Too much of a good thing: long-term treatment with salicylate strengthens outer hair cell function but impairs auditory neural activity

Abstract

Aspirin has been extensively used in clinical settings. Its side effects on auditory function, including hearing loss and tinnitus, are considered as temporary. A recent promising finding is that chronic treatment with high-dose salicylate (the active ingredient of aspirin) for several weeks enhances expression of the outer hair cell (OHC) motor protein (prestin), resulting in strengthened OHC electromotility and enhanced distortion product otoacoustic emissions (DPOAE). To follow up on these observations, we carried out two studies, one planned study of age-related hearing loss restoration and a second unrelated study of salicylate-induced tinnitus. Rats of different strains and ages were injected with salicylate at a dose of 200 mg/kg/day for 5 days per week for 3 weeks or at higher dose levels (250-350 mg/kg/day) for 4 days per week for 2 weeks. Unexpectedly, while an enhanced or sustained DPOAE was seen, permanent reductions in the amplitude of the cochlear compound action potential (CAP) and the auditory brainstem response (ABR) were often observed after the chronic salicylate treatment. The mechanisms underlying these unexpected, permanent salicylate-induced reductions in neural activity are discussed.

Fig. 1. The effects of a chronic salicylate treatment on DPOAE in rats of different strain and age

(A): DPOAE amplitudes as a function of stimulation intensity (L₂) at 12 kHz (F₂) in a group of young adult Sprague–Dawley (SD) rats (3 months, n=6). Salicylate treatment: 200 mg/kg/day for 5 days per week for 3 weeks; DPOAE recording: prior to and 4 weeks after the 3-week salicylate treatment; (B) DPOAE amplitudes at a stimulation level of 50 dB SPL (L₂) as a function of frequency (F₂) in the same animals as in (A); (C): DPOAE amplitudes at a stimulation level of 50 dB SPL (L₂) as a function of frequency (F₂) in the young Fischer 344 (F344) rats (3 months) receiving salicylate treatment (n=3) or saline injections (n=3). Salicylate treatment was the same as in (A); DPOAE recording: prior to and 4 days after the 3-week treatment; (D): DPOAE amplitudes at a stimulation level of 50 dB SPL (L₂) as a function of frequency (F₂) in the aged F344 rats (18 months) receiving salicylate treatment (n=6) or saline injections (n=6). Salicylate treatment was the same as in (A); DPOAE recording was the same as in (C); (E): DPOAE amplitudes at a stimulation level of 50 dB SPL (L₂) at 8, 12, and 16 kHz (F₂) as a function of time in a group of young adult SD rats (3 months, n=8). In the first week, three of them were treated with salicylate at 250 mg/kg/day, three at 300 mg/kg/day, and two at 350 mg/kg/day for 4 days and in the second week, all the animals received salicylate injection at 300 mg/kg/day for 4 days. The vertical bars represent standard errors (SE).

Fig. 2

The permanent effects of the chronic salicylate treatment on ABRs in a group of young adult SD rats (n=6). (A): ABR amplitudes as a function of stimulation level at 12 kHz; (B): ABR amplitudes at a stimulation level of 100 dB SPL as a function of frequency. Salicylate treatment: 200 mg/kg/day for 5 days per week for 3 weeks; ABR amplitude: N3-P3; ABR was measured prior to, 3 days, 2 weeks, and 4 weeks after the 3-week salicylate treatment. The vertical bars represent SE.

Fig. 3. The effects of the chronic salicylate treatment on CAP in rats of different strain and age

(A): CAP amplitudes as a function of stimulation level at 16 kHz in the young adult SD rats (3 months, n=6 in each group). Salicylate treatment: 200 mg/kg/day for 5 days per week for 3 weeks; CAP recording: 4 weeks after the last salicylate treatment; (B) CAP amplitudes at a stimulation level of 70 dB SPL as a function of frequency in the same animals as in (A); (C): CAP amplitudes at a stimulation level of 70 dB SPL as a function of frequency in the young F344 rats (3 months, n=3 in each group). Salicylate treatment and CAP recording were the same as in (A); (D): CAP amplitudes at a stimulation level of 70 dB SPL as a function of frequency in the aged F344 rats (18 months, n=6 in each group). Salicylate treatment and CAP recording were the same as in (A); (E): CAP amplitudes at a stimulation level of 90 dB SPL at 8, 20, and 40 kHz as a function of total salicylate injection (mg/kg) in a group of young adult SD rats (3 months, n=8) during 2 weeks. The vertical bars represent SE.

Fig. 4

Cochleogram in rats chronically exposed to salicylate (200 mg/kg/day for 5 days per week for 3 weeks). The vertical bars represent SE.