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Some Ototoxic Drugs Destroy Cochlear Support Cells Before Damaging Sensory Hair Cells

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Abstract

A wide variety of ototoxic drugs are capable of damaging the sensory hair cells in the mammalian cochlea resulting in permanent hearing loss. However, the toxic properties of these drugs suggest that some could potentially damage cochlear support cells as well. To test the hypothesis, we treated postnatal day three rat cochlear cultures with toxic doses of gentamicin, cisplatin, mefloquine, and cadmium. Gentamicin primarily destroyed the hair cells and disrupted the intercellular connection with the surrounding support cells. Gentamicin-induced hair cell death was initiated through the caspase-9 intrinsic apoptotic pathway followed by activation of downstream executioner caspase-3. In contrast, cisplatin, mefloquine, and cadmium initially damaged the support cells and only later damaged the hair cells. Support cell death was initiated through the caspase-8 extrinsic apoptotic pathway followed later by downstream activation of caspase-3. Cisplatin, mefloquine, and cadmium significantly reduced the expression of actin and laminin, in the extracellular matrix, leading to significant disarray of the sensory epithelium.

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Abbreviations

Cd:

Cadmium

CIS:

Cisplatin

DC:

Deiters cell

ECM:

Extracellular matrix

GM:

Gentamycin

HC:

Hensen cells

IHC:

Inner hair cells

IS:

Inner sulcus

ISC:

Inner sulcus cells

MEF:

Mefloquine

OHC:

Outer hair cells

OS:

Outer sulcus

PC:

Pillar cell

PBS:

Phosphate buffered saline

SC:

Support cells

References

  • Alam SA, Ikeda K, Oshima T, Suzuki M, Kawase T, Kikuchi T, Takasaka T (2000) Cisplatin-induced apoptotic cell death in Mongolian gerbil cochlea. Hear Res 141:28–38

    CAS  PubMed  Google Scholar 

  • Anttonen T, Belevich I, Kirjavainen A, Laos M, Brakebusch C, Jokitalo E, Pirvola U (2014) How to bury the dead: elimination of apoptotic hair cells from the hearing organ of the mouse. J Assoc Res Otolaryngol 15:975–992

    PubMed  PubMed Central  Google Scholar 

  • Boudreau N, Sympson CJ, Werb Z, Bissell MJ (1995) Suppression of ICE and apoptosis in mammary epithelial cells by extracellular matrix. Science 267:891–893

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bozzo C, Sabbatini M, Tiberio R, Piffanelli V, Santoro C, Cannas M (2006) Activation of caspase-8 triggers anoikis in human neuroblastoma cells. Neurosci Res 56:145–153

    CAS  PubMed  Google Scholar 

  • Chiarugi P, Giannoni E (2008) Anoikis: a necessary death program for anchorage-dependent cells. Biochem Pharmacol 76:1352–1364

    CAS  PubMed  Google Scholar 

  • Chuang CY, Degendorfer G, Davies MJ (2014) Oxidation and modification of extracellular matrix and its role in disease. Free Radic Res 48:970–989

    CAS  PubMed  Google Scholar 

  • Chun J, Joo EJ, Kang M, Kim YS (2013) Platycodin D induces anoikis and caspase-mediated apoptosis via p38 MAPK in AGS human gastric cancer cells. J Cell Biochem 114:456–470

    CAS  PubMed  Google Scholar 

  • Clerici WJ, Hensley K, DiMartino DL, Butterfield DA (1996) Direct detection of ototoxicant-induced reactive oxygen species generation in cochlear explants. Hear Res 98:116–124

    CAS  PubMed  Google Scholar 

  • Collado MS, Burns JC, Meyers JR, Corwin JT (2011) Variations in shape-sensitive restriction points mirror differences in the regeneration capacities of avian and mammalian ears. PLoS One 6:e23861

    CAS  PubMed  PubMed Central  Google Scholar 

  • D’Arcangelo G, Miao GG, Chen S-C, Soares HD, Morgan JI, Curran T (1975) A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature 374:719–723

    Google Scholar 

  • D’Arcy MS (2019) Cell death: a review of the major forms of apoptosis, necrosis and autophagy. Cell Biol Int 43:582–592

    PubMed  Google Scholar 

  • Davies D (2011) Cell-extracellular matrix versus cell-cell interactions during the development of the cochlear-vestibular ganglion. J Neurosci Res 89:1375–1387

    CAS  PubMed  Google Scholar 

  • Deng L, Ding D, Su J, Manohar S, Salvi R (2013) Salicylate selectively kills cochlear spiral ganglion neurons by paradoxically up-regulating superoxide. Neurotox Res 24:307–319

    CAS  PubMed  Google Scholar 

  • Ding D, Salvi R (2010) Paraquat-induced damage to the cochlear hair cells. Dalian Ding Science of the Inner Ear;China Science and Technology Press 325–9

  • Ding D, Jiang H, Wang P, Salvi R (2007) Cell death after co-administration of cisplatin and ethacrynic acid. Hear Res 226:129–139

    CAS  PubMed  Google Scholar 

  • Ding D, He J, Allman BL, Yu D, Jiang H, Seigel GM et al (2011) Cisplatin ototoxicity in rat cochlear organotypic cultures. Hear Res 282:196–203

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ding D, Qi W, Yu D, Jiang H, Han C, Katsuno K et al (2013a) NAD+ prevents mefloquine-induced neuroaxonal and hair cell degeneration through reduction of caspase-3-mediated apoptosis. PLoS One

  • Ding D, Qi W, Yu D, Jiang H, Han C, Kim MJ et al (2013b) Addition of exogenous NAD+ prevents mefloquine-induced neuroaxonal and hair cell degeneration through reduction of caspase-3-mediated apoptosis in cochlear organotypic cultures. PLoS One 8:e79817

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dong Y, Ding D, Jiang H, Shi JR, Salvi R, Roth JA (2014) Ototoxicity of paclitaxel in rat cochlear organotypic cultures. Toxicol Appl Pharmacol 280:526–533

    CAS  PubMed  Google Scholar 

  • Eichler T, Ma Q, Kelly C, Mishra J, Parikh S, Ransom RF, Devarajan P, Smoyer WE (2006) Single and combination toxic metal exposures induce apoptosis in cultured murine podocytes exclusively via the extrinsic caspase 8 pathway. Toxicol Sci 90:392–399

    CAS  PubMed  Google Scholar 

  • Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495–516

    CAS  PubMed  PubMed Central  Google Scholar 

  • Frisch SM (2000) Anoikis. Methods Enzymol 322:472–479

    CAS  PubMed  Google Scholar 

  • Frisch SM, Screaton RA (2001) Anoikis mechanisms. Curr Opin Cell Biol 13:555–562

    CAS  PubMed  Google Scholar 

  • Gonzalez-Garcia JA, Nevado J, Garcia-Berrocal JR, Sanchez-Rodriguez C, Trinidad A, Sanz R et al (2010) Endogenous protection against oxidative stress caused by cisplatin: role of superoxide dismutase. Acta Otolaryngol 130:453–457

    CAS  PubMed  Google Scholar 

  • Hamill KJ, Kligys K, Hopkinson SB, Jones JC (2009) Laminin deposition in the extracellular matrix: a complex picture emerges. J Cell Sci 122:4409–4417

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hammar E, Parnaud G, Bosco D, Perriraz N, Maedler K, Donath M, Rouiller DG, Halban PA (2004) Extracellular matrix protects pancreatic beta-cells against apoptosis: role of short- and long-term signaling pathways. Diabetes 53:2034–2041

    CAS  PubMed  Google Scholar 

  • He Z, Guo L, Shu Y, Fang Q, Zhou H, Liu Y, Liu D, Lu L, Zhang X, Ding X, Liu D, Tang M, Kong W, Sha S, Li H, Gao X, Chai R (2017) Autophagy protects auditory hair cells against neomycin-induced damage. Autophagy 13:1884–1904

    CAS  PubMed  PubMed Central  Google Scholar 

  • Heaney DL, Schulte BA, Niedzielski AS (2002) Dystroglycan expression in the developing and senescent gerbil cochlea. Hear Res 174:9–18

    CAS  PubMed  Google Scholar 

  • Hordichok AJ, Steyger PS (2007) Closure of supporting cell scar formations requires dynamic actin mechanisms. Hear Res 232:1–19

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hou S, Chen J, Yang J (2019) Autophagy precedes apoptosis during degeneration of the Kolliker’s organ in the development of rat cochlea. Eur J Histochem 63

  • Huang HL, Fang LW, Lu SP, Chou CK, Luh TY, Lai MZ (2003) DNA-damaging reagents induce apoptosis through reactive oxygen species-dependent Fas aggregation. Oncogene 22:8168–8177

    CAS  PubMed  Google Scholar 

  • Huang CR, Jin ZX, Dong L, Tong XP, Yue S, Kawanami T, Sawaki T, Sakai T, Miki M, Iwao H, Nakajima A, Masaki Y, Fukushima Y, Tanaka M, Fujita Y, Nakajima H, Okazaki T, Umehara H (2010) Cisplatin augments FAS-mediated apoptosis through lipid rafts. Anticancer Res 30:2065–2071

    CAS  PubMed  Google Scholar 

  • Hultcrantz M, Li HS (1995) Degeneration patterns of actin distribution in the organ of corti in two genotypes of mice. ORL: J Oto-Rhino-Laryngol Relat Spec 57:1–4

    CAS  Google Scholar 

  • Ishii K, Schroter-Kermani C, Xu D, Merker HJ, Jahnke V (1992) Extracellular matrix in the rat spiral limbus. Eur Arch Otorhinolaryngol 249:224–230

    CAS  PubMed  Google Scholar 

  • Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kim SJ, Jeong HJ, Myung NY, Kim MC, Lee JH, So HS, Park RK, Kim HM, Um JY, Hong SH (2008) The protective mechanism of antioxidants in cadmium-induced ototoxicity in vitro and in vivo. Environ Health Perspect 116:854–862

    CAS  PubMed  PubMed Central  Google Scholar 

  • Menardo J, Tang Y, Ladrech S, Lenoir M, Casas F, Michel C et al (2012) Oxidative stress, inflammation, and autophagic stress as the key mechanisms of premature age-related hearing loss in SAMP8 mouse cochlea. Antioxid Redox Signal 16:263–274

    CAS  PubMed  Google Scholar 

  • Micheau O, Solary E, Hammann A, Dimanche-Boitrel MT (1999) Fas ligand-independent, FADD-mediated activation of the Fas death pathway by anticancer drugs. J Biol Chem 274:7987–7992

    CAS  PubMed  Google Scholar 

  • Milner R, Campbell IL (2003) The extracellular matrix and cytokines regulate microglial integrin expression and activation. J Immunol 170:3850–3858

    CAS  PubMed  Google Scholar 

  • Miyazaki T, Shen M, Fujikura D, Tosa N, Kim HR, Kon S et al (2004) Functional role of death-associated protein 3 (DAP3) in anoikis. J Biol Chem 279:44667–44672

    CAS  PubMed  Google Scholar 

  • Nakagawa T, Yamane H, Takayama M, Sunami K, Nakai Y (1998) Apoptosis of guinea pig cochlear hair cells following chronic aminoglycoside treatment. Eur Arch Otorhinolaryngol 255:127–131

    CAS  PubMed  Google Scholar 

  • Nicotera T, Henderson D, Zheng X-Y, Ding D, McFadden SL (1999) Reactive oxygen species, apoptosis and necrosis in noise-exposed cochleas of chinchillas. Abstr Assoc Res Otolaryngol 22:626

    Google Scholar 

  • Pietrogrande G, Mabotuwana N, Zhao Z, Abdolhoseini M, Johnson SJ, Nilsson M et al (2018) Chronic stress induced disturbances in laminin: a significant contributor to modulating microglial pro-inflammatory tone? Brain Behav Immun 68:23–33

    CAS  PubMed  Google Scholar 

  • Qi W, Ding D, Salvi RJ (2008) Cytotoxic effects of dimethyl sulphoxide (DMSO) on cochlear organotypic cultures. Hear Res 236:52–60

    CAS  PubMed  Google Scholar 

  • Racz E, Gaal B, Kecskes S, Matesz C (2014) Molecular composition of extracellular matrix in the vestibular nuclei of the rat. Brain Struct Funct 219:1385–1403

    CAS  PubMed  Google Scholar 

  • Raphael Y (2002) Cochlear pathology, sensory cell death and regeneration. Br Med Bull 63:25–38

    CAS  PubMed  Google Scholar 

  • Raphael Y, Altschuler RA (1991) Reorganization of cytoskeletal and junctional proteins during cochlear hair cell degeneration. Cell Motil Cytoskeleton 18:215–227

    CAS  PubMed  Google Scholar 

  • Raphael Y, Altschuler RA (2003) Structure and innervation of the cochlea. Brain Res Bull 60:397–422

    PubMed  Google Scholar 

  • Richardson GP, Crossin KL, Chuong CM, Edelman GM (1987) Expression of cell adhesion molecules during embryonic induction. III. Development of the otic placode. Dev Biol 119:217–230

    CAS  PubMed  Google Scholar 

  • Setz C, Brand Y, Radojevic V, Hanusek C, Mullen PJ, Levano S, Listyo A, Bodmer D (2011) Matrix metalloproteinases 2 and 9 in the cochlea: expression and activity after aminoglycoside exposition. Neuroscience 181:28–39

    CAS  PubMed  Google Scholar 

  • Shanmugathasan M, Jothy S (2000) Apoptosis, anoikis and their relevance to the pathobiology of colon cancer. Pathol Int 50:273–279

    CAS  PubMed  Google Scholar 

  • Stupack DG, Puente XS, Boutsaboualoy S, Storgard CM, Cheresh DA (2001) Apoptosis of adherent cells by recruitment of caspase-8 to unligated integrins. J Cell Biol 155:459–470

    CAS  PubMed  PubMed Central  Google Scholar 

  • Taddei ML, Giannoni E, Fiaschi T, Chiarugi P (2012) Anoikis: an emerging hallmark in health and diseases. J Pathol 226:380–393

    CAS  PubMed  Google Scholar 

  • Tsuprun V, Santi P (1999) Ultrastructure and immunohistochemical identification of the extracellular matrix of the chinchilla cochlea. Hear Res 129:35–49

    CAS  PubMed  Google Scholar 

  • Yu D, Ding D, Jiang H, Stolzberg D, Salvi R (2011) Mefloquine damage vestibular hair cells in organotypic cultures. Neurotox Res 20:51–58

    CAS  PubMed  Google Scholar 

  • Yu J, Ding D, Sun H, Salvi R, Roth J (2015) Neurotoxicity of trimethyltin in rat cochlear organotypic cultures. Neurotox Res 28:43–54

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang J, Sun H, Salvi R, Ding D (2018) Paraquat initially damages cochlear support cells leading to anoikis-like hair cell death. Hear Res 364:129–141

    CAS  PubMed  PubMed Central  Google Scholar 

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Funding

The research is supported in part by a grant from NIOSH (R01OH010235) and in part by the Foundation of Science and Technology Commission of Shanghai Municipality (#15140900900).

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Author notes

  1. Dalian Ding and Jianhui Zhang contributed equally to this work.

Authors and Affiliations

  1. Center for Hearing and Deafness, University at Buffalo, 137 Cary Hall, Buffalo, NY, 14214, USA

    Dalian Ding, Haiyan Jiang & Richard Salvi

  2. Department of Otolaryngology Head and Neck Surgery, The Third People’s Hospital of Chengdu, Chengdu, China

    Dalian Ding & Jianhui Zhang

  3. Department of Otolaryngology, Ren-Ai Hospital, Guangxi University of Chinese Medicine, Nanning, China

    Weijun Xuan

  4. Department of Otolaryngology Head and Neck Surgery, Huashan Hospital, Fudan University, Shanghai, China

    Weidong Qi

  5. Department of Audiology and Speech-Language Pathology, Asia University, Taiwan, China

    Richard Salvi

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  1. Dalian Ding
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  2. Jianhui Zhang
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  3. Haiyan Jiang
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  4. Weijun Xuan
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  5. Weidong Qi
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  6. Richard Salvi
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Correspondence to Richard Salvi.

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Ding, D., Zhang, J., Jiang, H. et al. Some Ototoxic Drugs Destroy Cochlear Support Cells Before Damaging Sensory Hair Cells. Neurotox Res 37, 743–752 (2020). https://doi.org/10.1007/s12640-020-00170-8

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