Advertisement

Journal of Bioenergetics and Biomembranes

, Volume 47, Issue 1–2, pp 111–118 | Cite as

Idebenone and neuroprotection: antioxidant, pro-oxidant, or electron carrier?

  • Sausan Jaber
  • Brian M. Polster
Mini-review

Abstract

Ubiquinone, commonly called coenzyme Q10 (CoQ), is a lipophilic electron carrier and endogenous antioxidant found in all cellular membranes. In the mitochondrial inner membrane it transfers electrons to complex III of the electron transport chain. The short chain CoQ analogue idebenone is in clinical trials for a number of diseases that exhibit a mitochondrial etiology. Nevertheless, evidence that idebenone ameliorates neurological symptoms in human disease is inconsistent. Although championed as an antioxidant, idebenone can also act as a pro-oxidant by forming an unstable semiquinone at complex I. The antioxidant function of idebenone is critically dependent on two-electron reduction to idebenol without the creation of unstable intermediates. Recently, cytoplasmic NAD(P)H:quinone oxidoreductase 1 (NQO1) was identified as a major enzyme catalyzing idebenone reduction. While reduction allows idebenone to act as an antioxidant, evidence also suggests that NQO1 enables idebenone to shuttle reducing equivalents from cytoplasmic NAD(P)H to mitochondrial complex III, bypassing any upstream damage to the electron transport chain. In this mini-review we discuss how idebenone can influence mitochondrial function within the context of cytoprotection. Importantly, in the brain NQO1 is expressed primarily by glia rather than neurons. As NQO1 is an inducible enzyme regulated by oxidative stress and the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway, optimizing NQO1 expression in appropriate cell types within a specific disease context may be key to delivering on idebenone’s therapeutic potential.

Keywords

Coenzyme Q10 Quinone Mitochondria Complex I NQO1 Friedreich’s ataxia 

Abbreviations

ARE

antioxidant response element

CoQ

coenzyme Q10

ETC

electron transport chain

FMN

flavin mononucleotide

IdBH2

idebenol

Keap1

Kelch-like ECH-associated protein 1

NQO

NAD(P)H:quinone acceptor oxidoreductase

Nrf2

nuclear factor erythroid 2-related factor 2

Notes

Acknowledgments

The authors acknowledge support from National Institutes of Health R01 NS085165 to B.M.P. and from Sigma Tau Pharmaceuticals and the M. Jane Matjasko Endowment.

References

  1. Ahlgren-Beckendorf JA, Reising AM, Schander MA, Herdler JW, Johnson JA (1999) Coordinate regulation of NAD (P) H:quinone oxidoreductase and glutathione-S-transferases in primary cultures of rat neurons and glia: role of the antioxidant/electrophile responsive element. Glia 25:131–142CrossRefGoogle Scholar
  2. Bell KF, Al-Mubarak B, Fowler JH, Baxter PS, Gupta K, Tsujita T, Chowdhry S, Patani R, Chandran S, Horsburgh K, Hayes JD, Hardingham GE (2011) Mild oxidative stress activates Nrf2 in astrocytes, which contributes to neuroprotective ischemic preconditioning. Proc Natl Acad Sci U S A 108:E1–E2CrossRefGoogle Scholar
  3. Bergamasco B, Scarzella L, La CP (1994) Idebenone, a new drug in the treatment of cognitive impairment in patients with dementia of the Alzheimer type. Funct Neurol 9:161–168Google Scholar
  4. Beyer RE, Segura AJ, Di BS, Cavazzoni M, Fato R, Fiorentini D, Galli MC, Setti M, Landi L, Lenaz G (1996) The role of DT-diaphorase in the maintenance of the reduced antioxidant form of coenzyme Q in membrane systems. Proc Natl Acad Sci U S A 93:2528–2532CrossRefGoogle Scholar
  5. Briere JJ, Schlemmer D, Chretien D, Rustin P (2004) Quinone analogues regulate mitochondrial substrate competitive oxidation. Biochem Biophys Res Commun 316:1138–1142CrossRefGoogle Scholar
  6. Bruno V, Battaglia G, Copani A, Sortino MA, Canonico PL, Nicoletti F (1994) Protective action of idebenone against excitotoxic degeneration in cultured cortical neurons. Neurosci Lett 178:193–196CrossRefGoogle Scholar
  7. Cardoso SM, Pereira C, Oliveira CR (1998) The protective effect of vitamin E, idebenone and reduced glutathione on free radical mediated injury in rat brain synaptosomes. Biochem Biophys Res Commun 246:703–710CrossRefGoogle Scholar
  8. Chan TS, Teng S, Wilson JX, Galati G, Khan S, O’brien PJ (2002) Coenzyme Q cytoprotective mechanisms for mitochondrial complex I cytopathies involves NAD (P) H: quinone oxidoreductase 1 (NQO1). Free Radic Res 36:421–427CrossRefGoogle Scholar
  9. Conover TE, Ernster L (1962) DT diaphorase. II. relation to respiratory chain of intact mitochondira. Biochim Biophys Acta 58:189–200CrossRefGoogle Scholar
  10. Cooper JM, Schapira AH (2003) Friedreich’s Ataxia: disease mechanisms, antioxidant and Coenzyme Q10 therapy. Biofactors 18:163–171CrossRefGoogle Scholar
  11. Di Prospero NA, Baker A, Jeffries N, Fischbeck KH (2007) Neurological effects of high-dose idebenone in patients with Friedreich’s ataxia: a randomised, placebo-controlled trial. Lancet Neurol 6:878–886CrossRefGoogle Scholar
  12. Dinkova-Kostova AT, Talalay P (2010) NAD (P) H:quinone acceptor oxidoreductase 1 (NQO1), a multifunctional antioxidant enzyme and exceptionally versatile cytoprotector. Arch Biochem Biophys 501:116–123CrossRefGoogle Scholar
  13. Dong H, Shertzer HG, Genter MB, Gonzalez FJ, Vasiliou V, Jefcoate C, Nebert DW (2013) Mitochondrial targeting of mouse NQO1 and CYP1B1 proteins. Biochem Biophys Res Commun 435:727–732CrossRefGoogle Scholar
  14. Dragan M, Dixon SJ, Jaworski E, Chan TS, O’brien PJ, Wilson JX (2006) Coenzyme Q (1) depletes NAD (P) H and impairs recycling of ascorbate in astrocytes. Brain Res 1078:9–18CrossRefGoogle Scholar
  15. Erb M, Hoffmann-Enger B, Deppe H, Soeberdt M, Haefeli RH, Rummey C, Feurer A, Gueven N (2012) Features of idebenone and related short-chain quinones that rescue ATP levels under conditions of impaired mitochondrial complex I. PLoS One 7:e36153CrossRefGoogle Scholar
  16. Esposti MD, Ngo A, Ghelli A, Benelli B, Carelli V, McLennan H, Linnane AW (1996) The interaction of Q analogs, particularly hydroxydecyl benzoquinone (idebenone), with the respiratory complexes of heart mitochondria. Arch Biochem Biophys 330:395–400CrossRefGoogle Scholar
  17. Fash DM, Khdour OM, Sahdeo SJ, Goldschmidt R, Jaruvangsanti J, Dey S, Arce PM, Collin VC, Cortopassi GA, Hecht SM (2013) Effects of alkyl side chain modification of coenzyme Q10 on mitochondrial respiratory chain function and cytoprotection. Bioorg Med Chem 21:2346–2354, S0968-0896 (13) 00125-9CrossRefGoogle Scholar
  18. Fato R, Bergamini C, Leoni S, Lenaz G (2008) Mitochondrial production of reactive oxygen species: role of complex I and quinone analogues. Biofactors 32:31–39CrossRefGoogle Scholar
  19. Genova ML, Ventura B, Giuliano G, Bovina C, Formiggini G, Parenti CG, Lenaz G (2001) The site of production of superoxide radical in mitochondrial complex I is not a bound ubisemiquinone but presumably iron-sulfur cluster N2. FEBS Lett 505:364–368CrossRefGoogle Scholar
  20. Genova ML, Pich MM, Biondi A, Bernacchia A, Falasca A, Bovina C, Formiggini G, Parenti CG, Lenaz G (2003) Mitochondrial production of oxygen radical species and the role of Coenzyme Q as an antioxidant. Exp Biol Med Maywood 228:506–513Google Scholar
  21. Geromel V, Darin N, Chretien D, Benit P, DeLonlay P, Rotig A, Munnich A, Rustin P (2002) Coenzyme Q (10) and idebenone in the therapy of respiratory chain diseases: rationale and comparative benefits. Mol Genet Metab 77:21–30CrossRefGoogle Scholar
  22. Giorgio V, Petronilli V, Ghelli A, Carelli V, Rugolo M, Lenaz G, Bernardi P (2012) The effects of idebenone on mitochondrial bioenergetics. Biochim Biophys Acta 1817:363–369CrossRefGoogle Scholar
  23. Greco T, Fiskum G (2010) Neuroprotection through stimulation of mitochondrial antioxidant protein expression. J Alzheimers Dis 20(Suppl 2):S427–S437Google Scholar
  24. Gutzmann H, Hadler D (1998) Sustained efficacy and safety of idebenone in the treatment of Alzheimer’s disease: update on a 2-year double-blind multicentre study. J Neural Transm Suppl 54:301–310CrossRefGoogle Scholar
  25. Gutzmann H, Kuhl KP, Hadler D, Rapp MA (2002) Safety and efficacy of idebenone versus tacrine in patients with Alzheimer’s disease: results of a randomized, double-blind, parallel-group multicenter study. Pharmacopsychiatry 35:12–18CrossRefGoogle Scholar
  26. Habas A, Hahn J, Wang X, Margeta M (2013) Neuronal activity regulates astrocytic Nrf2 signaling. Proc Natl Acad Sci U S A 110:18291–18296CrossRefGoogle Scholar
  27. Haefeli RH, Erb M, Gemperli AC, Robay D, Courdier FI, Anklin C, Dallmann R, Gueven N (2011) NQO1-dependent redox cycling of idebenone: effects on cellular redox potential and energy levels. PLoS One 6:e17963CrossRefGoogle Scholar
  28. Heitz FD, Erb M, Anklin C, Robay D, Pernet V, Gueven N (2012) Idebenone protects against retinal damage and loss of vision in a mouse model of Leber’s hereditary optic neuropathy. PLoS One 7:e45182CrossRefGoogle Scholar
  29. Imada I, Fujita T, Sugiyama Y, Okamoto K, Kobayashi Y (1989) Effects of idebenone and related compounds on respiratory activities of brain mitochondria, and on lipid peroxidation of their membranes. Arch Gerontol Geriatr 8:323–341CrossRefGoogle Scholar
  30. Imada I, Sato EF, Kira Y, Inoue M (2008) Effect of CoQ homologues on reactive oxygen generation by mitochondria. Biofactors 32:41–48CrossRefGoogle Scholar
  31. Joseph P, Jaiswal AK (1994) NAD (P) H:quinone oxidoreductase1 (DT diaphorase) specifically prevents the formation of benzo [a] pyrene quinone-DNA adducts generated by cytochrome P4501A1 and P450 reductase. Proc Natl Acad Sci U S A 91:8413–8417CrossRefGoogle Scholar
  32. Kalen A, Norling B, Appelkvist EL, Dallner G (1987) Ubiquinone biosynthesis by the microsomal fraction from rat liver. Biochim Biophys Acta 926:70–78CrossRefGoogle Scholar
  33. Kim J, Lee S, Shim J, Kim HW, Kim J, Jang YJ, Yang H, Park J, Choi SH, Yoon JH, Lee KW, Lee HJ (2012) Caffeinated coffee, decaffeinated coffee, and the phenolic phytochemical chlorogenic acid up-regulate NQO1 expression and prevent H (2) O (2)-induced apoptosis in primary cortical neurons. Neurochem Int 60:466–474CrossRefGoogle Scholar
  34. Kim J, Kim SK, Kim HK, Mattson MP, Hyun DH (2013) Mitochondrial function in human neuroblastoma cells Is up-regulated and protected by NQO1, a plasma membrane redox enzyme. PLoS One 8:e69030CrossRefGoogle Scholar
  35. King MS, Sharpley MS, Hirst J (2009) Reduction of hydrophilic ubiquinones by the flavin in mitochondrial NADH:ubiquinone oxidoreductase (complex I) and production of reactive oxygen species. Biochemistry 48:2053–2062CrossRefGoogle Scholar
  36. Kowaltowski AJ, Castilho RF, Vercesi AE (2001) Mitochondrial permeability transition and oxidative stress. FEBS Lett 495:12–15CrossRefGoogle Scholar
  37. Kraft AD, Johnson DA, Johnson JA (2004) Nuclear factor E2-related factor 2-dependent antioxidant response element activation by tert-butylhydroquinone and sulforaphane occurring preferentially in astrocytes conditions neurons against oxidative insult. J Neurosci 24:1101–1112CrossRefGoogle Scholar
  38. Kutz K, Drewe J, Vankan P (2009) Pharmacokinetic properties and metabolism of idebenone. J Neurol 256(Suppl 1):31–35CrossRefGoogle Scholar
  39. Li W, Kong AN (2009) Molecular mechanisms of Nrf2-mediated antioxidant response. Mol Carcinog 48:91–104CrossRefGoogle Scholar
  40. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795CrossRefGoogle Scholar
  41. Lind C, Hochstein P, Ernster L (1982) DT-diaphorase as a quinone reductase: a cellular control device against semiquinone and superoxide radical formation. Arch Biochem Biophys 216:178–185CrossRefGoogle Scholar
  42. Lopez LC, Quinzii CM, Area E, Naini A, Rahman S, Schuelke M, Salviati L, Dimauro S, Hirano M (2010) Treatment of CoQ (10) deficient fibroblasts with ubiquinone, CoQ analogs, and vitamin C: time- and compound-dependent effects. PLoS One 5:e11897CrossRefGoogle Scholar
  43. Lynch DR, Perlman SL, Meier T (2010) A phase 3, double-blind, placebo-controlled trial of idebenone in friedreich ataxia. Arch Neurol 67:941–947CrossRefGoogle Scholar
  44. Meier T, Buyse G (2009) Idebenone: an emerging therapy for Friedreich ataxia. J Neurol 256(Suppl 1):25–30CrossRefGoogle Scholar
  45. Meier T, Perlman SL, Rummey C, Coppard NJ, Lynch DR (2012) Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich’s ataxia: data from a 6-month controlled study followed by a 12-month open-label extension study. J Neurol 259:284–291CrossRefGoogle Scholar
  46. Miyamoto M, Coyle JT (1990) Idebenone attenuates neuronal degeneration induced by intrastriatal injection of excitotoxins. Exp Neurol 108:38–45CrossRefGoogle Scholar
  47. Miyamoto M, Murphy TH, Schnaar RL, Coyle JT (1989) Antioxidants protect against glutamate-induced cytotoxicity in a neuronal cell line. J Pharmacol Exp Ther 250:1132–1140Google Scholar
  48. Mordente A, Martorana GE, Minotti G, Giardina B (1998) Antioxidant properties of 2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone (idebenone). Chem Res Toxicol 11:54–63CrossRefGoogle Scholar
  49. Murphy TH, Schnaar RL, Coyle JT (1990) Immature cortical neurons are uniquely sensitive to glutamate toxicity by inhibition of cystine uptake. FASEB J 4:1624–1633Google Scholar
  50. Murphy TH, Yu J, Ng R, Johnson DA, Shen H, Honey CR, Johnson JA (2001) Preferential expression of antioxidant response element mediated gene expression in astrocytes. J Neurochem 76:1670–1678CrossRefGoogle Scholar
  51. Nagai Y, Yoshida K, Narumi S, Tanayama S, Nagaoka A (1989) Brain distribution of idebenone and its effect on local cerebral glucose utilization in rats. Arch Gerontol Geriatr 8:257–272CrossRefGoogle Scholar
  52. Nagaoka A, Suno M, Shibota M, Kakihana M (1989) Effects of idebenone on neurological deficits, local cerebral blood flow, and energy metabolism in rats with experimental cerebral ischemia. Arch Gerontol Geriatr 8:193–202CrossRefGoogle Scholar
  53. Nicholls DG, Ferguson SJ (2013) Bioenergetics 4. Academic, LondonGoogle Scholar
  54. O’Brien PJ (1991) Molecular mechanisms of quinone cytotoxicity. Chem Biol Interact 80:1–41CrossRefGoogle Scholar
  55. Ohnishi ST, Ohnishi T, Muranaka S, Fujita H, Kimura H, Uemura K, Yoshida K, Utsumi K (2005) A possible site of superoxide generation in the complex I segment of rat heart mitochondria. J Bioenerg Biomembr 37:1–15CrossRefGoogle Scholar
  56. Parkinson MH, Schulz JB, Giunti P (2013) Co-enzyme Q10 and idebenone use in Friedreich’s ataxia. J Neurochem 126(Suppl 1):125–141CrossRefGoogle Scholar
  57. Pereira CF, Oliveira CR (2000) Oxidative glutamate toxicity involves mitochondrial dysfunction and perturbation of intracellular Ca2+ homeostasis. Neurosci Res 37:227–236CrossRefGoogle Scholar
  58. Petronilli V, Costantini P, Scorrano L, Colonna R, Passamonti S, Bernardi P (1994) The voltage sensor of the mitochondrial permeability transition pore is tuned by the oxidation-reduction state of vicinal thiols. Increase of the gating potential by oxidants and its reversal by reducing agents. J Biol Chem 269:16638–16642Google Scholar
  59. Raina AK, Templeton DJ, Deak JC, Perry G, Smith MA (1999) Quinone reductase (NQO1), a sensitive redox indicator, is increased in Alzheimer’s disease. Redox Rep 4:23–27CrossRefGoogle Scholar
  60. Ranen NG, Peyser CE, Coyle JT, Bylsma FW, Sherr M, Day L, Folstein MF, Brandt J, Ross CA, Folstein SE (1996) A controlled trial of idebenone in Huntington’s disease. Mov Disord 11:549–554CrossRefGoogle Scholar
  61. Ratan RR, Murphy TH, Baraban JM (1994) Oxidative stress induces apoptosis in embryonic cortical neurons. J Neurochem 62:376–379CrossRefGoogle Scholar
  62. Rauchova H, Drahota Z, Bergamini C, Fato R, Lenaz G (2008) Modification of respiratory-chain enzyme activities in brown adipose tissue mitochondria by idebenone (hydroxydecyl-ubiquinone). J Bioenerg Biomembr 40:85–93CrossRefGoogle Scholar
  63. Rotig A, De LP, Chretien D, Foury F, Koenig M, Sidi D, Munnich A, Rustin P (1997) Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. Nat Genet 17:215–217CrossRefGoogle Scholar
  64. SantaCruz KS, Yazlovitskaya E, Collins J, Johnson J, DeCarli C (2004) Regional NAD (P) H:quinone oxidoreductase activity in Alzheimer’s disease. Neurobiol Aging 25:63–69CrossRefGoogle Scholar
  65. Satoh T, Okamoto SI, Cui J, Watanabe Y, Furuta K, Suzuki M, Tohyama K, Lipton SA (2006) Activation of the Keap1/Nrf2 pathway for neuroprotection by electrophilic phase II inducers. Proc Natl Acad Sci U S A 103:768–773CrossRefGoogle Scholar
  66. Satoh T, Kosaka K, Itoh K, Kobayashi A, Yamamoto M, Shimojo Y, Kitajima C, Cui J, Kamins J, Okamoto S, Izumi M, Shirasawa T, Lipton SA (2008) Carnosic acid, a catechol-type electrophilic compound, protects neurons both in vitro and in vivo through activation of the Keap1/Nrf2 pathway via S-alkylation of targeted cysteines on Keap1. J Neurochem 104:1116–1131CrossRefGoogle Scholar
  67. Schinzel AC, Takeuchi O, Huang Z, Fisher JK, Zhou Z, Rubens J, Hetz C, Danial NN, Moskowitz MA, Korsmeyer SJ (2005) Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proc Natl Acad Sci U S A 102:12005–12010CrossRefGoogle Scholar
  68. Schultzberg M, Segura-Aguilar J, Lind C (1988) Distribution of DT diaphorase in the rat brain: biochemical and immunohistochemical studies. Neurosci 27:763–776CrossRefGoogle Scholar
  69. Senin U, Parnetti L, Barbagallo-Sangiorgi G, Bartorelli L, Bocola V, Capurso A, Cuzzupoli M, Denaro M, Marigliano V, Tammaro AE, Fioravanti M (1992) Idebenone in senile dementia of Alzheimer type: a multicentre study. Arch Gerontol Geriatr 15:249–260CrossRefGoogle Scholar
  70. Sherer TB, Richardson JR, Testa CM, Seo BB, Panov AV, Yagi T, Matsuno-Yagi A, Miller GW, Greenamyre JT (2007) Mechanism of toxicity of pesticides acting at complex I: relevance to environmental etiologies of Parkinson’s disease. J Neurochem 100:1469–1479Google Scholar
  71. Shih AY, Johnson DA, Wong G, Kraft AD, Jiang L, Erb H, Johnson JA, Murphy TH (2003) Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J Neurosci 23:3394–3406Google Scholar
  72. Siegel D, Ross D (2000) Immunodetection of NAD (P) H:quinone oxidoreductase 1 (NQO1) in human tissues. Free Radic Biol Med 29:246–253CrossRefGoogle Scholar
  73. Stringer JL, Gaikwad A, Gonzales BN, Long DJ Jr, Marks LM, Jaiswal AK (2004) Presence and induction of the enzyme NAD (P) H: quinone oxidoreductase 1 in the central nervous system. J Comp Neurol 471:289–297CrossRefGoogle Scholar
  74. Suno M, Nagaoka A (1984a) Inhibition of lipid peroxidation by a novel compound, idebenone (CV-2619). Jpn J Pharmacol 35:196–198CrossRefGoogle Scholar
  75. Suno M, Nagaoka A (1984b) Inhibition of lipid peroxidation by a novel compound (CV-2619) in brain mitochondria and mode of action of the inhibition. Biochem Biophys Res Commun 125:1046–1052CrossRefGoogle Scholar
  76. Suno M, Nagaoka A (1989) Inhibition of lipid peroxidation by idebenone in brain mitochondria in the presence of succinate. Arch Gerontol Geriatr 8:291–297CrossRefGoogle Scholar
  77. Tai KK, Pham L, Truong DD (2011) Idebenone induces apoptotic cell death in the human dopaminergic neuroblastoma SHSY-5Y cells. Neurotox Res 20:321–328CrossRefGoogle Scholar
  78. Thal LJ, Grundman M, Berg J, Ernstrom K, Margolin R, Pfeiffer E, Weiner MF, Zamrini E, Thomas RG (2003) Idebenone treatment fails to slow cognitive decline in Alzheimer’s disease. Neurology 61:1498–1502CrossRefGoogle Scholar
  79. Torii H, Yoshida K, Kobayashi T, Tsukamoto T, Tanayama S (1985) Disposition of idebenone (CV-2619), a new cerebral metabolism improving agent, in rats and dogs. J Pharmacobiodyn 8:457–467CrossRefGoogle Scholar
  80. van Muiswinkel FL, de Vos RA, Bol JG, Andringa G, Jansen Steur EN, Ross D, Siegel D, Drukarch B (2004) Expression of NAD (P) H:quinone oxidoreductase in the normal and Parkinsonian substantia nigra. Neurobiol Aging 25:1253–1262CrossRefGoogle Scholar
  81. Wang Y, Santa-Cruz K, DeCarli C, Johnson JA (2000) NAD (P) H:quinone oxidoreductase activity is increased in hippocampal pyramidal neurons of patients with Alzheimer’s disease. Neurobiol Aging 21:525–531CrossRefGoogle Scholar
  82. Weyer G, Babej-Dolle RM, Hadler D, Hofmann S, Herrmann WM (1997) A controlled study of 2 doses of idebenone in the treatment of Alzheimer’s disease. Neuropsychobiology 36:73–82CrossRefGoogle Scholar
  83. Wong A, Yang J, Cavadini P, Gellera C, Lonnerdal B, Taroni F, Cortopassi G (1999) The Friedreich’s ataxia mutation confers cellular sensitivity to oxidant stress which is rescued by chelators of iron and calcium and inhibitors of apoptosis. Hum Mol Genet 8:425–430CrossRefGoogle Scholar
  84. Yamada K, Tanaka T, Han D, Senzaki K, Kameyama T, Nabeshima T (1999) Protective effects of idebenone and alpha-tocopherol on beta-amyloid-(1-42)-induced learning and memory deficits in rats: implication of oxidative stress in beta-amyloid-induced neurotoxicity in vivo. Eur J Neurosci 11:83–90CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Anesthesiology, Center for Shock, Trauma and Anesthesiology Research (STAR)University of Maryland School of MedicineBaltimoreUSA

Personalised recommendations