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.

CONCLUSION:

Local round-window application of AM-101 may be a promising therapeutic intervention for the treatment of synaptopathic tinnitus.

• Authors: Dan Bing, Sze Chim Lee, Dario Campanelli, Hao Xiong, Masahiro Matsumoto, Rama Panford-Walsh, Stephan Wolpert, Mark Praetorius, Ulrike Zimmermann, Hanqi Chu, Marlies Knipper, Lukas Rüttiger, Wibke Singer
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 35 Issue 5 Pg. 1905-23 ( 2015) ISSN: 1421-9778 [Electronic] Germany
• PMID: 25871611 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 S. Karger AG, Basel.

Chemical References

• Apoptosis Regulatory Proteins
• PDCD5 protein, rat
• Receptors, N-Methyl-D-Aspartate

Topics

• Anesthesia
• Animals
• Apoptosis Regulatory Proteins (therapeutic use, toxicity)
• Auditory Threshold (drug effects)
• Behavior, Animal (drug effects)
• Cochlea (drug effects, metabolism)
• Disease Models, Animal
• Female
• Noise
• Rats
• Rats, Wistar
• Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors, metabolism)
• Synapses (drug effects, metabolism)
• Tinnitus (drug therapy, etiology)