AUTHOR=Nacher-Soler German , Lenglet Sébastien , Coelho Marta , Thomas Aurélien , Voruz François , Krause Karl-Heinz , Senn Pascal , Rousset Francis 

TITLE=Local Cisplatin Delivery in Mouse Reliably Models Sensorineural Ototoxicity Without Systemic Adverse Effects

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=Volume 15 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2021.701783

DOI=10.3389/fncel.2021.701783

ISSN=1662-5102

ABSTRACT=Cisplatin is a lifesaving chemotherapeutic drug with marked ototoxic side effects. Cisplatin-induced hearing loss affects a significant part of cancer surviving patients and is an unmet clinical need with important socio-economic consequences. Unfortunately, in current pre-clinical animal models of cisplatin ototoxicity, which are mainly based on systemic delivery, important morbidity is observed leading to premature sacrifice or death. This methodology not only raise obvious animal welfare concerns, but also increase the numbers of animals employed in ototoxicity studies to compensate for dropouts related with early sacrifice. To overcome these important limitations, we developed a local delivery model based on the application of a cisplatin solution directly into the otic bulla through a retroauricular approach. The local delivery model reliably induced significant hearing loss with a mean threshold shift ranging from 10 – 30 dB, strongly affecting the high frequencies (22 and 32 kHz). Importantly, mice did not show visible stress or distress indicators and no significant morbidity in comparison to a traditional systemic delivery control group of mice, injected intraperitoneally with 10 mg/Kg cisplatin, where significant weight loss >10 % in all treated animals (without any recovery) led to premature abortion of experiments at day 3. Mass spectrometry confirmed the absence of relevant systemic uptake following local delivery, with platinum accumulation restricted to the cochlea, whereas important platinum concentrations were detected in liver and kidney of the systemic cisplatin group. A clear correlation between the cochlear platinum concentration and the auditory threshold shift was observed. Immunohistochemistry revealed statistically significant loss of outer hair cells in the basal and apical turns of the cochlea and an important and statistically significant loss of auditory neurons and synapses in all cochlear regions. In conclusion, local cisplatin delivery induces robust hearing loss with minimal morbidity, thereby offering a reliable rodent model for human cisplatin ototoxicity, reducing the number of animals required and showing improved animal welfare compared with traditional systemic models.