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Keywords:

  • AM-111;
  • c-Jun N-terminal kinase;
  • labyrinthitis;
  • guinea pig;
  • hearing loss

Abstract

Objectives/Hypothesis: This study investigated the otoprotective properties of AM-111, an inhibitor of c-Jun N-terminal kinase-mediated apoptosis and inflammation.

Study Design: A controlled, prospective animal study using a guinea pig model of acute labyrinthitis.

Methods: Acute labyrinthitis was generated by injection of antigen into the scala tympani of sensitized guinea pigs. Treatment groups received 100 μL of AM-111 at concentrations of 100 μmol/L, 10 μmol/L, and 1 μmol/L in a hyaluronic acid gel formulation delivered over the round window niche within 1 hour of antigen challenge. Cochlear function was monitored over 21 days with serial auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) measurements followed by histologic analysis.

Results: The ABR results on day 21 demonstrated that untreated control ears for acute labyrinthitis had a mean hearing loss (HL) of 68 ± 12 dB. In contrast, ears treated with AM-111 (100 μmol/L) had a mean HL of 39 ± 31 dB. These two groups were statistically different (one-way analysis of variance, P = .03). Secondary outcomes, including DPOAE shift, inner hair cell survival, inflammatory cell counts, and spiral ganglion density, were also statistically significant in favor of an otoprotective effect of AM-111. Lower doses of AM-111 did not produce a statistically significant reduction in HL over controls.

Conclusion: AM-111 delivered over the round window membrane in a 100 μL hyaluronic acid formulation at a 100 μmol/L concentration immediately after induction of acute labyrinthitis in the guinea pig cochlea protects hearing, reduces hair cell loss, and reduces the number of inflammatory cells at 21 days after treatment.