Abstract:
Sensory deterioration, particularly auditory and vestibular impairment, is almost inevitable with ageing. Age-related changes in hearing reflect alterations in both the peripheral and central auditory systems and there is a paucity of preventative or treatment strategies. Considering the prevalence of age-related hearing loss (ARHL), there is an urgent need to develop interventions that can prevent or rescue age-related cochlear injury. In this study, we investigated a novel pharmacological strategy to delay the progression of ARHL using a mouse model. The focus was on adenosine A2A receptors in the inner ear. Previous studies in A2A receptor knockout mice have demonstrated that A2A receptor deficiency improves the survival of the outer hair cells (OHC) and afferent synapses after noise exposure. This has informed our current targeted approach to prevention of ARHL based on pharmacological inhibition of the A2A receptor in ageing mice. Methods: C57BL/6J mice were treated with weekly istradefylline (A2A receptor inhibitor; 200nM) injections from 6 to 12 months of age. Auditory function was assessed using auditory brainstem responses (ABR) to tone pips (4 – 32 kHz). ABR thresholds and suprathreshold responses (wave I amplitudes and latencies at 4, 16 and 32 kHz) were evaluated at 6 months (baseline), 9 months and 12 months (final) of age. Functional outcomes were correlated with quantitative histological assessments of sensory hair cells and afferent synapses. Results: Weekly injections of istradefylline significantly (p < 0.05) attenuated ABR threshold shifts (by approximately 20 dB) at mid to high frequencies (16 – 32 kHz). However, istradefylline did not improve ABR suprathreshold responses. Functional studies correlated with histological outcomes. Istradefylline treatment improved hair cell survival in a turn-dependent manner, but did not prevent the loss of afferent synapses. This study presents the first evidence for the rescue potential of istradefylline in ARHL or any other form of sensorineural hearing loss (SNHL).
Further studies are required to determine its potential as a clinical otological treatment.
