Transient Delivery of a KCNQ2/3-Specific Channel Activator 1 Week After Noise Trauma Mitigates Noise-Induced Tinnitus

Abstract

Exposure to loud noise can cause hearing loss and tinnitus in mice and humans. In mice, one major underlying mechanism of noise-induced tinnitus is hyperactivity of auditory brainstem neurons, due at least in part, to decreased Kv7.2/3 (KCNQ2/3) potassium channel activity. In our previous studies, we used a reflex-based mouse model of tinnitus and showed that administration of a non-specific KCNQ channel activator, immediately after noise trauma, prevented the development of noise-induced tinnitus, assessed 1 week after trauma. Subsequently, we developed RL-81, a very potent and highly specific activator of KCNQ2/3 channels. Here, to test the timing window within which RL-81 prevents tinnitus in mice, we modified and employed an operant animal model of tinnitus, where mice are trained to move in response to sound but not move in silence. Mice with behavioral evidence of tinnitus are expected to move in silence. We validated this mouse model by testing the effect of salicylate, which is known to induce tinnitus. We found that transient administration of RL-81 1 week after noise exposure did not affect hearing loss but reduced significantly the percentage of mice with behavioral evidence of tinnitus, assessed 2 weeks after noise exposure. Our results indicate that RL-81 is a promising drug candidate for further development for the treatment of noise-induced tinnitus.

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Acknowledgments

We thank Dr. Wai Lok Chang for help with initiating the behavioral paradigm of tinnitus, Patrick Cody for help with programming, and Dr. Thathiah for help with histology and imaging.

Funding

This work was supported by US Department of Defense grant W81XWH-14-1-0117 (TT and PW) and NIH grant DC007905 (TT).

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L.M, P.W, and T.T designed experiments; L.M, S.K, B.B, and B.H conducted experiments and performed data analysis; L.M, S.K, P.W, and T.T wrote the manuscript.

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Correspondence to Thanos Tzounopoulos.

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Marinos, L., Kouvaros, S., Bizup, B. et al. Transient Delivery of a KCNQ2/3-Specific Channel Activator 1 Week After Noise Trauma Mitigates Noise-Induced Tinnitus. JARO 22, 127–139 (2021). https://doi.org/10.1007/s10162-021-00786-3

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Keywords

  • KCNQ potassium channel activators
  • tinnitus
  • hearing loss
  • auditory brainstem
  • cochlea
  • therapeutic window