, Volume 18, Issue 4, pp 393–408 | Cite as

Profiling drug-induced cell death pathways in the zebrafish lateral line

  • Allison B. Coffin
  • Kay L. Williamson
  • Anna Mamiya
  • David W. Raible
  • Edwin W. Rubel
Original Paper


Programmed cell death (PCD) is an important process in development and disease, as it allows the body to rid itself of unwanted or damaged cells. However, PCD pathways can also be activated in otherwise healthy cells. One such case occurs in sensory hair cells of the inner ear following exposure to ototoxic drugs, resulting in hearing loss and/or balance disorders. The intracellular pathways that determine if hair cells die or survive following this or other ototoxic challenges are incompletely understood. We use the larval zebrafish lateral line, an external hair cell-bearing sensory system, as a platform for profiling cell death pathways activated in response to ototoxic stimuli. In this report the importance of each pathway was assessed by screening a custom cell death inhibitor library for instances when pathway inhibition protected hair cells from the aminoglycosides neomycin or gentamicin, or the chemotherapy agent cisplatin. This screen revealed that each ototoxin likely activated a distinct subset of possible cell death pathways. For example, the proteasome inhibitor Z-LLF-CHO protected hair cells from either aminoglycoside or from cisplatin, while d-methionine, an antioxidant, protected hair cells from gentamicin or cisplatin but not from neomycin toxicity. The calpain inhibitor leupeptin primarily protected hair cells from neomycin, as did a Bax channel blocker. Neither caspase inhibition nor protein synthesis inhibition altered the progression of hair cell death. Taken together, these results suggest that ototoxin-treated hair cells die via multiple processes that form an interactive network of cell death signaling cascades.


Hair cell Ototoxicity Neomycin Gentamicin Cisplatin 


  1. 1.
    Yuan J, Horvitz HR (2004) A first insight into the molecular mechanisms of apoptosis. Cell S116:S53–S56CrossRefGoogle Scholar
  2. 2.
    Kerr JFR, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257PubMedCrossRefGoogle Scholar
  3. 3.
    Zimmermann KC, Bonzon C, Green DR (2001) The machinery of programmed cell death. Pharmacol Ther 92(1):57–70PubMedCrossRefGoogle Scholar
  4. 4.
    Danial NN, Korsmeyer SJ (2004) Cell death: critical control points. Cell 116:205–219PubMedCrossRefGoogle Scholar
  5. 5.
    Baehrecke EH (2002) How death shapes life during development. Nat Reviews Mol Cell Biol 3:779–787CrossRefGoogle Scholar
  6. 6.
    Fuchs Y, Steller H (2011) Programmed cell death in animal development and disease. Cell 147:742–758PubMedCrossRefGoogle Scholar
  7. 7.
    Thompson HJ, Strange R, Schedin PJ (1992) Apoptosis in the genesis and prevention of cancer. Cancer Epidemiol Biomarkers Prev 1(7):597–602PubMedGoogle Scholar
  8. 8.
    Edinger AL, Thompson CB (2004) Death by design: apoptosis, necrosis, and autophagy. Curr Opin Cell Biol 16:663–669PubMedCrossRefGoogle Scholar
  9. 9.
    Fink SL, Cookson BT (2005) Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect Immun 73(4):1907–1916PubMedCrossRefGoogle Scholar
  10. 10.
    Mourbarak RS, Yuste VJ, Artus C, Bouharrour A, Greer PA, Menissier de Murcia J, Susin SA (2007) Sequential activation of poly(ADP-ribose) polymerase I, calpains, and Bax is essential in apoptosis-inducing factor-mediated programmed necrosis. Mol Cell Biol 27(13):4844–4862CrossRefGoogle Scholar
  11. 11.
    Baritaud M, Boujrad H, Lorenzo HK, Krantic S, Susin SA (2010) Histone H2AX: The missing link in AIF-mediated caspase-independent programmed necrosis. Cell Cycle 9(16):3166–3173PubMedCrossRefGoogle Scholar
  12. 12.
    Delavallée L, Cabon L, Galán-Malo P, Lorenzo HK, Susin SA (2011) AIF-mediated caspase-independent necroptosis: a new chance for targeted therapeutics. IUBMB Life 63(4):221–232PubMedCrossRefGoogle Scholar
  13. 13.
    Cabon L, Galán-Malo P, Bouharrour A, Delavallée L, Brunelle-Navas M-N, Lorenzo HK, Gross A, Susin SA (2012) BID regulates AIF-mediated caspase-independent necroptosis by promoting Bax activation. Cell Death Differ 19:245–256PubMedCrossRefGoogle Scholar
  14. 14.
    Forge A, Li L (2000) Apoptotic death of hair cells in mammalian vestibular sensory epithelia. Hear Res 139(1–2):97–115PubMedCrossRefGoogle Scholar
  15. 15.
    Jiang H, Sha SH, Forge A, Schacht J (2006) Caspase-independent pathways of hair cell death induced by kanamycin in vivo. Cell Death Differ 13(1):20–30PubMedCrossRefGoogle Scholar
  16. 16.
    Owens KN, Coffin AB, Hong LS, Bennett KO, Rubel EW, Raible DW (2009) Response of mechanosensory hair cells of the zebrafish lateral line to aminoglycosides reveals distinct cell death pathways. Hear Res 253(1–2):32–41PubMedCrossRefGoogle Scholar
  17. 17.
    Cheng AG, Cunningham LL, Rubel EW (2005) Mechanisms of hair cell death and protection. Curr Opin Otolaryngol Head Neck Surg 13(6):343–348PubMedCrossRefGoogle Scholar
  18. 18.
    Rybak LP (2007) Mechanisms of cisplatin ototoxicity and progress in otoprotection. Curr Opin Otolaryngol Head Neck Surg 15:364–369PubMedCrossRefGoogle Scholar
  19. 19.
    Schacht J, Talaska AE, Rybak LP (2012) Cisplatin and aminoglycoside antibiotics: hearing loss and its prevention. Anat Rec (Hoboken) 295(11):1837–1850CrossRefGoogle Scholar
  20. 20.
    Karasawa T, Steyger PS (2011) Intracellular mechanisms of aminoglycoside-induced cytotoxicity. Integr Biol (Camb) 3(9):879–886CrossRefGoogle Scholar
  21. 21.
    Hirose K, Westrum LE, Stone JS, Zirpel L, Rubel EW (1999) Dynamic studies of ototoxicity in mature avian auditory epithelium. Ann NY Acad Sci 884:389–409PubMedCrossRefGoogle Scholar
  22. 22.
    Hirose K, Westrum LE, Cunningham DE, Rubel EW (2004) Electron microscopy of degenerative changes in the chick basilar papilla after gentamicin exposure. J Comp Neurol 470(2):164–180PubMedCrossRefGoogle Scholar
  23. 23.
    Mangiardi DA, McLaughlin-Williamson K, May KE, Messana EP, Mountain DC, Cotanche DA (2004) Progression of hair cell ejection and molecular markers of apoptosis in the avian cochlea following gentamicin treatment. J Comp Neurol 475(1):1–18PubMedCrossRefGoogle Scholar
  24. 24.
    Matsui JI, Gale JE, Warchol ME (2004) Critical signaling events during the aminoglycoside-induced death of sensory hair cells in vitro. J Neurobiol 61(2):250–266PubMedCrossRefGoogle Scholar
  25. 25.
    Owens KN, Cunningham DE, MacDonald G, Rubel EW, Raible DW, Pujol R (2007) Ultrastructural analysis of aminoglycoside-induced hair cell death in the zebrafish lateral line reveals an early mitochondrial response. J Comp Neurol 502(4):522–543PubMedCrossRefGoogle Scholar
  26. 26.
    Cunningham LL, Cheng AG, Rubel EW (2002) Caspase activation in hair cells of the mouse utricle exposed to neomycin. J Neurosci 22(19):8532–8540PubMedGoogle Scholar
  27. 27.
    Matsui JI, Ogilvie JM, Warchol ME (2002) Inhibition of caspases prevents ototoxic and ongoing hair cell death. J Neurosci 22(4):1218–1227PubMedGoogle Scholar
  28. 28.
    Wang J, Ladrech S, Pujol R, Brabet P, Van de Water TR, Puel JL (2004) Caspase inhibitors, but not c-Jun NH2-terminal kinase inhibitor treatment, prevent cisplatin-induced hearing loss. Cancer Res 64(24):9217–9224CrossRefGoogle Scholar
  29. 29.
    Tabuchi K, Pak K, Chavez E, Ryan AF (2007) Role of inhibitor of apoptosis protein in gentamicin-induced cochlear hair cell damage. Neuroscience 149(1):213–222PubMedCrossRefGoogle Scholar
  30. 30.
    Chan DK, Lieberman DM, Musatov S, Goldfein JA, Selesnick SH, Kaplitt MG (2007) Protection against cisplatin-indued ototoxicity by adeno-associated virus-mediated delivery of the X-linked inhibitor of apoptosis protein is not dependent on caspase inhibition. Otol Neurotol 28:417–425PubMedCrossRefGoogle Scholar
  31. 31.
    Metcalfe WK, Kimmel CB, Schabtach E (1985) Anatomy of the posterior lateral line system in young larvae of the zebrafish. J Comp Neurol 233(3):377–389PubMedCrossRefGoogle Scholar
  32. 32.
    Coombs S, Görner P, Münz H (1989) The Mechanosensory Lateral Line: Neurobiology and Evolution. Springer-Verlag, NYCrossRefGoogle Scholar
  33. 33.
    Raible DW, Kruse GJ (2000) Organization of the lateral line system in embryonic zebrafish. J Comp Neurol 421(2):189–198PubMedCrossRefGoogle Scholar
  34. 34.
    Dijkgraaf S (1963) The functioning and significance of the lateral line organs. Biol Rev 38:51–105PubMedCrossRefGoogle Scholar
  35. 35.
    Montgomery JC, MacDonald JA (1987) Sensory tuning of lateral line receptors in Antarctic fish to the movements of planktonic prey. Science 235:195–196PubMedCrossRefGoogle Scholar
  36. 36.
    Montgomery JC, Baker CF, Carton AG (1997) The lateral line can mediate rheotaxis in fish. Nature 389:960–963CrossRefGoogle Scholar
  37. 37.
    Coombs S, Braun CB, Donovan B (2001) The orienting response of Lake Michigan mottled sculpin is mediated by canal neuromasts. J Exp Biol 204:337–348PubMedGoogle Scholar
  38. 38.
    New JG, Fewkes LA, Khan SN (2001) Strike feeding behavior in the muskellunge, Esox masquinongy: contributions of the lateral line and visual sensory systems. J Exp Biol 204:1207–1221PubMedGoogle Scholar
  39. 39.
    Suli A, Watson GM, Rubel EW, Raible DW (2012) Rheotaxis in larval zebrafish is mediated by lateral line mechanosensory hair cells. PLoS ONE 7(2):e29727PubMedCrossRefGoogle Scholar
  40. 40.
    Harris JA, Cheng AG, Cunningham LL, MacDonald G, Raible DW, Rubel EW (2003) Neomycin-induced hair cell death and rapid regeneration in the lateral line of zebrafish (Danio rerio). J Assoc Res Otolaryngol 4(2):219–234PubMedCrossRefGoogle Scholar
  41. 41.
    Coffin AB, Kelley MW, Manley GA, Popper AN (2004) Evolution of sensory hair cells. In: Manley GA, Fay RR, Popper AN (eds) Evolution of the Auditory System. Springer-Verlag, New YorkGoogle Scholar
  42. 42.
    Coffin AB, Ou H, Owens KN, Santos F, Simon JA, Rubel EW, Raible DW (2010) Chemical screening for hair cell loss and protection in the zebrafish lateral line. Zebrafish 7(1):3–11PubMedCrossRefGoogle Scholar
  43. 43.
    Santos F, MacDonald G, Rubel EW, Raible DW (2006) Lateral line hair cell maturation is a determinant of aminoglycoside susceptibility in zebrafish (Danio rerio). Hear Res 213(1–2):25–33PubMedCrossRefGoogle Scholar
  44. 44.
    Ou HC, Raible DW, Rubel EW (2007) Cisplatin-induced hair cell loss in zebrafish (Danio rerio) lateral line. Hear Res 233(1–2):46–53PubMedCrossRefGoogle Scholar
  45. 45.
    Owens KN, Cunningham DE, MacDonald G, Rubel EW, Raible DW, Pujol R (2007) Ultrastructural analysis of aminoglycoside-induced hair cell death in the zebrafish lateral line reveals an early mitochondrial response. J Comp Neurol 502(4):522–543PubMedCrossRefGoogle Scholar
  46. 46.
    Owens KN, Coffin AB, Hong LS, Bennett KO, Rubel EW, Raible DW (2009) Response of mechanosensory hair cells of the zebrafish lateral line to aminoglycosides reveals distinct cell death pathways. Hear Res 253(1–2):32–41PubMedCrossRefGoogle Scholar
  47. 47.
    Owens KN, Santos F, Roberts B, Linbo T, Coffin AB, Knisely AJ, Simon JA, Rubel EW, Raible DW (2008) Identification of genetic and chemical modulators of zebrafish mechanosensory hair cell death. PLoS Genet 4(2):e1000020PubMedCrossRefGoogle Scholar
  48. 48.
    Ou HC, Cunningham LL, Francis SP, Brandon CS, Simon JA, Raible DW, Rubel EW (2009) Identification of FDA-approved drugs and bioactives that protect hair cells in the zebrafish (Danio rerio) lateral line and mouse (Mus musculus) utricle. J Assoc Res Otolaryngol 10(2):191–203PubMedCrossRefGoogle Scholar
  49. 49.
    Ou H, Simon JA, Rubel EW, Raible DW (2012) Screening for chemicals that affect hair cell death and survival in the zebrafish lateral line. Hear Res 288(1–2):58–66PubMedCrossRefGoogle Scholar
  50. 50.
    Vlatsits AL, Simon JA, Raible DW, Rubel EW, Owens KN (2012) Screen of FDA-approved drug library reveals compounds that protect hair cells from aminoglycosides and cisplatin. Hear Res doi. doi:10.1016/j.heares.2012.08.002 Google Scholar
  51. 51.
    Coffin AB, Reinhart KE, Owens KN, Raible DW, Rubel EW (2009) Extracellular divalent cations modulate aminoglycoside-induced hair cell death in the zebrafish lateral line. Hear Res 253(1–2):42–51PubMedCrossRefGoogle Scholar
  52. 52.
    McFadden SL, Ding D, Salvemini D, Salvi RJ (2003) M40403, a superoxide dismutase mimetic, protects cochlear hair cells from gentamicin, but not cisplatin toxicity. Toxicol Appl Pharmacol 186:46–54PubMedCrossRefGoogle Scholar
  53. 53.
    Westerfield M (2000) The Zebrafish Book: A Guide for Laboratory Use of Zebrafish (Danio rerio), 4th edn. University of Oregon Press, EugeneGoogle Scholar
  54. 54.
    Nakatsuka M, Asagiri K, Noguchi S, Habara T, Kudo T (2000) Nafamostat mesilate, a serine protease inhibitor, suppresses lipopolysaccharide-induced nitric oxide synthesis and apoptosis in culture human trophoblasts. Life Sci 67(10):1243–1250PubMedCrossRefGoogle Scholar
  55. 55.
    Steyger PS, Peters SL, Rehling J, Hordichok A, Dai CF (2003) Uptake of gentamicin by bullfrog saccular hair cells in vitro. J Assoc Res Otolaryngol 4(4):565–578PubMedCrossRefGoogle Scholar
  56. 56.
    Dai CF, Mangiardi D, Cotanche DA, Steyger PS (2006) Uptake of fluorescent gentamicin by vertebrate sensory cells in vivo. Hear Res 213(1–2):64–78PubMedCrossRefGoogle Scholar
  57. 57.
    Geiger GA, Parker SE, Beothy AP, Tucker JA, Mullins MC, Kao GD (2006) Zebrafish as a “biosensor”? Effects of ionizing radiation and amifostine on embryonic viability and development. Cancer Res 66:8172–8181PubMedCrossRefGoogle Scholar
  58. 58.
    Dong W, Teraoka H, Yamazaki K, Tsukiyama S, Imani S, Imagawa T, Stegeman JJ, Peterson RE, Hiraga T (2002) 2,3,7,8-Tetrachlorodibenzo-p-dioxin toxicity in the zebrafish embryo: local circulation failure in the dorsal midbrain is associated with increased apoptosis. Toxicol Sci 69(1):191–201PubMedCrossRefGoogle Scholar
  59. 59.
    Rehen SK, Varella MH, Freitas FG, Moraes MO, Linden R (1996) Contrasting effects of protein synthesis inhibition and of cyclic AMP on apoptosis in the developing retina. Development 122(5):1439–1448PubMedGoogle Scholar
  60. 60.
    Ray SK, Matzelle DD, Wilford GG, Hogan EL, Banik NL (2001) Cell death in spinal cord injury (SCI) requires de novo protein synthesis. Calpain inhibitor E-64-d provides neuroprotection in SCI lesion and penumbra. Ann NY Acad Sci 939:436–449PubMedCrossRefGoogle Scholar
  61. 61.
    Liwak U, Faye MD, Holcik M (2012) Translation control in apoptosis. Exp Oncol 34(3):218–230PubMedGoogle Scholar
  62. 62.
    Negron JF, Lockshin RA (2004) Activation of apoptosis and caspase-3 in zebrafish early gastrulae. Dev Dyn 231(1):161–170PubMedCrossRefGoogle Scholar
  63. 63.
    Belting H-G, Wendik B, Lunde K, Leichsenring M, Mössner R, Driever W, Onichtchouk D (2011) Pou5f1 contributes to dorsoventral patterning by positive regulation of vox and modulation of fgf8a expression. Dev Biol 356(2):323–336PubMedCrossRefGoogle Scholar
  64. 64.
    Hayes RL, Wang KK, Kampfl A, Postmantur RM, Newcomb JK, Clifton GL (1998) Potential contribution of proteases to neuronal damage. Drug News Perspect 11(4):215–222PubMedGoogle Scholar
  65. 65.
    Furuhashi K (2002) Identification and characterization of a cathepsin B-like protease in Physarum sclerotium. Int J Biochem Cell Biol 34(10):1308–1316PubMedCrossRefGoogle Scholar
  66. 66.
    Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K, Takahashi R (2001) A serine protease, HtrA2, is release from the mitochondria and interacts with XIAP, inducing cell death. Mol Cell 8:613–621PubMedCrossRefGoogle Scholar
  67. 67.
    Ding D, Stracher A, Salvi RJ (2002) Leupeptin protects cochlear and vestibular hair cells from gentamicin ototoxicity. Hear Res 164(1–2):115–126PubMedCrossRefGoogle Scholar
  68. 68.
    Ladrech S, Guitton M, Saido T, Lenoir M (2004) Calpain activity in the amikacin-damaged rat cochlea. J Comp Neurol 477(2):149–160PubMedCrossRefGoogle Scholar
  69. 69.
    Momiyama J, Hashimoto T, Matsubara A, Futai K, Namba A, Shinkawa H (2006) Leupeptin, a calpain inhibitor, protects inner ear hair cells from aminoglycoside ototoxicity. Tohoku J Exp Med 209:89–97PubMedCrossRefGoogle Scholar
  70. 70.
    Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P, Moll UM (2003) p53 has a direct apoptogenic role at the mitochondria. Mol Cell 11(3):577–590PubMedCrossRefGoogle Scholar
  71. 71.
    Moll U, Wolff S, Speidel D, Deppert W (2005) Transcription-independent proapoptotic functions of p53. Curr Opin Cell Biol 17:631–636PubMedCrossRefGoogle Scholar
  72. 72.
    Chipuk J, Green D (2006) Dissecting p53-dependent apoptosis. Cell Death Differ 13:994–1002PubMedCrossRefGoogle Scholar
  73. 73.
    Cunningham LL, Matsui JI, Warchol ME, Rubel EW (2004) Overexpression of Bcl-2 prevents neomycin-induced hair cell death and caspase-9 activation in the adult mouse utricle in vitro. J Neurobiol 60(1):89–100PubMedCrossRefGoogle Scholar
  74. 74.
    Zhang M, Liu W, Ding D, Salvi R (2003) Pifithrin-alpha suppresses p53 and protects cochlear and vestibular hair cells from cisplatin-induced apoptosis. Neuroscience 120(1):191–205PubMedCrossRefGoogle Scholar
  75. 75.
    Huth ME, Ricci AJ, Cheng AG (2011) Mechanisms of aminoglycoside ototoxicity and targets of hair cell protection. Int J Otolaryngol doi. doi:10.1155/2011/937861 Google Scholar
  76. 76.
    Orlowski RZ (1999) The role of the ubiquitin-proteasome pathway in apoptosis. Cell Death Differ 6:303–313PubMedCrossRefGoogle Scholar
  77. 77.
    Taylor RC, Adrain C, Martin SJ (2005) Proteases, proteasomes and apoptosis: breaking Ub is hard to do. Cell Death Differ 12(9):1213–1217PubMedCrossRefGoogle Scholar
  78. 78.
    Moreau P, Richardson PG, Cavo M, Orlowski RZ, San Miguel JF, Palumbo A, Harousseau JL (2012) Proteasome inhibitors in multiple myeloma: 10 years later. Blood 120(5):947–959. doi:10.1182/blood-2012-04-403733 PubMedCrossRefGoogle Scholar
  79. 79.
    Sadoul R, Fernandez PA, Quiquerez AL, Martinou I, Maki M, Schröter M, Becherer JD, Irmler M, Tschopp J, Martinou JC (1996) Involvement of the proteasome in the programmed cell death of NGF-deprived sympathetic neurons. EMBO J 15(15):3845–3852PubMedGoogle Scholar
  80. 80.
    Yang W, Monroe J, Zhang Y, George D, Bremer E, Li H (2006) Proteasome inhibition induces both pro- and anti-cell death pathways in prostate cancer cells. Cancer Lett 243:217–227PubMedCrossRefGoogle Scholar
  81. 81.
    Yamaguchi H, Hsu JL, Hung M-C (2012) Regulation of ubiquitin-mediated protein degradation by survival kinases in cancer. Front Oncol 2(15):1–9Google Scholar
  82. 82.
    Hirose K, Hockenbery DM, Rubel EW (1997) Reactive oxygen species in chick hair cells after gentamicin exposure in vitro. Hear Res 104:1–14PubMedCrossRefGoogle Scholar
  83. 83.
    Kopke RD, Liu W, Gabaizadeh R, Jacono A, Feghali J, Spray D, Garcia P, Steinman H, Melgrange B, Ruben RJ, Rybak L, Van de Water TR (1997) Use of organotypic cultures of Corti’s organ to study the protective effects of antioxidant molecules on cisplatin-induced damage of auditory hair cells. Am J Otol 18(5):559–571Google Scholar
  84. 84.
    Schacht J (1999) Antioxidant therapy attenuates aminoglycoside-induced hearing loss. Ann NY Acad Sci 884:125–130PubMedGoogle Scholar
  85. 85.
    Campbell KCM, Meech RP, Klemens JJ, Gerberi MT, Dyrstad SSW, Larsen DL, Mitchell DL, El-Azizi M, Verhulst SJ, Hughes LF (2007) Prevention of noise- and drug-induced hearing loss with d-methionine. Hear Res 226:92–103PubMedCrossRefGoogle Scholar
  86. 86.
    Choung YH, Taura A, Pak K, Choi SJ, Masuda M, Ryan AF (2009) Generation of highly-reactive oxygen species is closely related to hair cell damage in rat organ of Corti treated with gentamicin. Neuroscience 161(1):214–226PubMedCrossRefGoogle Scholar
  87. 87.
    Ton C, Parng C (2005) The use of zebrafish for assessing ototoxic and otoprotective agents. Hear Res 208(1–2):79–88PubMedCrossRefGoogle Scholar
  88. 88.
    Evans P, Halliwell B (1999) Free radicals and hearing. Causes, consequences, and criteria. Ann NY Acad Sci 844:19–20CrossRefGoogle Scholar
  89. 89.
    Piantadosi CA, Suliman HB (2012) Redox regulation of mitochondrial biogenesis. Free Radic Biol Med S0891–5849(12):01139–01140. doi:10.1016/j.freeradbiomed.2012.09.014 Google Scholar
  90. 90.
    Wall SB, Oh JY, Diers AR, Landar A (2012) Oxidative modification of proteins: an emerging mechanism of cell signaling. Front Physiol 3:369. doi:10.3389/fphys.2012.00369 PubMedCrossRefGoogle Scholar
  91. 91.
    Song BB, Schacht J (1996) Variable efficacy of radical scavengers and iron chelators to attenuate gentamicin ototoxicity in guinea pig in vivo. Hear Res 94(1–2):87–93PubMedCrossRefGoogle Scholar
  92. 92.
    Conlon BJ, Perry BP, Smith DW (1998) Attenuation of neomycin ototoxicity by iron chelation. Laryngoscope 108(2):284–287PubMedCrossRefGoogle Scholar
  93. 93.
    Sha SH, Schacht J (1999) Stimulation of free radical formation by aminoglycoside antibiotics. Hear Res 128(1–2):112–118PubMedCrossRefGoogle Scholar
  94. 94.
    Sha SH, Oiu JH, Schacht J (2006) Aspirin to prevent gentamicin-induced hearing loss. N Engl J Med 354(17):1856–1857PubMedCrossRefGoogle Scholar
  95. 95.
    Bas E, Van De Water TR, Gupta C, Dinh J, Vu L, Martínez-Soriano F, Láinez JM, Marco J (2012) Efficacy of three drugs for protecting against gentamicin-induced hair cell and hearing losses. Br J Pharmacol 166(6):1888–1904CrossRefGoogle Scholar
  96. 96.
    Xie J, Talaska AE, Schacht J (2011) New developments in aminoglycoside therapy and ototoxicity. Hear Res 281(1–2):28–37PubMedCrossRefGoogle Scholar
  97. 97.
    Giansanti V, Torriglia A, Scovassi AI (2011) Conversation between apoptosis and autophagy: “Is it your turn or mine?”. Apoptosis 16:321–333PubMedCrossRefGoogle Scholar
  98. 98.
    Long JS, Ryan KM (2012) New frontiers in promoting tumour cell death: targeting apoptosis, necroptosis, and autophagy. Oncogene 2012:1–16Google Scholar
  99. 99.
    Marquez RT, Xu L (2012) Bcl-2:Beclin 1 complex: multiple mechanisms regulating autophagy/apoptosis toggle switch. Am J Cancer Res 2(2):214–221PubMedGoogle Scholar
  100. 100.
    Levine B, Sinha S, Kroemer G (2008) Bcl-2 family members: dual regulators of apoptosis and autophagy. Autophagy 4(5):600–606PubMedGoogle Scholar
  101. 101.
    Aoyama T, Ino Y, Ozeki M, Oda M, Sato T, Koshiyama Y, Suzuki S, Fukita M (1984) Pharmacological studies of FUT-175, nafamstat mesilate. I. Inhibition of protease activity in in vitro and in vivo experiments. Jpn J Pharmacol 35(3):203–227PubMedCrossRefGoogle Scholar
  102. 102.
    Chen CC, Wang SS, Lee FY (2007) Action of antiproteases on the inflammatory response in acute pancreatitis. JOP 8:488–494PubMedGoogle Scholar
  103. 103.
    Shinoda T (2010) Anticoagulation in acute blood purification for acute renal failure in critical care. Contrib Nephrol 116:119–125CrossRefGoogle Scholar
  104. 104.
    Gale JE, Marcotti W, Kennedy HJ, Kros CJ, Richardson GP (2001) FM1-43 dye behaves as a permeant blocker of the hair-cell mechanotransducer channel. J Neurosci 21(18):7013–7025PubMedGoogle Scholar
  105. 105.
    Marcotti W, van Netten SM, Kros CJ (2005) The aminoglycoside antibiotic dihydrostreptomycin rapidly enters mouse outer hair cells through the mechano-electrical transducer channels. J Physiol 567(Pt 2):505–521PubMedCrossRefGoogle Scholar
  106. 106.
    Alharazneh A, Luk L, Huth M, Monfared A, Steyger PS, Cheng AG, Ricci AJ (2011) Functional hair cell mechanotransducer channels are required for aminoglycoside ototoxicity. PLoS ONE 6(7):e22347PubMedCrossRefGoogle Scholar
  107. 107.
    Thomas, AJ, Hailey DW, Stawicki TM, Wu P, Coffin AB, Rubel EW, Raible DW, Simon JA, Ou HC (submitted) Functional mechanotransduction is required for cisplatin-induced hair cell death in the zebrafish lateral line. J NeurosciGoogle Scholar
  108. 108.
    Hagiwara S, Iwasaka H, Noguchi T (2007) Nafamostat mesilate inhibits the expression of HMGB1 in lipopolysaccharide-induced acute lung injury. J Anesth 21:164–170PubMedCrossRefGoogle Scholar
  109. 109.
    Livesey KM, Kang R, Vernon P, Buchser W, Loughran P, Watkins SC, Zhang L, Manfredi JJ, Zeh HJ III, Li L, Lotze MT, Tang D (2012) p53/HMGB1 complexes regulate autophagy and apoptosis. Cancer Res 72(8):1996–2005PubMedCrossRefGoogle Scholar
  110. 110.
    Cregan SP, Fortin A, MacLaurin JG, Callaghan SM, Cecconi F, Yu SW, Dawson TM, Dawson VL, Park DS, Kroemer G, Slack RS (2002) Apoptosis-inducing factor is involved in the regulation of caspase-independent neuronal cell death. J Cell Biol 158(3):507–517PubMedCrossRefGoogle Scholar
  111. 111.
    Pradelli LA, Bénéteau Ricci JE (2010) Mitochondrial control of caspase-dependent and –independent cell death. Cell Mol Life Sci 67:1589–1597PubMedCrossRefGoogle Scholar
  112. 112.
    Cheung ECC, Melanson-Drapeau L, Cregan SP, Vanderluit JL, Ferguson KL, McIntosh WC, Park DS, Bennett SAL, Slack RS (2005) Apoptosis-inducing factor is a key factor in neuronal cell death propagated by BAX-dependent and BAX-independent mechanisms. J Neurosci 25(6):1324–1334PubMedCrossRefGoogle Scholar
  113. 113.
    Matsui JI, Haque A, Huss D, Messana EP, Alosi JA, Roberson DW, Cotanche DA, Dickman JD, Warchol ME (2003) Caspase inhibitors promote vestibular hair cell survival and function after aminoglycoside treatment in vivo. J Neurosci 23(14):6111–6122PubMedGoogle Scholar
  114. 114.
    Kaiser CL, Chapman BJ, Guidi JL, Terry CE, Mangiardi DA, Cotanche DA (2008) Comparison of activated caspase detection methods in the gentamicin-treated chick cochlea. Hear Res 240(1–2):1–11PubMedCrossRefGoogle Scholar
  115. 115.
    Williams JA, Holder N (2000) Cell turnover in neuromasts of zebrafish larvae. Hear Res 143:171–181PubMedCrossRefGoogle Scholar
  116. 116.
    Nakagawa T, Yamane H, Takayama M, Sunami K, Nakai Y (1998) Apoptosis of guinea pig cochlear hair cells following aminoglycoside treatment. Eur Arch Otorhinolaryngol 255:127–131PubMedCrossRefGoogle Scholar
  117. 117.
    Taylor RR, Nevill G, Forge A (2008) Rapid hair cell loss: a mouse model for cochlear lesions. J Assoc Res Otolaryngol 9(1):44–64PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Allison B. Coffin
    • 1
    • 2
    • 5
  • Kay L. Williamson
    • 1
    • 2
    • 5
  • Anna Mamiya
    • 3
  • David W. Raible
    • 1
    • 4
  • Edwin W. Rubel
    • 1
    • 2
  1. 1.Virginia Merrill Bloedel Hearing Research CenterUniversity of WashingtonSeattleUSA
  2. 2.Department of Otolaryngology–Head and Neck SurgeryUniversity of WashingtonSeattleUSA
  3. 3.Department of Speech and Hearing ScienceUniversity of WashingtonSeattleUSA
  4. 4.Department of Biological StructureUniversity of WashingtonSeattleUSA
  5. 5.Department of Veterinary and Comparative Anatomy, Pharmacology, and PhysiologyCollege of Arts and Sciences, Washington State UniversityVancouverUSA

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