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Inhibition of the Adenosine A2A Receptor Mitigates Excitotoxic Injury in Organotypic Tissue Cultures of the Rat Cochlea

Department of Physiology and The Eisdell Moore Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
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Cells 2019, 8(8), 877; https://doi.org/10.3390/cells8080877
Received: 16 July 2019 / Revised: 9 August 2019 / Accepted: 9 August 2019 / Published: 12 August 2019
(This article belongs to the Special Issue Adenosine Receptors: From Cell Biology to Human Diseases)
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Abstract

The primary loss of cochlear glutamatergic afferent nerve synapses due to noise or ageing (cochlear neuropathy) often presents as difficulties in speech discrimination in noisy conditions (hidden hearing loss (HHL)). Currently, there is no treatment for this condition. Our previous studies in mice with genetic deletion of the adenosine A2A receptor (A2AR) have demonstrated better preservation of cochlear afferent synapses and spiral ganglion neurons after noise exposure compared to wildtype mice. This has informed our current targeted approach to cochlear neuroprotection based on pharmacological inhibition of the A2AR. Here, we have used organotypic tissue culture of the Wistar rat cochlea at postnatal day 6 (P6) to model excitotoxic injury induced by N-methyl-d-aspartate (NMDA)/kainic acid (NK) treatment for 2 h. The excitotoxic injury was characterised by a reduction in the density of neural processes immediately after NK treatment and loss of afferent synapses in the presence of intact sensory hair cells. The administration of istradefylline (a clinically approved A2AR antagonist) reduced deafferentation of inner hair cells and improved the survival of afferent synapses after excitotoxic injury. This study thus provides evidence that A2AR inhibition promotes cochlear recovery from excitotoxic injury, and may have implications for the treatment of cochlear neuropathy and prevention of HHL. View Full-Text
Keywords: glutamate excitotoxicity; cochlear synaptopathy; cochlear explant; adenosine A2A receptor; istradefylline; hidden hearing loss glutamate excitotoxicity; cochlear synaptopathy; cochlear explant; adenosine A2A receptor; istradefylline; hidden hearing loss
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Han, B.R.; Lin, S.C.; Espinosa, K.; Thorne, P.R.; Vlajkovic, S.M. Inhibition of the Adenosine A2A Receptor Mitigates Excitotoxic Injury in Organotypic Tissue Cultures of the Rat Cochlea. Cells 2019, 8, 877.

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