Abstract:
Noise-induced hearing loss (NIHL) is a significant source of hearing loss in modern society; however, management strategies are still limited to prosthetic devices such as hearing aids. Pharmacological treatments of hearing loss are relatively novel, and this study investigated the potential of therapeutic strategies based on the regulation of adenosine levels in the cochlea. The inhibition of adenosine metabolising enzymes, adenosine kinase (ADK) and adenosine deaminase (ADA), was used in this study to mitigate hearing loss caused by exposure to traumatic noise. In the present study, we first investigated the expression and distribution of adenosine deaminase (ADA) in the rat cochlea using RT-PCR and immunohistochemistry respectively. It was confirmed that ADA1 is expressed as the main isozyme in the mammalian cochlea, mostly in the supporting cells of the sensory organ of Corti and blood vessel walls. However, the transcript levels of ADA assessed by quantitative RT-PCR were not altered by exposure to traumatic noise for 24 hour. We also investigated the effects of ADA and ADK inhibitors [erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride (EHNA) and 5-iodotubercidin respectively] when applied locally to the round window membrane on noise-induced hearing loss and cochlear injury. Rats exposed to traumatic noise [8 – 16 kHz at 110 dB sound pressure level (SPL) for 20 hr] displayed auditory threshold shifts ranging from 29 to 56 dB SPL, measured using auditory brainstem responses (ABRs). Noise-exposed cochleae showed free radical damage (assessed using nitrotyrosine immunohistochemistry) in the outer hair cells and supporting cells in the organ of Corti, and the loss of outer hair cells in the middle and basal cochlear turns. Noise exposure also induced apoptotic cell death in the organ of Corti, stria vascularis, and the spiral limbus. This indicates the role of oxidative stress and apoptosis in noise-induced cochlear injury. Our study showed that treatment with EHNA and 5-iodotubercidin neither reduced ABR threshold shifts, nor hair cell loss in the noise-exposed cochleae. The results suggest that EHNA and 5-ITU are not otoprotective when applied onto the round window membrane after noise exposure. Further studies are therefore required to determine the role of endogenous adenosine levels in cochlear response to injury and the therapeutic potential of ADA and ADK inhibitors.