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Effects of ototoxins on quinuclidinyl benzylate binding in the rat cochlea
S Bartolami1, M Planche, R Pujol
1Laboratoire de Neurobiologie de l'Audition, INSERM U254, CHU Saint Charles, Montpellier, France.
Abstract:
Ototoxins inhibit the muscarinic receptor-activated inositol phosphate synthesis in the rat cochlea. In order to study this inhibitory mechanism, we investigated the effects of the ototoxins ethacrynate, cisplatin, HgCl2 and neomycin on [3H]quinuclidinyl benzylate binding to muscarinic receptors in adult and 12-day-old rat cochleas. The results are similar whatever the age: at concentrations that inhibit the inositol phosphate synthesis, ethacrynate is without effect. Neomycin only reduces [3H]quinuclidinyl benzylate binding at concentrations in the millimolar range. Cisplatin and HgCl2 block the binding in a dose-dependent way. These results suggest that the block of the transduction system by cisplatin and HgCl2 is due to direct interactions with muscarinic binding sites. Moreover, considering these data together with previous results, ethacrynate and neomycin may affect the phosphoinositide signalling pathway at targets including phosphoinositides and G proteins.
Insights
Ototoxins like cisplatin and HgCl2 directly block muscarinic receptors in the rat cochlea, while ethacrynate and neomycin affect downstream signaling. This reveals distinct mechanisms of ototoxicity impacting hearing.
Area of Science:
- Oto-toxicology
- Neuropharmacology
- Auditory Science
Background:
- Ototoxins are known to inhibit muscarinic receptor-activated inositol phosphate synthesis in the rat cochlea.
- Understanding the precise inhibitory mechanisms of various ototoxins is crucial for auditory health research.
Purpose of the Study:
- To investigate the effects of specific ototoxins (ethacrynate, cisplatin, HgCl2, neomycin) on muscarinic receptor binding in the rat cochlea.
- To elucidate the molecular targets through which these ototoxins exert their inhibitory effects on the phosphoinositide signaling pathway.
Main Methods:
- Radioligand binding assays using [3H]quinuclidinyl benzylate to quantify muscarinic receptor binding.
- Assessment of ototoxin effects on adult and 12-day-old rat cochlear tissues.
- Dose-response analysis of ototoxin interactions with muscarinic binding sites.
Main Results:
- Ethacrynate did not affect muscarinic receptor binding at concentrations inhibiting inositol phosphate synthesis.
- Neomycin reduced binding only at millimolar concentrations.
- Cisplatin and HgCl2 demonstrated dose-dependent blockade of muscarinic receptor binding.
Conclusions:
- Cisplatin and HgCl2 likely interact directly with muscarinic binding sites to inhibit signaling.
- Ethacrynate and neomycin may target other components of the phosphoinositide pathway, such as phosphoinositides or G proteins.
- These findings differentiate the mechanisms of ototoxicity among tested compounds, impacting the auditory system.