Adenosine Amine Congener (ADAC) As a Cochlear Rescue Agent

Abstract

Noise-induced hearing loss (NIHL) is a global health problem affecting up to 5% of the population worldwide. In many instances, NIHL results from acute exposure to traumatic noise. As the injury to the inner ear is mostly due to oxidative stress which continues after the cessation of noise exposure, there is a brief window of opportunity to rescue cochlear tissues and prevent the hearing loss within the first 2-3 days after exposure. We have shown that NIHL can be prevented by administration of drugs acting on adenosine receptors in the inner ear, and a selective A1 adenosine receptor agonist Adenosine Amine Congener (ADAC) has emerged as a potentially effective treatment for cochlear injury and resulting hearing loss. This study investigated pharmacokinetic properties of ADAC in rat plasma, cochlear tissue and perilymph after systemic (intravenous) and local (intratympanic) administrations using reverse phase high pressure liquid chromatography (RP-HPLC) and liquid chromatography-tandem mass spectrometry (LCMS/MS). Both methods were developed and validated in accordance with the USA FDA guidelines including accuracy, precision, specificity and linearity. Our study shows that ADAC remains stable for 4 hours at 37°C, with no metabolites detected by RP-HPLC. The pharmacokinetics (PK) of ADAC in rat plasma are characterised by one-compartment PK model with a short half-life (5 minutes). ADAC was detected in cochlear perilymph within 2 minutes following systemic administration, and remained in perilymph above its minimal effective concentration (MEC) for at least 2 hours. The pharmacokinetics of ADAC in rat plasma was similar to another selective A1 adenosine receptor agonist N6-Cyclopentyladenosine (CPA), but distinct from the others, such as R- and S-N6-Phenylisopropyladenosine (R- and S-PIA). Previous studies supported ADAC as an effective cochlear rescue agent for noise- and drug- induced hearing loss. This study further investigated the potential of ADAC as a therapeutic agent after acoustic trauma caused by exposure to impulse noise. Both systemic (intraperitoneal) and local (intratympanic) drug administration routes were investigated. The outcomes were measured functionally (ABR thresholds and suprathreshold responses) and histologically (quantitative assessment of the loss of hair cells and spiral ganglion neurons). Our results demonstrated that ADAC was ineffective in mitigating cochlear injury caused by exposure to impulse noise, regardless of the drug administration route. Possible reasons include the largely mechanical nature of cochlear injury associated with impulse noise, and low permeability of the cochlear round window membrane (RWM) for ADAC. Further studies are therefore required to explore alternative routes of drug administration and potentially focus on drug combinations for the treatment of impulse noise-induced cochlear injury, which could include anti-apoptotic and antioxidant agents.