Preclinical Development of Use-Dependent Selective Blockers of GluA2-Lacking AMPA Receptors to Prevent Noise-Induced Neurodegeneration
Abstract
The cochlea or hearing organ of our ear is exquisitely sensitive to sound. The downside to this is that in modern times we are exposed to intensely loud occupational and recreational sounds that can overwhelm the protective mechanisms of the ear and damage the cells that detect the sound and the nerve cells that transmit the information to the brain. These cells cannot regenerate so noise damage is permanent and accumulates with age and noise exposure. Moreover, there are currently no approved therapeutics specifically directed at preventing noise-induced hearing disorders (NIHDs) or repairing noise damage. Because military personnel are often and unavoidably exposed to high levels of noise, they are especially prone to NIHDs, which are up to four times more prevalent among Veterans than non-Veterans and are the most common service-related disabilities. Very loud noise damages or destroys the delicate sensory cells that detect sound. Current guidelines on noise exposure and hearing protection devices (ear plugs, earmuffs) are aimed mainly at preventing this damage. However, more recently, it has been discovered that noise can also destroy fragile synapses that connect the sensory cells to the nerve cells that carry information to the brain. These synapses can be damaged at noise levels lower than those that damage the sensory cells. Even moderate noise commonly encountered in many occupational or recreational activities can cause this synaptopathy. Although synaptopathy is generally not detectable on conventional audiometric tests, it has been implicated as a cause of NIHDs including deficits in speech perception in noise (SPiN), a common complaint among people who have a history of noise exposure, especially military Veterans. We are developing novel compounds to prevent synaptopathy when given orally either before or during the noise exposure. While it is possible to prevent synaptopathy through the use of hearing protective devices (HPDs), e.g., earplugs or earmuffs, these have the drawback of compromising situational awareness and impede hearing commands or instructions. This can have disastrous consequences in combat situations or in dangerous and noisy workplaces, such as construction sites. Our objective is to prevent cochlear synaptopathy while avoiding effect on normal hearing or other systemic side-effects. We have shown this is possible using a unique pharmacological approach. At cochlear synapses the nerve cells have two categories of receptors for the chemical signals released by the sensory cells. We found that only one of these contributes to noise damage to the synapses. With support from a previous DoD grant, we showed, in experiments using mice, that compounds able to selectively block the receptors causing damage while leaving the other receptors completely functional have the desired effect of preventing synaptopathy while leaving normal hearing intact. We call this technology chemical earmuffs. Clearly, this will greatly benefit not only Service personnel but also people in noisy occupational or recreational environments. NIHDs such as SpiN deficits are among the most prevalent injuries to Service Members and workers despite required use of hearing protection devices (HPDs). This may be due to improper use of the HPDs, perhaps to maintain situational awareness. Moreover, because synaptopathy can be caused by even moderate noise, it is possible that in very loud noise situations, the noise experienced even with HPDs can cause synaptopathy. We propose chemical earmuffs as a supplement to HPDs for full protection. In the previous experiments, the protective compound was delivered directly into the cochlea, which required invasive surgery, was delivered at a relatively high dosage, and was delivered prior to noise exposure. Our current lead compound is fully effective at moderate doses delivered orally or by injection and is effective even if delivered after the onset of n
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210683
Entities
People
- Steven H Green
Organizations
- United States Army
- University of Iowa