title: Cochlear NMDA receptors as a therapeutic target of noise-induced tinnitus.
abstract: BACKGROUND
  Accumulating evidence suggests that tinnitus may occur despite normal auditory sensitivity, probably linked to partial degeneration of the cochlear nerve and damage of the inner hair cell (IHC) synapse. Damage to the IHC synapses and deafferentation may occur even after moderate noise exposure. For both salicylate- and noise-induced tinnitus, aberrant N-methyl-d-aspartate (NMDA) receptor activation and related auditory nerve excitation have been suggested as origin of cochlear tinnitus. Accordingly, NMDA receptor inhibition has been proposed as a pharmacologic approach for treatment of synaptopathic tinnitus.
  
  
  METHODS
  Round-window application of the NMDA receptor antagonist AM-101 (Esketamine hydrochloride gel; Auris Medical AG, Basel, Switzerland) was tested in an animal model of tinnitus induced by acute traumatic noise. The study included the quantification of IHC ribbon synapses as a correlate for deafferentation as well as the measurement of the auditory brainstem response (ABR) to close-threshold sensation level stimuli as an indication of sound-induced auditory nerve activity.
  
  
  RESULTS
  We have shown that AM-101 reduced the trauma-induced loss of IHC ribbons and counteracted the decline of ABR wave I amplitude generated in the cochlea/auditory nerve.
  
  
  CONCLUSIONS
  Local round-window application of AM-101 may be a promising therapeutic intervention for the treatment of synaptopathic tinnitus.
authors: Huazhong University of Science & Technology, Tongji Medical College, Tongji Hospital, Department of Otorhinolaryngology, Head & Neck Surgery, Wuhan, P. R. China.
authors: Dan
authors: D
authors: Bing
authors: Sze Chim
authors: SC
authors: Lee
authors: Dario
authors: D
authors: Campanelli
authors: Hao
authors: H
authors: Xiong
authors: Masahiro
authors: M
authors: Matsumoto
authors: Rama
authors: R
authors: Panford-Walsh
authors: Stephan
authors: S
authors: Wolpert
authors: Mark
authors: M
authors: Praetorius
authors: Ulrike
authors: U
authors: Zimmermann
authors: Hanqi
authors: H
authors: Chu
authors: Marlies
authors: M
authors: Knipper
authors: Lukas
authors: L
authors: Rüttiger
authors: Wibke
authors: W
authors: Singer
mesh_terms: D000758:Anesthesia; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000627:therapeutic use / Q000633:toxicity; D001309:Auditory Threshold / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D003051:Cochlea / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D009622:Noise; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D014012:Tinnitus / Q000188:drug therapy / Q000209:etiology
chemical_list: D051017:Apoptosis Regulatory Proteins; C000592906:PDCD5 protein, rat; D016194:Receptors, N-Methyl-D-Aspartate