Otoprotection by adenosine receptors: Insights from adenosine receptor knockout mice

Abstract

Hearing loss is a significant health concern (WHO, 2014) and noise induced hearing loss (NIHL) is a major contributing factor responsible for about 16% of hearing impairment worldwide. Current treatment of NIHL is limited to the fitting of hearing aids and so critical research into pharmacological treatments for NIHL is ongoing.This study investigated the functional role of the two major types of adenosine receptors found in the inner ear in the development of cochlear injury induced by noise exposure. In this study we utilized transgenic mice (C57BL/6 strain) that lack genes for adenosine A1 and A2A adenosine receptors to assess their responses to noise stress. Mice homozygous and heterozygous for mutation (adenosine receptor deletion) and wildtype mice were exposed to acute traumatic noise (8 – 16 kHz, 105 dB SPL) for 2 hours. Auditory thresholds in response to tone pips and auditory clicks were assessed before and 14 days after the noise exposure using auditory brainstem responses (ABRs)and auditory threshold shift wascalculated.Amplitude input-output functions for ABR wave I were produced in order to analyse the effect of gene deletion on auditory nerve integrity after noise exposure. Our results demonstrate similar ABR thresholds in mutant and wildtype mice at ambient sound levels. After noise exposure, we have observed a significantly greater ABR threshold shiftinA1ARKO mice compared to the wildtype mice.In contrast, threshold shifts were similar in noise-exposed A2AARKO and wild type mice. These results support an otoprotective role of A1AR and its potential targeting for pharmacological management of NIHL. It appears that the loss of function of A2AAR is less significant in cochlear response to noise injury, raising the possibility that the lack of A2A receptor can be compensated by cellular mechanisms of defence. Further investigation into the therapeutic potential of A1AR is required to establish the mechanisms of cochlear protection and the receptor’s influence on the survival of sensory hair cells and spiral ganglion neurones. This has important implications for the development of future therapies of NIHL and other forms sensorineural hearing loss based on stimulation of A1 adenosine receptors.