Riluzole rescues cochlear sensory cells from acoustic trauma in the guinea-pig

doi:10.1016/S0306-4522(02)00004-0

Neuroscience

Volume 111, Issue 3, 30 May 2002, Pages 635-648

https://doi.org/10.1016/S0306-4522(02)00004-0 Get rights and content

Abstract

Acoustic trauma is the major cause of hearing loss in industrialised nations. We show in guinea-pigs that sound exposure (6 kHz, 120 dB sound pressure level for 30 min) leads to sensory cell death and subsequent permanent hearing loss. Ultrastructural analysis reveals that degeneration of the noise-damaged hair cells involved different mechanisms, including typical apoptosis, autolysis and, to a lesser extent, necrosis. Whatever the mechanisms, a common feature of noise damage to hair cells was mitochondrial alteration. Riluzole (2-amino-6-trifluoromethoxy benzothiazole) is a neuroprotective agent that prevents apoptosis- and necrosis-induced cell death. Perfusion of riluzole into the cochlea via an osmotic minipump prevents mitochondrial damage and subsequent translocation of cytochrome c, DNA fragmentation, and hair cell degeneration. This was confirmed by functional tests showing a clear dose-dependent reduction (ED₅₀=16.8 μM) of permanent hearing loss and complete protection at 100 μM. Although less efficient than intracochlear perfusion, intraperitoneal injection of riluzole rescues the cochlea within a therapeutic window of 24 h after acoustic trauma.

These results show that riluzole is able to prevent and rescue the cochlea from acoustic trauma. It may thus be an interesting molecule for the treatment of inner ear injuries.

Section snippets

Experimental procedures

These experiments were designed to test whether riluzole can rescue the cochlea from acoustic trauma in guinea-pigs. The care and use of animals followed the animal welfare guidelines of the ‘Institut National de la Santé et de la Recherche Medicale’ (INSERM), and under the approval of the French ‘Ministère de l’Agriculture et de la Forêt’. All efforts were made to minimise the number of animals used and their suffering.

Electrophysiological studies

In the non-perfused contralateral control ear, the average hearing thresholds measured 20 min after acoustic trauma were elevated to between 60 and 70 dB in the higher frequencies of the CAP audiogram, with a maximum threshold elevation between 10 and 16 kHz (Fig. 2A). During the first 24 h following the acoustic trauma, there was a partial recovery of CAP thresholds of around 30 dB. Over the next 24 h, CAP thresholds continued to recover slowly, by around 10 dB, to reach a final threshold

Discussion

In our model of acoustic trauma in the guinea-pig, 30 min of a 6 kHz tone at 120 dB SPL induced a PTS that affected a wide range of frequencies, between 6 and 16 kHz. However, maximal hair cell loss was restricted to a precise region, 14–16 mm from the apex, which was the site maximally stimulated by our noise paradigm. Fragmented hair cell nuclei were observed in the same region using morphological analyses and specific DNA labelling. Ultrastructural examination revealed mitochondrial damage

Acknowledgements

The authors want to thank the anonymous reviewers for their comments and constructive criticisms. Help from Dr Adam Doble in interpreting the data was highly appreciated. The authors are also indebted to Jérôme Ruel, Régis Nouvian and Matthieu Guitton for their helpful discussions concerning the experiments, Ruth Lloyd Faulconbridge and Jean Louis Pasquier for editing work and Sabine Ladrech, Ghyslaine Humbert and Nicole Renard for their technical assistance.

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View full text

Riluzole rescues cochlear sensory cells from acoustic trauma in the guinea-pig

Abstract

Section snippets

Experimental procedures

Electrophysiological studies

Discussion

Acknowledgements

Curr. Opin. Neurobiol.

Hepatology

Neuropharmacology

Hear. Res.

Neuron

Brain Res.

Hear. Res.

Cell

Brain Res.

Hear. Res.

Hear. Res.

Neurosci. Lett.

Hear. Res.

Exp. Neurol.

Curr. Opin. Neurobiol.

Hear. Res.

Brain Res.

Calpain as a novel target for treating acute neurodegenerative disorders

Neurol. Res.

Electrophysiological and morphological correlates in the guinea-pig cochlea after exposure to ‘impulsive’ noise

Scand. Audiol. Suppl.

Treatment of acoustic trauma

Ann. N. Y. Acad. Sci.

The pharmacology and mechanism of action of riluzole

Neurology