Journal Club: Potassium channel blocker can dampen the cochlear damage caused by exposure to loud noise.

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Today's journal article

Zhao HB, Liu LM, Lu X, Quinonez AT, Roberts RA, Zhai TY, Liang C. Prevention and treatment of noise-induced hearing loss and cochlear synapse degeneration by potassium channel blockers in vivo. 

Why I picked this article

Excessive noise exposure can lead to damage to auditory neurons (= spiral ganglion neurons) and sensory hair cells (= outer hair cells and inner hair cells). In animal models, severe noise exposure can cause permanent hearing loss, while milder noise exposure can cause temporary hearing loss, which can recover over time. Temporal hearing loss is thought to occur because of the uncoupling of synapses between spiral ganglion neurons and sensory hair cells. Some of such pathology is thought to be the cause of "hidden hearing loss" in humans, where hearing sensitivity is not obvious with a diagnostic audiogram, but the patients still experience some difficulty hearing sounds in noisy background sound levels. 

The present research provides a proof of concept using a preclinical animal model (mice) for the use of the compound, potassium (K+) channel blocker tetraethylammonium (TEA). Potassium channels are a type of protein found in sensory hair cells, where they allow potassium ions to permeate when hair cells are stimulated by sounds. Over-activation of potassium channels leads to toxicity of having too much K+ ions. 

Some of the research findings

Animal models:
  • Adult male CBA/CaJ mice (12-16 weeks old, The Jackson Lab)
  • Noise exposure group: white-noise (95-98 dB SPL) for 2 h
  • Drug treatment: 
    • Control group received vehicle and no drug (pre or post noise exposure). 
    • Pre-TEA group, tetraethylammonium (TEA) (35 mg/ kg, Cat#86614, Sigma-Aldrich, USA) was administrated by intraperitoneal injection 2 hours before noise exposure. 
    • Post-TEAx1d group, TEA was administered immediately after the noise exposure once/day for 1 day.
    • Post-TEAx3d group, TEA was administered immediately after the noise exposure once/day for 3 day.
    • BK blocker group: received specific BK channel blocker GAL-021 (Cat#22609, Cayman Chemical, Ann Arbor, MI, USA), only the post-exposure intraperitoneal injection (10 mg/kg)
  • Auditory brainstem response (ABR), DPOAE, startle response (ASR) were used to assess animal's ability to hear. 
Finding: 
  • Noise-exposure induced hearing loss, as seen by elevated hearing thresholds in ABR. 
  • Both pre- and post-noise treatment with TEA reduced ABR threshold shifts and preserved suprathreshold ABR amplitudes when compared to the vehicle control group (with noise). 
  • The protective effect of pre- and post-noise TEA treatment was observed on the day of exposure, but not back to the normal baseline. 
  • Pre-TEA treatment group recovered the most after 28 days. Post-TEA treatment group had better hearing than the group without drugs. 
  • DPOAE reductions (indicative of OHC dysfunction) caused by noise exposure were attenuated by TEA, particularly with post-TEA administration. 
  • When comparing the recovery of hearing (as measured by ABR), a 3-day administration regimen gave better results than pre-TEA or 1-day post-TEA treatment. 
  • When testing the BK channel's specific blocker, application of pre-noise exposure BK was very effective in mitigating noise-induced hearing threshold shift. 
  • 28 days after noise exposure, the BK blocker in a 3-day post-noise regimen performed as well as the TEA. 
  • The above functional observations agreed with the observation on the number of functional or "coupled" synapses investigated with microscopy. 
Figure 2B. Suprathreshold ABR after noise exposure in three groups. Zhao 2025

Haruna's takeaway

This research provides some proof of concept for the idea that we can pharmacologically “blunt” the excitotoxic cascade after noise and preserve synapses, using potassium channel blockers. Potassium channel blockers have been investigated/developed as therapeutic candidates by other groups/companies, too. The observed effect looks very promising. 

In practice, the opportunities for immediate administration of these compounds after noise exposure, or pre-administration before noise exposure, may be very limited. Often in such cases, intratympanic injection is assumed, but in this research, systemic injection was used as the drug administration mode. I wonder if this is the intended methodology, or perhaps systemic delivery by oral medication, etc, is what they are thinking, and how feasible it may be when clinical risks are considered. 

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This is Haruna's 52/100 of the 100-day challenge to post a science blog article every day! I love inner ear biology & cochlear physiology.