Pharmacokinetic Properties of Adenosine Amine Congener in Cochlear Perilymph after Systemic Administration

Noise-induced hearing loss (NIHL) is a global health problem affecting over 5% of the population worldwide. We have shown previously that acute noise-induced cochlear injury can be ameliorated 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 perilymph after systemic (intravenous) administration using a newly developed liquid chromatography-tandem mass spectrometry detection method. The method was developed and validated in accordance with the USA FDA guidelines including accuracy, precision, specificity, and linearity. Perilymph was sampled from the apical turn of the cochlea to prevent contamination with the cerebrospinal fluid. ADAC was detected in cochlear perilymph within two minutes following intravenous administration and remained in perilymph above its minimal effective concentration for at least two hours. The pharmacokinetic pattern of ADAC was significantly altered by exposure to noise, suggesting transient changes in permeability of the blood-labyrinth barrier and/or cochlear blood flow. This study supports ADAC development as a potential clinical otological treatment for acute sensorineural hearing loss caused by exposure to traumatic noise

Adenosine Amine Congener as a Cochlear Rescue Agent

We have previously shown that adenosine amine congener (ADAC), a selective A1 adenosine receptor agonist, can ameliorate noise- and cisplatin-induced cochlear injury. Here we demonstrate the dose-dependent rescue effects of ADAC on noise-induced cochlear injury in a rat model and establish the time window for treatment. Methods. ADAC (25–300 μg/kg) was administered intraperitoneally to Wistar rats (8–10 weeks old) at intervals (6–72 hours) after exposure to traumatic noise (8–16 kHz, 110 dB sound pressure level, 2 hours). Hearing sensitivity was assessed using auditory brainstem responses (ABR) before and 12 days after noise exposure. Pharmacokinetic studies investigated ADAC concentrations in plasma after systemic (intravenous) administration. Results. ADAC was most effective in the first 24 hours after noise exposure at doses >50 μg/kg, providing up to 21 dB protection (averaged across 8–28 kHz). Pharmacokinetic studies demonstrated a short (5 min) half-life of ADAC in plasma after intravenous administration without detection of degradation products. Conclusion. Our data show that ADAC mitigates noise-induced hearing loss in a dose- and time-dependent manner, but further studies are required to establish its translation as a clinical otological treatment

Reduced P2x2 receptor-mediated regulation of endocochlear potential in the ageing mouse cochlea

Extracellular adenosine triphosphate (ATP) has profound effects on the cochlea, including an effect on the regulation of the endocochlear potential (EP). Noise-induced release of ATP into the endolymph activates a shunt conductance mediated by P2X2 receptors in tissues lining the endolymphatic compartment, which reduces the EP and, consequentially, hearing sensitivity. This may be a mechanism of adaptation or protection from high sound levels. As inaction of such a process could contribute to hearing loss, this study examined whether the action of ATP on EP changes with age and noise exposure in the mouse. The EP and the endolymphatic compartment resistance (CoPR) were measured in mice (CBA/CaJ) aged between 3 and 15 months. The EP and CoPR declined slightly with age with an associated small, but significant, reduction in auditory brainstem response thresholds. ATP (100–1,000 μM) microinjected into the endolymphatic compartment caused a dose-dependent decline in EP correlated to a similar decrease in CoPR. This was blocked by pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonate, consistent with a P2X2 receptor-mediated shunt conductance. There was no substantial difference in the ATP response with age. Noise exposure (octave-band noise 80–100 decibels sound pressure level (dBSPL), 48 h) in young animals induced an upregulation of the P2X2 receptor expression in the organ of Corti and spiral limbus, most noticeably with the 90-dB exposure. This did not occur in the aged animals except following exposure at 90 dBSPL. The EP response to ATP was muted in the noise-exposed aged animals except following the 90-dB exposure. These findings provide some evidence that the adaptive response of the cochlea to noise may be reduced in older animals, and it is speculated that this could increase their susceptibility to noise-induced injury