Sex Effects for Hearing Loss Drug Therapies

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Age-related hearing loss (ARHL), also known as presbycusis, is the predominant sensory disorder and neurodegenerative condition of our aged population. Like many other body systems, hearing and its associated structures decline with age, with most people experiencing some form of hearing loss by the age 60. ARHL is gradual deterioration of auditory sensitivity, speech perception and binaural processing with age. There are both health and social implications associated with ARHL as it has been related to other health problems, such as an increased risk for dementia, depression, distress, and loneliness. It also decreases ability of our elderly to live independently and increases their reliance on family and/or community support. There is no way to prevent or reverse ARHL, and currently, there is no FDA-approved drugs to prevent or treat sensorineural hearing loss. Most pre-clinical studies carried out so far have targeted one pathway. Here, I propose to investigate a therapy that can target various pathways simultaneously. Specifically, the therapeutic potential of L-ergothioneine will be investigated. Ergothioneine is a naturally occurring “super-antioxidant/anti- inflammatory” that has intrigued many researchers since the discovery of its specific receptor OCTN1 in the human body in 2005. It accumulates in various parts of the body depending upon its receptor expression levels. It exists in tautomer equilibrium (thiol and thione forms), with the thione form favored at physiological pH. Furthermore, its high redox potential (-0.06 V vs -0.2 to -0.32 V for other antioxidant thiols like glutathione) and high safety profile (NAOEL = 800 mg/kg/day) makes it a stable and effective antioxidant. We anticipate that it will also help in mitigating some of the key aspects of age-related hearing loss as well, since it is also an anti-apoptotic. We have produced some exciting preliminary results – protective effects on auditory brainstem response thresholds and on distortion product otoacoustic emission thresholds & amplitudes for aging CBA/CaJ male mice (~25 months old, 6-month longitudinal study) but not for females These preliminary results are novel and groundbreaking as no previous reports are available about EGT beneficial effects on the aging auditory system. In the present proposal, we will further develop the treatment paradigm of EGT in females by applying EGT therapies at different time points (pre, peri and post-menopausal) during the menopause transition with the hypothesis that there is a “golden-window” during this phase where ergothioneine will be beneficial for the females. This grant will help us to generate more initial results for pre- clinical treatment paradigms of ergothioneine to treat hearing loss. Note that EGT has a very safe and is readily available for human use, hence, if successful, our new findings will be rapidly translatable to the clinic.