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Chemical Compound Review

Ebselene     8-phenyl-7-selena-8- azabicyclo[4.3.0]nona...

Synonyms: Ebseleno, Ebselenum, ebselen, Harmokisane, Lopac-E-3520, ...
 
 
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Disease relevance of ebselen

 

High impact information on ebselen

 

Chemical compound and disease context of ebselen

 

Biological context of ebselen

  • The inherent H2O2 reductase activity of mammalian TrxR dependent on its active-site selenocysteine residue was stimulated 10-fold by 2 microM ebselen and 25-fold in the additional presence of 5 microM Trx [7].
  • Reduction of pre-existing lipid peroxides using ebselen delayed HbLDL kinetics and inhibited HO-1 induction [12].
  • Ebselen (2-phenyl-1,2-benzisoselenazol-3[2H]one) also diminished reduction of ferricytochrome c (IC50 = 10 mumol/L), indicating a suppression of superoxide anion formation [13].
  • Both MitoPeroxidase and ebselen decreased apoptosis induced by oxidative stress, suggesting that they can decrease mitochondrial oxidative stress [14].
  • MitoPeroxidase and ebselen were effective antioxidants that degraded phospholipid hydroperoxides, prevented lipid peroxidation, and protected mitochondria from oxidative damage [14].
 

Anatomical context of ebselen

 

Associations of ebselen with other chemical compounds

  • Our results demonstrate that the mechanism of action of ebselen may be predominantly via the Trx system rather than via glutathione [7].
  • Human and bovine TrxR catalyzed the reduction of ebselen to ebselen selenol by NADPH with an apparent K(M)-value of 2.5 microM and a kcat of 588 min(-1) [7].
  • However, the rapid increase in ROS production and the marked reduction of cell death with the antioxidants ebselen and N-acetylcysteine, indicate that ROS have a key role in glitazone cytotoxicity [17].
  • The antioxidative effect of ebselen is attributed to its selective blockade of leukocyte infiltration and activation leading to attenuation of the H(2)O(2) level [18].
  • This analysis indicated that much of the ebselen present within mitochondria is bound to protein thiols through reversible selenenylsulfide bonds [14].
  • While ebselen and its analogues are poor catalysts in aromatic thiol assays, these compounds exhibit high GPx activity when GSH is used as the cosubstrate [19].
 

Gene context of ebselen

  • These findings suggest that ebselen prevents TNF-alpha-induced EC activation through the inhibition of TRAF2-ASK1-SEK1 signaling pathway, which leads to JNK activation [20].
  • TcR-induced activation of ERK was selectively augmented and sustained in the presence of pharmacologic antioxidants that can quench or inhibit H(2)O(2) production (NAC, MnTBAP and Ebselen, but not DPI), while activation of JNK and Akt were largely unaffected [21].
  • Inhibition of JNK by ebselen may imply its usefulness for the prevention of atherosclerosis relevant to EC activation [20].
  • Analysis of key apoptotic regulators during NO-induced apoptosis of differentiated PC12 cells showed that ebselen blocks the activation of the apoptosis signaling-regulating kinase 1 (ASK1), and inhibits phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal protein kinase (JNK) [22].
  • Moreover, ebselen did not prevent IL-1 beta-induced NF-kappa B activation [23].
 

Analytical, diagnostic and therapeutic context of ebselen

  • These results are in agreement with the reported low toxicity of ebselen, which is now in Phase I clinical trials as an antiinflammatory drug [24].
  • Oral administration of ebselen granules suspended in water (150 mg BID) or placebo was started immediately after admission and was continued for 2 weeks [25].
  • Bronchoalveolar lavage (BAL) examination showed that airway inflammation was significantly suppressed by ebselen at 10 mg/kg [26].
  • Although ebselen, a seleno-organic compound, inhibits inflammation in various animal models, its efficacy as an anti-asthma drug remains to be clarified [26].
  • To elucidate the difference between GSH and L(SH)2, the molecular mechanism of the peroxidase activity of ebselen was investigated, using UV spectrophotometry, high pressure liquid chromatography, 77Se NMR, and mass spectrometry [27].

References

  1. In vitro cell injury by oxidized low density lipoprotein involves lipid hydroperoxide-induced formation of alkoxyl, lipid, and peroxyl radicals. Coffey, M.D., Cole, R.A., Colles, S.M., Chisolm, G.M. J. Clin. Invest. (1995) [Pubmed]
  2. Antioxidant ebselen reduces oxidative damage in focal cerebral ischemia. Imai, H., Graham, D.I., Masayasu, H., Macrae, I.M. Free Radic. Biol. Med. (2003) [Pubmed]
  3. Ebselen prevents early alcohol-induced liver injury in rats. Kono, H., Arteel, G.E., Rusyn, I., Sies, H., Thurman, R.G. Free Radic. Biol. Med. (2001) [Pubmed]
  4. Efficacy of the antioxidant ebselen in experimental uveitis. Bosch-Morell, F., Romá, J., Puertas, F.J., Marín, N., Díaz-Llopis, M., Romero, F.J. Free Radic. Biol. Med. (1999) [Pubmed]
  5. The neuroprotective agent ebselen modifies NMDA receptor function via the redox modulatory site. Herin, G.A., Du, S., Aizenman, E. J. Neurochem. (2001) [Pubmed]
  6. Selective impairment of hippocampal neurogenesis by chronic alcoholism: protective effects of an antioxidant. Herrera, D.G., Yague, A.G., Johnsen-Soriano, S., Bosch-Morell, F., Collado-Morente, L., Muriach, M., Romero, F.J., Garcia-Verdugo, J.M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  7. Ebselen: a substrate for human thioredoxin reductase strongly stimulating its hydroperoxide reductase activity and a superfast thioredoxin oxidant. Zhao, R., Masayasu, H., Holmgren, A. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  8. Anti-oxidant ebselen delays microvascular thrombus formation in the rat cremaster muscle by inhibiting platelet P-selectin expression. Lindenblatt, N., Schareck, W., Belusa, L., Nickels, R.M., Menger, M.D., Vollmar, B. Thromb. Haemost. (2003) [Pubmed]
  9. The influence of ebselen on the toxicity of cisplatin in LLC-PK1 cells. Baldew, G.S., Boymans, A.P., Mol, J.G., Vermeulen, N.P. Biochem. Pharmacol. (1992) [Pubmed]
  10. Ebselen induced C6 glioma cell death in oxygen and glucose deprivation. Shi, H., Liu, S., Miyake, M., Liu, K.J. Chem. Res. Toxicol. (2006) [Pubmed]
  11. Hypoxia-induced dysfunction of rat diaphragm: role of peroxynitrite. Zhu, X., Heunks, L.M., Versteeg, E.M., van der Heijden, H.F., Ennen, L., van Kuppevelt, T.H., Vina, J., Dekhuijzen, P.N. Am. J. Physiol. Lung Cell Mol. Physiol. (2005) [Pubmed]
  12. Heme and lipid peroxides in hemoglobin-modified low-density lipoprotein mediate cell survival and adaptation to oxidative stress. Asatryan, L., Ziouzenkova, O., Duncan, R., Sevanian, A. Blood (2003) [Pubmed]
  13. Inhibition of superoxide and nitric oxide release and protection from reoxygenation injury by Ebselen in rat Kupffer cells. Wang, J.F., Komarov, P., Sies, H., de Groot, H. Hepatology (1992) [Pubmed]
  14. Synthesis and characterization of a triphenylphosphonium-conjugated peroxidase mimetic. Insights into the interaction of ebselen with mitochondria. Filipovska, A., Kelso, G.F., Brown, S.E., Beer, S.M., Smith, R.A., Murphy, M.P. J. Biol. Chem. (2005) [Pubmed]
  15. Differential effects of ebselen on neutrophil recruitment, chemokine, and inflammatory mediator expression in a rat model of lipopolysaccharide-induced pulmonary inflammation. Haddad, e.l.-.B., McCluskie, K., Birrell, M.A., Dabrowski, D., Pecoraro, M., Underwood, S., Chen, B., De Sanctis, G.T., Webber, S.E., Foster, M.L., Belvisi, M.G. J. Immunol. (2002) [Pubmed]
  16. Doxorubicin-induced apoptosis in endothelial cells and cardiomyocytes is ameliorated by nitrone spin traps and ebselen. Role of reactive oxygen and nitrogen species. Kotamraju, S., Konorev, E.A., Joseph, J., Kalyanaraman, B. J. Biol. Chem. (2000) [Pubmed]
  17. Glitazones differentially regulate primary astrocyte and glioma cell survival. Involvement of reactive oxygen species and peroxisome proliferator-activated receptor-gamma. Pérez-Ortiz, J.M., Tranque, P., Vaquero, C.F., Domingo, B., Molina, F., Calvo, S., Jordán, J., Ceña, V., Llopis, J. J. Biol. Chem. (2004) [Pubmed]
  18. Ebselen, a glutathione peroxidase mimetic seleno-organic compound, as a multifunctional antioxidant. Implication for inflammation-associated carcinogenesis. Nakamura, Y., Feng, Q., Kumagai, T., Torikai, K., Ohigashi, H., Osawa, T., Noguchi, N., Niki, E., Uchida, K. J. Biol. Chem. (2002) [Pubmed]
  19. Synthesis, characterization, and antioxidant activity of some ebselen analogues. Bhabak, K.P., Mugesh, G. Chemistry (2007) [Pubmed]
  20. Ebselen inhibits tumor necrosis factor-alpha-induced c-Jun N-terminal kinase activation and adhesion molecule expression in endothelial cells. Yoshizumi, M., Fujita, Y., Izawa, Y., Suzaki, Y., Kyaw, M., Ali, N., Tsuchiya, K., Kagami, S., Yano, S., Sone, S., Tamaki, T. Exp. Cell Res. (2004) [Pubmed]
  21. T cell receptor-stimulated generation of hydrogen peroxide inhibits MEK-ERK activation and lck serine phosphorylation. Kwon, J., Devadas, S., Williams, M.S. Free Radic. Biol. Med. (2003) [Pubmed]
  22. 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. Sarker, K.P., Biswas, K.K., Rosales, J.L., Yamaji, K., Hashiguchi, T., Lee, K.Y., Maruyama, I. J. Neurochem. (2003) [Pubmed]
  23. Ebselen and cytokine-induced nitric oxide synthase expression in insulin-producing cells. de-Mello, M.A., Flodström, M., Eizirik, D.L. Biochem. Pharmacol. (1996) [Pubmed]
  24. Selective reduction of cis-diamminedichloroplatinum(II) nephrotoxicity by ebselen. Baldew, G.S., McVie, J.G., van der Valk, M.A., Los, G., de Goeij, J.J., Vermeulen, N.P. Cancer Res. (1990) [Pubmed]
  25. Ebselen in acute ischemic stroke: a placebo-controlled, double-blind clinical trial. Ebselen Study Group. Yamaguchi, T., Sano, K., Takakura, K., Saito, I., Shinohara, Y., Asano, T., Yasuhara, H. Stroke (1998) [Pubmed]
  26. Ebselen suppresses late airway responses and airway inflammation in guinea pigs. Zhang, M., Nomura, A., Uchida, Y., Iijima, H., Sakamoto, T., Iishii, Y., Morishima, Y., Mochizuki, M., Masuyama, K., Hirano, K., Sekizawa, K. Free Radic. Biol. Med. (2002) [Pubmed]
  27. Mechanism of the reaction of ebselen with endogenous thiols: dihydrolipoate is a better cofactor than glutathione in the peroxidase activity of ebselen. Haenen, G.R., De Rooij, B.M., Vermeulen, N.P., Bast, A. Mol. Pharmacol. (1990) [Pubmed]
 
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