title: Adenosine kinase inhibition in the cochlea delays the onset of age-related hearing loss.
abstract: This study was undertaken to determine the role of adenosine signalling in the development of age-related hearing loss (ARHL). We and others have shown previously that adenosine signalling via A(1) receptors is involved in cochlear protection from noise-induced cochlear injury. Here we demonstrate that enhanced adenosine signalling in the cochlea provides partial protection from ARHL in C57BL/6J mice. We targeted adenosine kinase (ADK), the key enzyme in adenosine metabolism, using a treatment regime with the selective ADK inhibitor ABT-702 (1.5mg/kg intraperitoneally twice a week) commencing at the age of three months or six months. This treatment, intended to increase free adenosine levels in the cochlea, was maintained until the age of nine months and hearing thresholds were evaluated monthly using auditory brainstem responses (ABR). At nine months, when C57BL/6J mice normally exhibit significant ARHL, both groups treated with ABT-702 showed lower ABR threshold shifts at 10 and 16kHz compared to control animals receiving the vehicle solution. The better thresholds of the ABT-702-treated mice at these frequencies were supported by increased survival of hair cells in the apical region of the cochlea. This study provides the first evidence that ARHL can be mitigated by enhancing adenosine signalling in the cochlea.
authors.affiliation: Department of Physiology, Faculty of Medical and Health Sciences, The University of Auckland, New Zealand. s.vlajkovic@auckland.ac.nz
authors.forename: Srdjan M
authors.initials: SM
authors.lastname: Vlajkovic
authors.forename: Cindy X
authors.initials: CX
authors.lastname: Guo
authors.forename: Ravindra
authors.initials: R
authors.lastname: Telang
authors.forename: Ann Chi Yan
authors.initials: AC
authors.lastname: Wong
authors.forename: Vinthiya
authors.initials: V
authors.lastname: Paramananthasivam
authors.forename: Detlev
authors.initials: D
authors.lastname: Boison
authors.forename: Gary D
authors.initials: GD
authors.lastname: Housley
authors.forename: Peter R
authors.initials: PR
authors.lastname: Thorne
mesh_terms: D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D003051:Cochlea / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D006198:Hair Cells, Auditory / Q000473:pathology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology*; D011304:Presbycusis / Q000201:enzymology* / Q000503:physiopathology / Q000517:prevention & control*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D009025:Morpholines; D011743:Pyrimidines; C416933:ABT 702; D000248:Adenosine Kinase