Role of adenosine kinase in cochlear development and response to noise

Vlajkovic, Srdjan M.; Guo, Cindy X.; Dharmawardana, Nuwan; Wong, Ann Chi Yan; Boison, Detlev; Housley, Gary D.; Thorne, Peter R.

doi:10.1002/jnr.22421

Cited by 9 publications

(15 citation statements)

References 57 publications

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“…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.…”

Section: B Applications In Preclinical Studiesmentioning

confidence: 97%

“…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.…”

mentioning

confidence: 98%

“…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).…”

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confidence: 98%

“…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).…”

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confidence: 99%

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Adenosine Kinase: Exploitation for Therapeutic Gain

2013

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Section: B Applications In Preclinical Studiesmentioning

confidence: 97%

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confidence: 98%

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confidence: 98%

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confidence: 99%

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Adenosine Kinase: Exploitation for Therapeutic Gain

2013

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Vlajkovic¹,

Guo²,

Telang³

et al. 2011

Experimental Gerontology

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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 A1 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 (1.5 mg/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 16 kHz 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.

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Long-term omega-3 fatty acid supplementation prevents expression changes in cochlear homocysteine metabolism and ameliorates progressive hearing loss in C57BL/6J mice

Martínez-Vega

Partearroyo

Vallecillo

et al. 2015

The Journal of Nutritional Biochemistry

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Omega-3 polyunsaturated fatty acids (PUFAs) are essential nutrients well known for their beneficial effects, among others on cognitive development and maintenance, inflammation and oxidative stress. Previous studies have shown an inverse association between high plasma levels of PUFAs and age-related hearing loss, and the relationship between low serum folate and elevated plasma homocysteine levels and hearing loss. Therefore, we used C57BL/6J mice and long-term omega-3 supplementation to evaluate the impact on hearing by analyzing their auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) thresholds. The omega-3 group showed significantly lower ABR hearing thresholds (~25 dB sound pressure level) and higher DPOAE amplitudes in mid-high frequencies when compared to the control group. These changes did not correlate with alterations between groups in plasma homocysteine or serum folate levels as measured by high-performance liquid chromatography and a microbiological method, respectively. Aging in the control group was associated with imbalanced cytokine expression toward increased proinflammatory cytokines as determined by quantitative reverse transcriptase polymerase chain reaction; these changes were prevented by omega-3 supplementation. Genes involved in homocysteine metabolism showed decreased expression during aging of control animals, and only alterations in Bhmt and Cbs were significantly prevented by omega-3 feeding. Western blotting showed that omega-3 supplementation precluded the CBS protein increase detected in 10-month-old controls but also produced an increase in BHMT protein levels. Altogether, the results obtained suggest a long-term protective role of omega-3 supplementation on cochlear metabolism and progression of hearing loss.

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Role of adenosine kinase in cochlear development and response to noise

Cited by 9 publications

References 57 publications

Adenosine Kinase: Exploitation for Therapeutic Gain

Adenosine Kinase: Exploitation for Therapeutic Gain

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

Long-term omega-3 fatty acid supplementation prevents expression changes in cochlear homocysteine metabolism and ameliorates progressive hearing loss in C57BL/6J mice

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