Adenosine amine congener mitigates noise-induced cochlear injury

Abstract

Hearing loss from noise exposure is a leading occupational disease, with up to 5% of the population at risk world-wide. Here, we present a novel purine-based pharmacological intervention that can ameliorate noiseinduced cochlear injury. Wistar rats were exposed to narrow-band noise (8-12 kHz, 110 dB SPL, 2-24 h) to induce cochlear damage and permanent hearing loss. The selective adenosine A 1 receptor agonist, adenosine amine congener (ADAC), was administered intraperitoneally (100 µg/kg/day) at time intervals after noise exposure. Hearing thresholds were assessed using auditory brainstem responses and the hair cell loss was evaluated by quantitative histology. Free radical damage in the organ of Corti was assessed using nitrotyrosine immunohistochemistry. The treatment with ADAC after noise exposure led to a significantly greater recovery of hearing thresholds compared with controls. These results were upheld by increased survival of sensory hair cells and reduced nitrotyrosine immunoreactivity in ADAC-treated cochlea. We propose that ADAC could be a valuable treatment for noise-induced cochlear injury in instances of both acute and extended noise exposures.

Structural Sweet Spot for A1 Adenosine Receptor Activation by Truncated (N)-Methanocarba Nucleosides: Receptor Docking and Potent Anticonvulsant Activity

“…N 6 -[4-[[[4-[[[(2-Aminoethyl)amino]carbonyl]methyl]anilino]carbonyl]methyl]phenyl]adenosine ( 46 , ADAC) is a potent A 1 AR agonist that has been shown to be neuroprotective in various models. 6,30 Full agonist 10 displayed efficacy in a seizure model in mice without the toxicity observed in the active dose range (tested up to 30 mg/kg, i.p.). Other A 1 AR agonists began to show toxicity, i.e.…”

Purinergic signaling in cochleovestibular hair cells and afferent neurons

“…In the cochlear partition, perfusion of adenosine in either perilymph or endolymph showed no changes in cochlear physiological parameters such as CAP [23,25] and no in vitro study has been published. However, Vlajkovic et al [42] (this issue; see also [43]) provides evidence that A1 receptor activation facilitates recovery from noise-induced hearing loss. In addition, prophylactic treatment with P1 receptor agonists confers otoprotection from noise damage [44,45].…”

Role of adenosine kinase in cochlear development and response to noise

“…The absence of ADK in the inner hair cells and Deiters' cells in the adult cochlea suggests reduced adenosine removal from the local pericellular spaces and enhanced adenosine signalling via adenosine receptors abundantly expressed in these cells (Vlajkovic et al,2007). Stimulation of A 1 receptors may be crucial for the survival of these cells under stress (Vlajkovic et al,2010; Wong et al,2010).…”

“…In addition, R ‐PIA and 2‐chloro‐N6‐cyclopentyladenosine (CCPA) reduce cisplatin‐induced auditory threshold shifts (Whithworth et al,2004), most likely by promoting the antioxidant defense system (Ford et al,1997a). More recent studies (Wong et al,2010; Vlajkovic et al,2010) have demonstrated that adenosine and the selective A 1 adenosine receptor agonists CCPA and adenosine amine congener (ADAC) ameliorate cochlear injury and reverse hearing loss after exposure to traumatic noise. Further studies are thus warranted to determine the full potential of adenosine signalling in mitigating cochlear pathologies based on oxidative stress.…”