Purinergic Signaling and Aminoglycoside Ototoxicity: The Opposing Roles of P1 (Adenosine) and P2 (ATP) Receptors on Cochlear Hair Cell Survival
| Autor: | Srdjan M. Vlajkovic, Shelly C. Y. Lin, Gary D. Housley, Peter R. Thorne |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
cochlear explant Stimulation P2 receptor lcsh:RC321-571 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine medicine otorhinolaryngologic diseases lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Cochlea Original Research Chemistry Purinergic receptor sensory hair cells aminoglycoside ototoxicity Purinergic signalling P1 receptor Adenosine receptor Adenosine Cell biology ATP 030104 developmental biology medicine.anatomical_structure Organ of Corti adenosine sense organs 030217 neurology & neurosurgery medicine.drug Neuroscience purinergic signaling |
| Zdroj: | Frontiers in Cellular Neuroscience Frontiers in Cellular Neuroscience, Vol 13 (2019) |
| ISSN: | 1662-5102 |
| Popis: | Purinergic signaling regulates important physiological processes and the homeostatic response to stress in the cochlea via extracellular nucleosides (adenosine) and nucleotides (ATP, UTP). Using a previously established organotypic culture model, the current study investigated the effect of purinergic P1 (adenosine) and P2 (ATP) receptor activation on the survival of the sensory hair cell population in the cochlea exposed to the ototoxic aminoglycoside neomycin. Organ of Corti explants were obtained from C57BL/6 mice at postnatal day 3 (P3) and maintained in normal culture medium (with or without purine receptor agonists or analogs) for 19.5 h prior to neomycin exposure (1 mM, 3 h) followed by a further incubation for 19.5 h in culture medium. The cochlear explants were then fixed in 4% paraformaldehyde (PFA) and sensory hair cells labeled with Alexa 488-phalloidin. Neomycin induced a substantial loss of the sensory hair cells, mostly in the middle segment of the cochlea. This neomycin-induced ototoxicity was unaffected by the addition of P2 receptor agonists (ATP and UTP) in the culture medium, whilst the addition of their slowly-hydrolyzable analogs (ATPγS, UTPγS) aggravated neomycin-induced sensory hair cell loss. In contrast, the activation of P1 receptors by adenosine or adenosine amine congener (ADAC) conferred partial protection from neomycin ototoxicity. This study demonstrates a pro-survival effect of P1 receptor stimulation, whilst prolonged activation of P2 receptors has an opposite effect. Based on these findings, we postulate that P1 and P2 receptors orchestrate differential responses to cochlear injury and that the balance of these receptors is important for maintaining cochlear homeostasis following ototoxic injury. |
| Databáze: | OpenAIRE |
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