Circadian Rhythm Dependent Kanamycin-induced Hearing Loss in Rodents Assessed by Auditory Brainstem Responses

Abstract

An antimicrobial agent, kanamycin, has been shown to produce as an untoward effect, ototoxicity. The purpose of this study was to investigate differential effects of kanamycin ototoxicity as a function of Rx timing with regard to circadian rhythms. Four groups of comparable weight Sprague-Dawley rats received a daily subcutaneous dosage of 225 mg/kg kanamycin sulfate with each receiving the antibiotic at a different time: 8 AM (8A), 2 PM (2P), 8 PM (8P), and 2 AM (2A). The rats were housed in separate cages, in a room on a light-dark (12:12) illumination cycle with light between 6 AM and 6 PM. Hearing loss was assessed with the auditory brainstem response (ABR) using pure tone stimuli at 8, 16, 24, and 32 kHz. ABR measures were obtained before dosing began and 2, 4, and 6 weeks after the initial dosing. Kanamycin produced a hearing loss which reflected the total dosage given to each group. Significant differences in physiologic thresholds were observed for both timing of the daily dosage (p < 0.05). and the 2, 4 and 6 week testings (p < 0.001). After 2 weeks, the 8A group showed an average hearing loss of 11.5 dB at 32 kHz, with the other timed treatment groups exhibiting minimal effects (3.0–6.5 dB). For the 8A group at this frequency, the loss progressed at 4(19.5 dB) and 6 (22.5 dB) weeks. The 2P group after 4 weeks exhibited similar losses as the 8A group for this frequency, with the loss at 6 weeks being even greater (34.0 dB). The 8P and 2A groups exhibited only slight losses over all frequencies. Waveform latencies for the ABR using and 80 dB stimulus at each test frequency indicated the site of losses as cochlear in origin. Ototoxicity was greater for kanamycin when given to the rodents during their diurnal rest span (8A and 2P) in comparison to their nocturnal activity span (8P and 2A).

Key Words:

• ototoxicity
• kanamycin
• circadian rhythm