglot AD, Mlochowski J, Zielinska-Jenczylik J, Piasecki E, Ledwon TK, Kloc K (1996) Seleno-organic compounds as immunostimulants: an approach to the structure-activity relationship. Arch Immunol Therap Exp 44(1):67–75Google Scholar
  96. 96.
    Tiegs G, Kusters S, Kunstle G, Hentze H, Kiemer AK, Wendel A (1998) Ebselen protects mice against T cell-dependent, TNF-mediated apoptotic liver injury. J Pharmacol Exp Therap 287(3):1098–1104Google Scholar
  97. 97.
    Gladilin S, Bidmon HJ, Divanach A, Arteel GE, Witte OW, Zilles K, Sies H (2000) Ebselen lowers plasma interleukin-6 levels and glial heme oxygenase-1 expression after focal photothrombotic brain ischemia. Arch Biochem Biophys 380(2):237–242. doi: 10.1006/abbi.2000.1943 PubMedGoogle Scholar
  98. 98.
    Matsushita T, Fukuda K, Yamamoto H, Yamazaki K, Tomiyama T, Oh M, Hamanishi C (2004) Effect of ebselen, a scavenger of reactive oxygen species, on chondrocyte metabolism. Mod Rheumatol 14(1):25–30. doi: 10.1007/s10165-003-0261-6 PubMedGoogle Scholar
  99. 99.
    Jean Harry G, Bruccoleri A, Lefebvre d’Hellencourt C (2003) Differential modulation of hippocampal chemical-induced injury response by ebselen, pentoxifylline, and TNFalpha-, IL-1alpha-, and IL-6-neutralizing antibodies. J Neurosci Res 73(4):526–536. doi: 10.1002/jnr.10653 PubMedGoogle Scholar
  100. 100.
    Shimohashi N, Nakamuta M, Uchimura K, Sugimoto R, Iwamoto H, Enjoji M, Nawata H (2000) Selenoorganic compound, ebselen, inhibits nitric oxide and tumor necrosis factor-alpha production by the modulation of jun-N-terminal kinase and the NF-kappab signaling pathway in rat Kupffer cells. J Cell Biochem 78(4):595–606PubMedGoogle Scholar
  101. 101.
    Koyanagi T, Nakamuta M, Enjoji M, Iwamoto H, Motomura K, Sakai H, Nawata H (2001) The selenoorganic compound ebselen suppresses liver injury induced by Propionibacterium acnes and lipopolysaccharide in rats. Int J Mol Med 7(3):321–327PubMedGoogle Scholar
  102. 102.
    Zhao H, Lu HG, Shi YB, Zhao LM, Bai C, Wang X (2006) Role of enteral nutrition supplemented with ebselen and EHEC in pancreatitis-associated multiple organ dysfunction in rats. Inflamm Res 55(10):423–429. doi: 10.1007/s00011-006-6008-z PubMedGoogle Scholar
  103. 103.
    Belvisi MG, Haddad EB, Battram C, Birrell M, Foster M, Webber S (2000) Anti-inflammatory properties of ebselen in a model of sephadex-induced lung inflammation. Eur Respir J 15(3):579–581PubMedGoogle Scholar
  104. 104.
    Issekutz AC, Lopes N (1992) Effect of Ebselen on polymorphonuclear leukocyte adhesion to and migration through cytokine-activated vascular endothelium. Int J Immunopharmacol 14(8):1383–1390PubMedGoogle Scholar
  105. 105.
    Bosch-Morell F, Roma J, Puertas FJ, Marin N, Diaz-Llopis M, Romero FJ (1999) Efficacy of the antioxidant ebselen in experimental uveitis. Free Radical Biol Med 27(3–4):388–391Google Scholar
  106. 106.
    Chen J, Li H, Addabbo F, Zhang F, Pelger E, Patschan D, Park HC, Kuo MC, Ni J, Gobe G, Chander PN, Nasjletti A, Goligorsky MS (2009) Adoptive transfer of syngeneic bone marrow-derived cells in mice with obesity-induced diabetes: selenoorganic antioxidant ebselen restores stem cell competence. Am J Pathol 174(2):701–711. doi: 10.2353/ajpath.2009.080606 PubMedCentralPubMedGoogle Scholar
  107. 107.
    Buckett PD, Wessling-Resnick M (2009) Small molecule inhibitors of divalent metal transporter-1. Am J Physiol Gastrointest Liver Physiol 296(4):G798–G804. doi: 10.1152/ajpgi.90342.2008 PubMedCentralPubMedGoogle Scholar
  108. 108.
    Soe-Lin S, Apte SS, Mikhael MR, Kayembe LK, Nie G, Ponka P (2010) Both Nramp1 and DMT1 are necessary for efficient macrophage iron recycling. Exp Hematol 38(8):609–617. doi: 10.1016/j.exphem.2010.04.003 PubMedGoogle Scholar
  109. 109.
    Wetli HA, Buckett PD, Wessling-Resnick M (2006) Small-molecule screening identifies the selanazal drug ebselen as a potent inhibitor of DMT1-mediated iron uptake. Chem Biol 13(9):965–972. doi: 10.1016/j.chembiol.2006.08.005 PubMedCentralPubMedGoogle Scholar
  110. 110.
    Xie L, Zheng W, Xin N, Xie JW, Wang T, Wang ZY (2012) Ebselen inhibits iron-induced tau phosphorylation by attenuating DMT1 up-regulation and cellular iron uptake. Neurochem Int. doi: 10.1016/j.neuint.2012.05.016 Google Scholar
  111. 111.
    Erikson KM, Aschner M (2006) Increased manganese uptake by primary astrocyte cultures with altered iron status is mediated primarily by divalent metal transporter. Neurotoxicology 27(1):125–130. doi: 10.1016/j.neuro.2005.07.003 PubMedGoogle Scholar
  112. 112.
    Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gollan JL, Hediger MA (1997) Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388(6641):482–488. doi: 10.1038/41343 PubMedGoogle Scholar
  113. 113.
    Xie L, Zheng W, Xin N, Xie JW, Wang T, Wang ZY (2012) Ebselen inhibits iron-induced tau phosphorylation by attenuating DMT1 up-regulation and cellular iron uptake. Neurochem Int 61(3):334–340. doi: 10.1016/j.neuint.2012.05.016 PubMedGoogle Scholar
  114. 114.
    Brune B, Diewald B, Ullrich V (1991) Ebselen affects calcium homeostasis in human platelets. Biochem Pharmacol 41(12):1805–1811PubMedGoogle Scholar
  115. 115.
    Dimmeler S, Brune B, Ullrich V (1991) Ebselen prevents inositol (1,4,5)-trisphosphate binding to its receptor. Biochem Pharmacol 42(5):1151–1153PubMedGoogle Scholar
  116. 116.
    Salazar M, Pariente JA, Salido GM, Gonzalez A (2008) Ebselen increases cytosolic free Ca2+ concentration, stimulates glutamate release and increases GFAP content in rat hippocampal astrocytes. Toxicology 244(2–3):280–291. doi: 10.1016/j.tox.2007.12.002 PubMedGoogle Scholar
  117. 117.
    Cotgreave IA, Duddy SK, Kass GE, Thompson D, Moldeus P (1989) Studies on the anti-inflammatory activity of ebselen. Ebselen interferes with granulocyte oxidative burst by dual inhibition of NADPH oxidase and protein kinase C? Biochem Pharmacol 38(4):649–656PubMedGoogle Scholar
  118. 118.
    Halliwell B (1992) Reactive oxygen species and the central nervous system. J Neurochem 59(5):1609–1623PubMedGoogle Scholar
  119. 119.
    Coyle JT, Puttfarcken P (1993) Oxidative stress, glutamate, and neurodegenerative disorders. Science 262(5134):689–695PubMedGoogle Scholar
  120. 120.
    Mylonas C, Kouretas D (1999) Lipid peroxidation and tissue damage. In Vivo 13(3):295–309PubMedGoogle Scholar
  121. 121.
    Whittemore ER, Loo DT, Cotman CW (1994) Exposure to hydrogen peroxide induces cell death via apoptosis in cultured rat cortical neurons. NeuroReport 5(12):1485–1488PubMedGoogle Scholar
  122. 122.
    Greenlund LJ, Deckwerth TL, Johnson EM Jr (1995) Superoxide dismutase delays neuronal apoptosis: a role for reactive oxygen species in programmed neuronal death. Neuron 14(2):303–315PubMedGoogle Scholar
  123. 123.
    Takasago T, Peters EE, Graham DI, Masayasu H, Macrae IM (1997) Neuroprotective efficacy of ebselen, an anti-oxidant with anti-inflammatory actions, in a rodent model of permanent middle cerebral artery occlusion. Br J Pharmacol 122(6):1251–1256. doi: 10.1038/sj.bjp.0701426 PubMedCentralPubMedGoogle Scholar
  124. 124.
    Kalayci M, Coskun O, Cagavi F, Kanter M, Armutcu F, Gul S, Acikgoz B (2005) Neuroprotective effects of ebselen on experimental spinal cord injury in rats. Neurochem Res 30(3):403–410PubMedGoogle Scholar
  125. 125.
    Porciuncula LO, Rocha JB, Boeck CR, Vendite D, Souza DO (2001) Ebselen prevents excitotoxicity provoked by glutamate in rat cerebellar granule neurons. Neurosci Lett 299(3):217–220PubMedGoogle Scholar
  126. 126.
    Dalla Corte CL, Bastos LL, Dobrachinski F, Rocha JB, Soares FA (2012) The combination of organoselenium compounds and guanosine prevents glutamate-induced oxidative stress in different regions of rat brains. Brain Res 1430:101–111. doi: 10.1016/j.brainres.2011.10.049 PubMedGoogle Scholar
  127. 127.
    Mazzanti CM, Spanevello R, Ahmed M, Pereira LB, Goncalves JF, Correa M, Schmatz R, Stefanello N, Leal DB, Mazzanti A, Ramos AT, Martins TB, Danesi CC, Graca DL, Morsch VM, Schetinger MR (2009) Pre-treatment with ebselen and vitamin E modulate acetylcholinesterase activity: interaction with demyelinating agents. Int J Dev Neurosci 27(1):73–80. doi: 10.1016/j.ijdevneu.2008.09.005 PubMedGoogle Scholar
  128. 128.
    He M, Xing S, Yang B, Zhao L, Hua H, Liang Z, Zhou W, Zeng J, Pei Z (2007) Ebselen attenuates oxidative DNA damage and enhances its repair activity in the thalamus after focal cortical infarction in hypertensive rats. Brain Res 1181:83–92. doi: 10.1016/j.brainres.2007.08.072 PubMedGoogle Scholar
  129. 129.
    Geddes JR, Goodwin GM, Rendell J, Azorin JM, Cipriani A, Ostacher MJ, Morriss R, Alder N, Juszczak E (2010) Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet 375(9712):385–395. doi: 10.1016/S0140-6736(09)61828-6 PubMedGoogle Scholar
  130. 130.
    McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM, Geddes JR (2012) Lithium toxicity profile: a systematic review and meta-analysis. Lancet 379(9817):721–728. doi: 10.1016/S0140-6736(11)61516-X PubMedGoogle Scholar
  131. 131.
    Berridge MJ, Downes CP, Hanley MR (1989) Neural and developmental actions of lithium—a unifying hypothesis. Cell 59(3):411–419. doi: 10.1016/0092-8674(89)90026-3 PubMedGoogle Scholar
  132. 132.
    Belmaker RH, Bersudsky Y, Agam G, Levine J, Kofman O (1996) How does lithium work on manic depression? Clinical and psychological correlates of the inositol theory. Annu Rev Med 47:47–56PubMedGoogle Scholar
  133. 133.
    Singh N, Halliday AC, Thomas JM, Kuznetsova OV, Baldwin R, Woon ECY, Aley PK, Antoniadou I, Sharp T, Vasudevan SR, Churchill GC (2013) A safe lithium mimetic for bipolar disorder. Nat Commun 4:1332. doi: 10.1038/Ncomms2320 PubMedCentralPubMedGoogle Scholar
  134. 134.
    Hoshida S, Aoki K, Nishida M, Yamashita N, Igarashi J, Hori M, Kuzuya T, Tada M (1997) Effects of preconditioning with ebselen on glutathione metabolism and stress protein expression. J Pharmacol Exp Therap 281(3):1471–1475Google Scholar
  135. 135.
    deMello MAR, Flodstrom M, Eizirik DL (1996) Ebselen and cytokine-induced nitric oxide synthase expression in insulin-producing cells. Biochem Pharmacol 52(11):1703–1709. doi: 10.1016/S0006-2952(96)00520-5 Google Scholar
  136. 136.
    Mahadevan J, Parazzoli S, Oseid E, Hertzel AV, Bernlohr DA, Vallerie SN, Liu CQ, Lopez M, Harmon JS, Robertson RP (2013) Ebselen treatment prevents islet apoptosis, maintains intranuclear Pdx-1 and MafA levels, and preserves beta-cell mass and function in ZDF rats. Diabetes 62(10):3582–3588. doi: 10.2337/Db13-0357 PubMedCentralPubMedGoogle Scholar
  137. 137.
    Bubolz AH, Wu Q, Larsen BT, Gutterman DD, Liu Y (2007) Ebselen reduces nitration and restores voltage-gated potassium channel function in small coronary arteries of diabetic rats. Am J Physiol Heart Circ Physiol 293(4):H2231–H2237. doi: 10.1152/ajpheart.00717.2007 PubMedGoogle Scholar
  138. 138.
    Afanas’ev I (2011) ROS and RNS signaling in heart disorders: could antioxidant treatment be successful? Oxid Med Cell Longev 2011:293769. doi: 10.1155/2011/293769 PubMedCentralPubMedGoogle Scholar
  139. 139.
    Sugamura K, Keaney JF Jr (2011) Reactive oxygen species in cardiovascular disease. Free Radical Biol Med 51(5):978–992. doi: 10.1016/j.freeradbiomed.2011.05.004 Google Scholar
  140. 140.
    Hermenegildo C, Nies E, Monsalve E, Puertas FJ, Higueras V, Romero FJ (1990) Some aspects of cardiac antioxidant defense—ebselen (Pz51) treatment increases glutathione-peroxidase activity in the rat-heart. Biochem Soc Trans 18(6):1193–1194PubMedGoogle Scholar
  141. 141.
    Baljinnyam E, Hasebe N, Morihira M, Sumitomo K, Matsusaka T, Fujino T, Fukuzawa J, Ushikubi F, Kikuchi K (2006) Oral pretreatment with ebselen enhances heat shock protein 72 expression and reduces myocardial infarct size. Hypertens Res 29(11):905–913. doi: 10.1291/hypres.29.905 PubMedGoogle Scholar
  142. 142.
    Maulik N, Yoshida T, Das DK (1998) Oxidative stress developed during the reperfusion of ischemic myocardium induces apoptosis. Free Radical Biol Med 24(5):869–875Google Scholar
  143. 143.
    Hoshida S, Kuzuya T, Nishida M, Yamashita N, Hori M, Kamada T, Tada M (1994) Ebselen protects against ischemia-reperfusion injury in a canine model of myocardial infarction. Am J Physiol 267(6 Pt 2):H2342–H2347PubMedGoogle Scholar
  144. 144.
    Sui H, Wang W, Wang PH, Liu LS (2005) Effect of glutathione peroxidase mimic ebselen (PZ51) on endothelium and vascular structure of stroke-prone spontaneously hypertensive rats. Blood Press 14(6):366–372. doi: 10.1080/08037050500210781 PubMedGoogle Scholar
  145. 145.
    de Haan JB, Cooper ME (2011) Targeted antioxidant therapies in hyperglycemia-mediated endothelial dysfunction. Front Biosci (Schol Ed) 3:709–729Google Scholar
  146. 146.
    Davis MT, Bartfay WJ (2004) Ebselen decreases oxygen free radical production and iron concentrations in the hearts of chronically iron-overloaded mice. Biol Res Nurs 6(1):37–45. doi: 10.1177/1099800403261350 PubMedGoogle Scholar
  147. 147.
    Saad SY, Najjar TA, Arafah MM (2006) Cardioprotective effects of subcutaneous ebselen against daunorubicin-induced cardiomyopathy in rats. Basic Clin Pharmacol Toxicol 99(6):412–417. doi: 10.1111/j.1742-7843.2006.pto_523.x PubMedGoogle Scholar
  148. 148.
    Pritsos CA, Sokoloff M, Gustafson DL (1992) PZ-51 (Ebselen) in vivo protection against adriamycin-induced mouse cardiac and hepatic lipid peroxidation and toxicity. Biochem Pharmacol 44(4):839–841PubMedGoogle Scholar
  149. 149.
    Ardais AP, Santos FW, Nogueira CW (2008) Ebselen attenuates cadmium-induced testicular damage in mice. J Appl Toxicol 28(3):322–328. doi: 10.1002/Jat.1282 PubMedGoogle Scholar
  150. 150.
    Husain K, Morris C, Whitworth C, Trammell GL, Rybak LP, Somani SM (1998) Protection by ebselen against cisplatin-induced nephrotoxicity: antioxidant system. Mol Cell Biochem 178(1–2):127–133. doi: 10.1023/A:1006889427520 PubMedGoogle Scholar
  151. 151.
    Yoshida M, Iizuka K, Terada A, Hara M, Nishijima H, Shimada A, Nakada K, Satoh Y, Akama Y (2000) Prevention of nephrotoxicity of cisplatin by repeated oral administration of ebselen in rats. Tohoku J Exp Med 191(4):209–220. doi: 10.1620/Tjem.191.209 PubMedGoogle Scholar
  152. 152.
    Hardej D, Trombetta LD (2002) The effects of ebselen on cisplatin and diethyldithiocarbamate (DDC) cytotoxicity in rat hippocampal astrocytes. Toxicol Lett 131(3):215–226. doi: 10.1016/S0378-4274(02)00056-5 PubMedGoogle Scholar
  153. 153.
    Yin Z, Lee E, Ni M, Jiang H, Milatovic D, Rongzhu L, Farina M, Rocha JBT, Aschner M (2011) Methylmercury-induced alterations in astrocyte functions are attenuated by ebselen. Neurotoxicology 32(3):291–299. doi: 10.1016/j.neuro.2011.01.004 PubMedCentralPubMedGoogle Scholar
  154. 154.
    Usuki F, Yamashita A, Fujimura M (2011) Post-transcriptional defects of antioxidant selenoenzymes cause oxidative stress under methylmercury exposure. J Biol Chem 286(8):6641–6649. doi: 10.1074/jbc.M110.168872 PubMedCentralPubMedGoogle Scholar
  155. 155.
    Baldew GS, McVie JG, van der Valk MA, Los G, de Goeij JJ, Vermeulen NP (1990) Selective reduction of cis-diamminedichloroplatinum(II) nephrotoxicity by ebselen. Cancer Res 50(21):7031–7036PubMedGoogle Scholar
  156. 156.
    Marreilha Dos Santos AP, Lucas RL, Andrade V, Mateus ML, Milatovic D, Aschner M, Batoreu MC (2012) Protective effects of ebselen (Ebs) and para-aminosalicylic acid (PAS) against manganese (Mn)-induced neurotoxicity. Toxicol Appl Pharmacol 258(3):394–402. doi: 10.1016/j.taap.2011.12.003 Google Scholar
  157. 157.
    Moretto MB, Funchal C, Zeni G, Rocha JB, Pessoa-Pureur R (2005) Organoselenium compounds prevent hyperphosphorylation of cytoskeletal proteins induced by the neurotoxic agent diphenyl ditelluride in cerebral cortex of young rats. Toxicology 210(2–3):213–222. doi: 10.1016/j.tox.2005.02.003 PubMedGoogle Scholar
  158. 158.
    Hardej D, Billack B (2007) Ebselen protects brain, skin, lung and blood cells from mechlorethamine toxicity. Toxicol Ind Health 23(4):209–221PubMedGoogle Scholar
  159. 159.
    Pino MA, Billack B (2008) Reduction of vesicant toxicity by butylated hydroxyanisole in A-431 skin cells. Cutan Ocul Toxicol 27(3):161–172. doi: 10.1080/15569520802092070 PubMedGoogle Scholar
  160. 160.
    Blasiak J, Sikora A, Czechowska A, Drzewoski J (2003) Free radical scavengers can modulate the DNA-damaging action of alloxan. Acta biochimica Polonica 50(1):205–210PubMedGoogle Scholar
  161. 161.
    Blasiak J, Sikora A, Wozniak K, Drzewoski J (2004) Genotoxicity of streptozotocin in normal and cancer cells and its modulation by free radical scavengers. Cell Biol Toxicol 20(2):83–96PubMedGoogle Scholar
  162. 162.
    Blasiak J, Gloc E, Drzewoski J, Wozniak K, Zadrozny M, Skorski T, Pertynski T (2003) Free radical scavengers can differentially modulate the genotoxicity of amsacrine in normal and cancer cells. Mutat Res 535(1):25–34PubMedGoogle Scholar
  163. 163.
    Wu Q, Huang K (2006) Protective effect of ebselen on cytotoxicity induced by cholestane-3 beta, 5 alpha, 6 beta-triol in ECV-304 cells. Biochim Biophys Acta 1761(3):350–359. doi: 10.1016/j.bbalip.2006.02.017 PubMedGoogle Scholar
  164. 164.
    Huther AM, Zhang Y, Sauer A, Parnham MJ (1989) Antimalarial properties of ebselen. Parasitol Res 75(5):353–360PubMedGoogle Scholar
  165. 165.
    Harris MT, Walker DM, Drew ME, Mitchell WG, Dao K, Schroeder CE, Flaherty DP, Weiner WS, Golden JE, Morris JC (2013) Interrogating a hexokinase-selected small-molecule library for inhibitors of Plasmodium falciparum hexokinase. Antimicrob Agents Chemother 57(8):3731–3737. doi: 10.1128/AAC.00662-13 PubMedCentralPubMedGoogle Scholar
  166. 166.
    Billack B, Santoro M, Lau-Cam C (2009) Growth inhibitory action of ebselen on fluconazole-resistant Candida albicans: role of the plasma membrane H+-ATPase. Microb Drug Resist 15(2):77–83. doi: 10.1089/mdr.2009.0872 PubMedGoogle Scholar
  167. 167.
    Billack B, Pietka-Ottlik M, Santoro M, Nicholson S, Mlochowski J, Lau-Cam C (2010) Evaluation of the antifungal and plasma membrane H+-ATPase inhibitory action of ebselen and two ebselen analogs in S. cerevisiae cultures. J Enzyme Inhib Med Chem 25(3):312–317. doi: 10.3109/14756360903179419 PubMedGoogle Scholar
  168. 168.
    Lieberman OJ, Orr MW, Wang Y, Lee VT (2013) High-throughput screening using the differential radial capillary action of ligand assay identifies ebselen as an inhibitor of diguanylate cyclases. ACS Chem Biol. doi: 10.1021/cb400485k PubMedCentralGoogle Scholar
  169. 169.
    Favrot L, Grzegorzewicz AE, Lajiness DH, Marvin RK, Boucau J, Isailovic D, Jackson M, Ronning DR (2013) Mechanism of inhibition of Mycobacterium tuberculosis antigen 85 by ebselen. Nat Commun 4:2748. doi: 10.1038/ncomms3748 PubMedCentralPubMedGoogle Scholar
  170. 170.
    Sinha R, Ei-Bayoumy K (2004) Apoptosis is a critical cellular event in cancer chemoprevention and chemotherapy by selenium compounds. Curr Cancer Drug Tar 4(1):13–28. doi: 10.2174/1568009043481614 Google Scholar
  171. 171.
    Tewari R, Sharma V, Koul N, Ghosh A, Joseph C, Hossain SkU, Sen E (2009) Ebselen abrogates TNFalpha induced pro-inflammatory response in glioblastoma. Mol Oncol 3(1):77–83. doi: 10.1016/j.molonc.2008.10.004 PubMedGoogle Scholar
  172. 172.
    Sharma V, Tewari R, Sk UH, Joseph C, Sen E (2008) Ebselen sensitizes glioblastoma cells to Tumor Necrosis Factor (TNFalpha)-induced apoptosis through two distinct pathways involving NF-kappaB downregulation and Fas-mediated formation of death inducing signaling complex. Int J Cancer 123(9):2204–2212. doi: 10.1002/ijc.23771 PubMedGoogle Scholar
  173. 173.
    Gealekman O, Brodsky SV, Zhang F, Chander PN, Friedli C, Nasjletti A, Goligorsky MS (2004) Endothelial dysfunction as a modifier of angiogenic response in Zucker diabetic fat rat: amelioration with Ebselen. Kidney Int 66(6):2337–2347. doi: 10.1111/j.1523-1755.2004.66035.x PubMedGoogle Scholar
  174. 174.
    Saito I, Asano T, Sano K, Takakura K, Abe H, Yoshimoto T, Kikuchi H, Ohta T, Ishibashi S (1998) Neuroprotective effect of an antioxidant, ebselen, in patients with delayed neurological deficits after aneurysmal subarachnoid hemorrhage. Neurosurgery 42 (2):269–277; discussion 277–268Google Scholar
  175. 175.
    Aruoma OI (2003) Methodological considerations for characterizing potential antioxidant actions of bioactive components in plant foods. Mutat Res 523–524:9–20PubMedGoogle Scholar
  176. 176.
    Young IS, Woodside JV (2001) Antioxidants in health and disease. J Clin Pathol 54(3):176–186. doi: 10.1136/Jcp.54.3.176 PubMedCentralPubMedGoogle Scholar
  177. 177.
    Luo Z, Sheng J, Sun Y, Lu C, Yan J, Liu A, Luo HB, Huang L, Li X (2013) Synthesis and evaluation of multi-target-directed ligands against Alzheimer’s disease based on the fusion of donepezil and ebselen. J Med Chem 56(22):9089–9099. doi: 10.1021/jm401047q PubMedGoogle Scholar
  178. 178.
    Xu KH, Qiang MM, Gao W, Su RX, Li N, Gao Y, Xie YX, Kong FP, Tang B (2013) A near-infrared reversible fluorescent probe for real-time imaging of redox status changes in vivo. Chem Sci 4(3):1079–1086. doi: 10.1039/C2sc22076h Google Scholar

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© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  1. 1.Laboratory of Chromatin Biology, Department of Biological SciencesIndian Institute of Science Education and ResearchBhopalIndia

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