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Mechanisms of aminoglycoside ototoxicity: opportunities for otoprotection

Mechanisms of aminoglycoside ototoxicity: opportunities for otoprotection. Corné Kros – c.j.kros@sussex.ac.uk. Structure of the ear. From Tortora & Grabowski. Cochlear cultures as a model for studying hair cell physiology and ototoxicity. Aminoglycoside antibiotics damage hair cells in vitro.

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Mechanisms of aminoglycoside ototoxicity: opportunities for otoprotection

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  1. Mechanisms of aminoglycoside ototoxicity: opportunities for otoprotection Corné Kros – c.j.kros@sussex.ac.uk

  2. Structure of the ear From Tortora & Grabowski

  3. Cochlear cultures as a model for studying hair cell physiology and ototoxicity

  4. Aminoglycoside antibiotics damage hair cells in vitro • A: Outer hair cell damage after exposure to 1 mM neomycin for 1 hour • B: Pre-treatment with the Ca2+ chelator BAPTA (5 mM) prevents damage

  5. How do aminoglycoside antibiotics damage hair cells? • Aminoglycoside antibiotics (e.g. dihydrostreptomycin) are bactericidal with a broad anti-bacterial spectrum: used to prevent or treat life-threatening infections • Large, polycationic molecules enter mechano-electrical transducer (MET) channels • Hearing damage occurs in 20-50% of treated patients • Oto- and nephro-toxic • Trigger cell death through apoptosis

  6. Recording MET currents in the mouse cochlea with a fluid jet Kros, Rüsch & Richardson (1992) Proc R Soc

  7. Extracellular DHS blocks MET currents at hyperpolarized potentials Marcotti, Van Netten & Kros (2005) J Physiol

  8. Block by extracellular DHS is reduced at extreme positive and also negative potentials: evidence of permeant block Marcotti, Van Netten & Kros (2005) J Physiol

  9. + + + + + + A model of the MET channel pore DHS Van Netten & Kros (2007) in Curr Topics Membr 59

  10. Otoprotection strategies with competing, non-toxic transducer channel blockers can be considered Van Netten & Kros (2007) in Curr Topics Membr 59

  11. In the cochlea the styryl dye FM1-43 selectively labels hair cells • Basal end • high-freq • more mature • Apical end • low-freq • immature

  12. 1 mM neomycin 1 mM neomycin FM1-43 protects hair cells from damage by aminoglycoside antibiotics Control 5 mM BAPTA pre 1 mM neomycin 30 M FM1-43 30 M FM1-43 pre 1 mM neomycin

  13. How to try and get this funded as a research programme? • Collaborate, both within institution and with external partners • Show you can do it: plenty of preliminary experiments • Formulate realistic aims • Work out detailed timeline and plan for experiments and publication of results • Carefully consider pathways to impact: • Hearing research community • Medicine • Pharmaceutical industry • Don’t underestimate time needed to hone the proposal: one year between outline and submission of full proposal

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