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The outer hair cell electromotile response is believed to underlie the sharp tuning and exquisite sensitivity of the mammalian inner ear, and contribute to the production of electrically evoked otoacoustic emissions (EEOAEs) and sound-evoked otoacoustic emissions (OAEs). Avian ears are also sharply tuned, extremely sensitive and generate spontaneous and sound-evoked OAEs, but avian hair cells do not exhibit somatic electromotility. However, stereocilia bundle movements have been observed in avian and amphibian hair cells suggesting that EEOAEs might arise from electrically evoked bundle movements. Here, we demonstrate for the first time that AC current applied to the round window of the chicken evokes EEOAE of up to 18 dB SPL. The EEOAE produces a bandpass response with maximum amplitude in the 1000-3000 Hz range; the response drops off rapidly above 4000 Hz and below 500 Hz. The impulse response to current pulses is characterized by a large peak sometimes followed by a damped oscillation with a frequency around 2000 Hz. EEOAEs decreased significantly after anoxia and paraformaldehyde damage of the cochlea. Kanamycin-induced hair cell loss also caused a significant reduction in EEOAE and distortion product OAE; these emissions showed only a small recovery at long recovery times, when most hair cells should have regenerated. These results suggest that the EEOAE has a biological origin in the cochlea, which could presumably involve electrically evoked stereocilia bundle movements.

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The availability of genetic information, transgenic and knock-out animals make the mouse a primary model in biomedical research. Aminoglycoside ototoxicity, however, has rarely been studied in mature mice because they are considered highly resistant to the drugs. This study presents models for kanamycin ototoxicity in adult CBA/J, C57BL/6 and BALB/c mouse strains and a comparison to Sprague-Dawley rats. Five-week-old mice were injected subcutaneously twice daily with 400-900 mg kanamycin base/kg body weight for 15 days. Kanamycin induced dose-dependent auditory threshold shifts of up to 70 dB at 24 kHz as measured by auditory brain stem-evoked responses. Vestibular function was also affected in all strains. The functional deficits were accompanied by hair cell loss in both cochlear and vestibular neurosensory epithelia. Concomitant administration of the antioxidant 2,3-dihydroxybenzoate significantly attenuated the kanamycin-induced threshold shifts. In adult male Sprague-Dawley rats, doses of 1 x 500 mg or 2 x 300 mg kanamycin base/kg body weight/day x 14 days induced threshold shifts of approximately 50 dB at 20 kHz. These were accompanied by loss of outer hair cells. The order of susceptibility, BALB>CBA>C57, was not due to differences in the pharmacokinetics of kanamycin. It also did not correlate with the presence of Ahl/Ahl2 genes which predispose C57 and BALB strains, respectively, to accelerated age-related hearing loss. Pigmentation, however, paralleled this rank order suggesting an influence of melanin on cochlear antioxidant status.

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Although clinical observations suggest that males are more susceptible than females to ototoxic drugs, controlled experimental studies investigating gender susceptibility have not been performed. Aminoglycosides initially attack the cochlea's outer hair cells (OHCs). We investigated the effects of the aminoglycoside, kanamycin, on electrophysiological function of OHCs in male and female rats. Animals were grouped by gender and treated with kanamycin (400 mg/kg/day kanamycin base, intramuscular injection) or equivolume normal saline. Administration was continued until distortion product otoacoustic emissions (DPOAEs) suggested a loss in OHC function in kanamycin-treated rats. Males treated with kanamycin showed changes in DPOAE thresholds and amplitudes as early as treatment day 10 which spread to all test frequencies by treatment day 13. In contrast, females treated with kanamycin did not show significant changes in thresholds or amplitudes until treatment day 22. The mechanism of increased male susceptibility to kanamycin cochleotoxicity has not been determined.

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Measurement of distortion-product otoacoustic emissions (DPOAE) is widely accepted as one of the most valuable tools for evaluating the frequency of specific cochlear pathology. Previous studies have revealed that distortion-product levels in the ear canal are definitely correlated with degree of damage in the cochlea. However, there seem to be no clear data of help in predicting the distribution and grade of damage in the cochlea quantitatively on the basis of the results of this non-invasive test. The present study is designed to assess correlations between degree of outer hair cell (OHC) damage by a potent ototoxic antibiotic, kanamycin, and DPOAE levels at the characteristic frequency at the site. Guinea pigs were used after daily intramuscular administration of kanamycin for 7 or 10 days. DPOAE levels were measured using a system (CUBDIS: Etymotic Research) with 78 frequency combinations of iso-intensity primaries from 0.5kHz to 16kHz of f2. The frequency ratio (f2/f1) was set at 1.2. Distortion-product level plots versus f2 (DP-grams) were constructed. The integrity of the OHC system was evaluated histologically by the succinic dehydrogenase (SDH) method under a light microscope. Cochleograms were constructed by calculating percentages of intact OHCs along the basilar membrane in 1-mm blocks. The DP-grams and the histopathological cochleograms showed essentially identical patterns in the kanamycin-damaged guinea pig cochlea. The results suggest that: 1) The generation of DPOAE requires functioning OHCs. 2) DPOAE measurement provides information allowing prediction of OHC damage distribution in the cochlea without histological investigations. 3) Careful setting of primary levels and other parameters is necessary to reliably predict the pathology. 4) Attempts to detect of minimal OHC damage could fail. 5) DPOAE seem very useful for monitoring cochlear function in clinically.

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The effect of calcium pantothenate (CPN)B 4'-phospho-CPN (PCP), pantetheine (PT) and calcium S-sulfopantetheine (SPN) on acute toxicity of kanamycin sulfate was studied on albino mice. The above derivatives of pantothenic acid except PT lowered the antibiotic toxicity. The coefficient of the antitoxic effect (LD50/ED50) of SPN and PCP was 1.3-1.4 times higher than that of CPN. The combined use of kanamycin (1/5 of the LD50) with CPN, PCP or PT (30 mg/kg bw was equivalent to CPN) for 15 days prevented the increase in the total content of CoA and in the content of the fraction of free CoA and the precursors of its biosynthesis participating in the reaction of N-acetylation in the liver and brain. The contents of these substances were within the normal during the whole experiment. A certain increase in the activity of pantothenate kinase in the liver cytosol due to the use of kanamycin was eliminated by the simultaneous use of PCP and PT. The vitamin-containing compounds PCP and SPN were recommended for the clinical trials as agents preventing complications of kanamycin therapy.

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The endocochlear dc potential (EP) was measured in normal guinea pigs and in a group poisoned with kanamycin sulfate for 60 minutes after the administration of furosemide intravenously (IV) or by perfusion into the scala tympani. The EP decreased rapidly and developed a large negative potential after IV administration of furosemide, but the EP decreased more slowly and did not develop a negative potential in kanamycin-poisoned animals. With perfusion of the scala media, the EP declined slowly and did not develop a large negative potential in either group. With perfusion of the scala tympani, the EP declined slowly in the kanamycin-poisoned animals and did not develop a large negative potential, while in the normal animals the EP declined rapidly and developed a large negative potential.

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The following hypothesis is presented: A dysfunction of the hair cell cilia, either in the form of ciliary pathology or as a temporary loss of ciliary stiffness, both of which are documented, ought to lead to a partial decoupling of the involved hair cells from the tectorial membrane. Consequently, 1) energy transmission should be attenuated (= hearing loss), 2) the noise level at the hair cell input should be increased (= tinnitus) and, owing to the concomitant center-clipping of the signal waveform, 3) the input/output function should become steeper (= recruitment) and 4) the formant structure of speech should be largely destroyed (= relatively poor speech discrimination). The above signs and symptoms are characteristic of a number of acute cochlear disorders and would thus find a common explanation.

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The structural ototoxic effect of kanamycin during intrauterine life has been shown in guinea pigs. The extent of the loss mostly affected the outer hair cells of the basal part of the cochlea. Ultrastructural studies demonstrated a hair cell degeneration pattern similar to that previously described in adult animals following antibiotic intoxication.

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