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Chronotolerance for cisplatin ototoxicity in the rat
Eric C Bielefeld1, Alex Markle1, J Riley DeBacker1
1Department of Speech and Hearing Science, The Ohio State University, 110 Pressey Hall, 1070 Carmack Road, Columbus, OH, 43210, USA.
Hearing Research
|September 26, 2018
Summary
Timing cisplatin chemotherapy administration to the active period in rats significantly reduces ototoxicity and cochlear injury. This finding highlights the impact of circadian timing on platinum-based drug side effects.
Area of Science:
- Chronopharmacology
- Ototoxicology
- Cancer Therapeutics
Background:
- Cisplatin is a widely used chemotherapy drug with a significant side effect of ototoxicity.
- Previous research indicates cisplatin's efficacy and reduced nephrotoxicity are influenced by circadian timing, with optimal administration during the active (dark) phase in rodents.
Purpose of the Study:
- To investigate the influence of circadian time on cisplatin-induced ototoxicity.
- To determine if administering cisplatin during the active or inactive period affects cochlear injury.
Main Methods:
- Fifty-seven Fischer 344/NHsd rats received intraperitoneal cisplatin (12 mg/kg) at six different time points across a 12-hour light-12-hour dark cycle.
- Ototoxicity was assessed via auditory brainstem response (ABR) threshold shifts and postmortem quantification of outer hair cell (OHC) loss.
Main Results:
- All rats exhibited threshold shifts at high frequencies (30 and 40 kHz).
- Rats treated 6 hours after light onset (during the inactive period) showed significantly greater mid-frequency ABR threshold shifts and OHC loss compared to those treated during the dark (active) hours.
- Circadian timing significantly impacts susceptibility to cisplatin ototoxicity.
Conclusions:
- Administering cisplatin during the active period (dark hours) in rats minimizes ototoxicity and cochlear damage.
- These findings align with previous observations of reduced nephrotoxicity when cisplatin is given during the active phase.
- Circadian-based administration strategies may mitigate cisplatin-induced hearing loss.
