Cisplatin and gentamicin ototoxicity: a search for protectants and comparison of entry routes into sensory hair cells

Kitcher, Siân Rachel (2019) Cisplatin and gentamicin ototoxicity: a search for protectants and comparison of entry routes into sensory hair cells. Doctoral thesis (PhD), University of Sussex.

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The aminoglycoside class of antibiotics and the chemotherapy agent cisplatin are commonly used in clinical settings to treat life-threatening illnesses; however both compounds also cause permanent sensorineural hearing loss as a side effect. Aminoglycosides are known to rapidly enter cochlear hair cells through mechanoelectrical transducer (MET) channels and accumulate inside where they trigger various pathways that lead to cell death. Although it has been suggested that cisplatin may also enter hair cells through the MET channel, there is currently no direct evidence of this and research into the topic has suggested several other channels may be involved. The main aims of this research are to identify compounds that may offer protection against the aminoglycoside, gentamicin, by utilising a mouse cochlear culture screening assay, develop such an assay for identifying compounds that protect against cisplatin and also investigate the MET channel as an entry route of cisplatin into mouse cochlear hair cells. Several methods have been used, including protection assays, several different imaging techniques and whole-cell patch-clamp electrophysiology. This project yielded 22 and 4 compounds that protect or partially protect against gentamicin induced- and/or cisplatininduced cell death respectively and the work details the development of a cisplatin screening assay and includes a discussion on appropriate analysis of screening data. The screening results were further used to inform discussion on mechanisms of protection and possible differences between the two ototoxins tested. The investigation of cisplatin entry routes into cochlear hair cells yielded interesting results; no evidence of MET current block in the presence of cisplatin was found but a reduction in toxicity in mice with non-functional MET channels was evident. It was also found that while fluorescently-conjugated gentamicin rapidly enters cochlear hair cells, fluorescently-conjugated cisplatin does not and so while the mechanism of entry is still not completely elucidated these data highlight relevant differences between cisplatin and gentamicin not previously investigated.

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Neuroscience
Subjects: R Medicine > RM Therapeutics. Pharmacology > RM0300 Drugs and their actions
Depositing User: Library Cataloguing
Date Deposited: 28 Mar 2019 08:14
Last Modified: 28 Mar 2019 08:14

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