title: Therapeutic potential of a gamma-secretase inhibitor for hearing restoration in a guinea pig model with noise-induced hearing loss.
abstract: BACKGROUND
  Notch signaling plays a crucial role in the fate determination of cochlear progenitor cells, hair cells, and supporting cells in the developing cochlea. Recent studies have demonstrated the temporal activation of Notch signaling in damaged mature cochleae, and have demonstrated the induction of new hair cells by pharmacologically inhibiting Notch signaling. The present study aimed to illustrate the feasibility of pharmacologically inhibiting Notch signaling by using a gamma-secretase inhibitor for treating sensorineural hearing loss.
  
  
  RESULTS
  The effect of the sustained local delivery of MDL28170, a gamma-secretase inhibitor, on hearing and hair cell induction was tested in a guinea pig model with noise-induced hearing loss. MDL28170 was directly delivered into the cochlear fluids via a micro-osmotic pump. Drug application was initiated 7 days after noise exposure. Measurements of auditory brainstem responses revealed better hearing in the MDL28170-treated animals than in the vehicle controls. Histological analysis demonstrated a higher number of outer hair cells in the MDL28170-treated cochleae than the vehicle-treated cochleae.
  
  
  CONCLUSIONS
  These findings strongly suggest that local sustained delivery of a gamma-secretase inhibitor into the cochlea could be a novel strategy for treating acute hearing loss that is refractory to conventional treatment.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Tona
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Hamaguchi
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Takushi
authors.initials: T
authors.lastname: Miyoshi
authors.forename: Norio
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Kohei
authors.initials: K
authors.lastname: Yamahara
authors.forename: Juichi
authors.initials: J
authors.lastname: Ito
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Graduate School of Medicine, Kyoto University, Kawaharacho 54, Shogoin, Sakyoku, Kyoto 606-8507, Japan. tnakagawa@ent.kuhp.kyoto-u.ac.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakagawa
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use; D004151:Dipeptides / Q000627:therapeutic use*; D005240:Feasibility Studies; D006168:Guinea Pigs; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects* / Q000473:pathology*; D006317:Hearing Loss, Noise-Induced / Q000175:diagnosis / Q000503:physiopathology* / Q000628:therapy*; D006801:Humans; D051880:Receptors, Notch / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; C058076:calpain inhibitor III