The ARHL locus ahl that contributes to
The ARHL locus (ahl) that contributes to the hearing loss in the C57BL/6J mouse has been mapped to chromosome 10 (Erway et al., 1993, Johnson et al., 1997). It has been shown that strains susceptible to early onset ARHL carry a specific mutation in the cadherin 23 gene (Cdh23), which encodes a component of the hair cell stereocilia tip-link associated with the mechanical-to-electrical transduction lgk974 (Noben-Trauth et al., 2003). There is also evidence that the ahl locus on chromosome 10 is not the only region involved in the development of hearing loss in inbred mice (Johnson and Zheng, 2002, Keithley et al., 2004, Mashimo et al., 2006, Zheng et al., 2009). Ahl3 on chromosome 17, for example, contributes to susceptibility of C57BL/6J mice to age- and noise-induced hearing loss (Morita et al., 2007). In keeping with the mitochondrial theory of ageing (Loeb et al., 2005), it was proposed that the ahl locus at mouse chromosome 10 mediates a decrease in protective anti-oxidant enzymes and consequently increased impact of oxidative stress on tissues (Staecker et al., 2001). This notion has been confirmed in a recent study (Someya et al., 2009) demonstrating that Bak-mediated mitochondrial apoptosis in response to oxidative stress is a key mechanism of ARHL in C57BL/6J mice. The Cdh23 allele thus affects the age of onset of ARHL, but the basic mechanisms of cochlear ageing such as oxidative imbalance appear to be similar in early and late onset ARHL mouse strains (Someya et al., 2009). As the prevalence of hearing impairment increases with an ageing population (Gates and Mills, 2005), there is a demand for novel treatment strategies that would target the principal mechanisms of ARHL and reduce the impairment. We and others have shown that the adenosine signalling system in the cochlea has an important role in its protection from oxidative stress (for review, see Vlajkovic et al., 2009). For example, the administration of A1 adenosine receptor agonists onto the round window membrane (a membrane separating the middle ear from the perilymph of the cochlea) can prevent cochlear injury from noise (Hu et al., 1997, Hight et al., 2003) or partially reverse hearing loss after noise exposure (Wong et al., 2010, Vlajkovic et al., 2010a). In addition, selective A1 adenosine receptor agonists can reduce cisplatin-induced auditory threshold shifts (Whitworth et al., 2004), most likely by promoting the antioxidant defence system (Ford et al., 1997). Adenosine signalling is known to decline in the ageing brain (Cunha, 2005), and a similar process has been postulated to occur in the ageing cochlea (Vlajkovic et al., 2009). Given the evidence of an otoprotective effect of adenosine described above, restoring adenosine signalling may protect the cochlea from age-related degeneration. Adenosine kinase (ADK) is the primary route for adenosine metabolism and the principal negative regulator of intracellular and extracellular adenosine concentrations in the brain (Boison, 2006) and the cochlea (Vlajkovic et al., 2010b). We have previously demonstrated that physiological reduction of ADK expression is associated with an increase in endogenous adenosine in the brain (Pignataro et al., 2008); conversely, experimental overexpression of ADK in the brain is associated with a reduced concentration of adenosine (Fedele et al., 2005). Subsequently, we demonstrated that ADK-expression levels are key determinants for adenosine-based neuroprotection in the brain (Li et al., 2008, Pignataro et al., 2007, Theofilas et al., 2011). Drawing on this background, it is reasonable to speculate that activity of ADK and the resultant enhancement of endogenous adenosine levels in the cochlea has potential to ameliorate ARHL. In this study, we measured auditory thresholds and hair cell loss in C57BL/6J mice in the period spanning 3–9months of age (by which point this strain of mice develops significant ARHL) to investigate the otoprotective potential of the selective ADK inhibitor ABT-702. This study provides the first evidence that a manipulation of the adenosine signalling system in the cochlea can delay the onset of ARHL.