Role of adenosine kinase in cochlear development and response to noise

Abstract

Adenosine signalling has an important role in cochlear protection from oxidative stress. In most tissues, intracellular adenosine kinase (ADK) is the primary route of adenosine metabolism and the key regulator of intracellular and extracellular adenosine levels. The present study provides the first evidence for ADK distribution in the adult and developing rat cochlea. In the adult cochlea ADK was localised to the nuclear or perinuclear region of spiral ganglion neurones, lateral wall tissues and epithelial cells lining scala media. In the developing cochlea, ADK was strongly expressed in multiple cell types at birth, and reached its peak level of expression at postnatal day 21 (P21). Ontogenetic changes in ADK expression were evident in the spiral ganglion, organ of Corti and stria vascularis. In the spiral ganglion, ADK showed a shift from predominantly satellite cell immunolabelling at P1 to neuronal expression from P14 onwards. In contrast to the role of ADK in various aspects of cochlear development, ADK contribution to the cochlear response to noise stress was less obvious. Transcript and protein levels of ADK were unaltered in the cochlea exposed to broadband noise (90–110dBSPL, 24 hours) and the selective inhibition of ADK in the cochlea with ABT-702 failed to restore hearing thresholds after exposure to traumatic noise. This study indicates that ADK is involved in purine salvage pathways for nucleotide synthesis in the adult cochlea, but its role in the regulation of adenosine signalling under physiological and pathological conditions is yet to be established.

Adenosine Kinase: Exploitation for Therapeutic Gain

“…Only two studies tested the otoprotective potential of the ADK inhibitor ABT-702. Although ABT-702 failed to restore hearing thresholds after exposure to traumatic noise (Vlajkovic et al, 2010), the chronic treatment with ABT-702 (1.5 mg/kg intraperitoneally twice a week) attenuated hair cell loss and age-related hearing loss in C57BL/6 mice (Vlajkovic et al, 2011). It remains to be determined why ABT-702 had an opposite outcome in those studies.…”

“…Therefore, adenosine metabolic enzymes, such as ADK, have emerged as attractive targets for controlling oxidative stress in the cochlea (Vlajkovic et al, 2009). In the adult cochlea of the rat, ADK immunoreactivity was mostly localized to the nuclear or perinuclear region of spiral ganglion neurons, to lateral wall tissue, and to epithelial cells lining the scala media (Vlajkovic et al, 2010). Like in the brain, ADK expression was subject to highly coordinated expression changes during early postnatal development of the cochlea (Vlajkovic et al, 2010), implicating a putative role of ADK in the regulation of developmental processes.…”

“…In the adult cochlea of the rat, ADK immunoreactivity was mostly localized to the nuclear or perinuclear region of spiral ganglion neurons, to lateral wall tissue, and to epithelial cells lining the scala media (Vlajkovic et al, 2010). Like in the brain, ADK expression was subject to highly coordinated expression changes during early postnatal development of the cochlea (Vlajkovic et al, 2010), implicating a putative role of ADK in the regulation of developmental processes. Therapeutically, the chronic application of the ADK inhibitor ABT-702 (1.5 mg/kg twice per week for 3 or 6 months) was shown to attenuate the development of age-related hearing loss in C57Bl/6 mice (Vlajkovic et al, 2011).…”

“…Importantly, the treated animals were also characterized by increased hair cell survival in the apical cochlea (Vlajkovic et al, 2011). Although ADK inhibition was shown to be a promising therapeutic approach for the attenuation of age-related hearing loss, ABT-702 treatment was not able to prevent the development of sound-induced hearing loss (Vlajkovic et al, 2010).…”

Adenosine kinase inhibition in the cochlea delays the onset of age-related hearing loss

“…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).…”