Berit Engström

The ototoxic effect of cisplatin on guinea pigs in relation to dosage.

The effect on the electrophysiological hearing thresholds and the endocochlear DC potential (EP) was studied in four groups of guinea pigs receiving different doses of cisplatin. By multiple low-dose intraperitoneal injections a permanent hearing loss was produced without a permanent decrease of the EP. On the other hand, when cisplatin was given as a single high-dose intravenous injection, there was an impairment of the electrophysiological hearing thresholds and EP, depending upon the level of cisplatin dose. It is concluded that cisplatin-induced hearing loss is not necessarily a sequela to a loss of EP.

Eighth nerve fiber firing features in normal-hearing rabbits

Neural activity of single eighth nerve fibers was recorded with glass microelectrodes in anesthetized normal-hearing rabbits. The units had a spontaneous rate ranging from 0 to approximately 120 spikes/s. In a large number of fibers this rate was below 2 spikes/s. The frequency tuning curves (FTCs) had a tip and a tail region for fibers with a high or medium characteristic frequency (CF). For low-frequency units the FTC was more symmetrically U-shaped. The tip threshold reached the behavioral threshold and units with thresholds of up to more than 60 dB above the mean behavioral threshold were found. There was a weak negative correlation between spontaneous rate and tip threshold. Frequency selectivity, Q10, was about 2 for units with CF below 2 kHz and about 5 for those with CF above 4 kHz. The peristimulus time (PST) histogram showed an initial peak, a plateau, and poststimulus inhibition. For the majority of fibers the dynamic range was 20-30 dB. Some fibers did not reach saturation within the stimulus intensity available. The tip-to-tail distance was 50 dB for high-frequency units at one octave below CF, a matter of potential interest for further studies of animals with inner ear lesions.

Distribution of cisplatin in perilymph and cerebrospinal fluid after intravenous administration in the guinea pig

The concentration of free cisplatin was followed in plasma, scala tympani perilymph and cerebrospinal fluid (CSF) after an intravenous injection (12.5 mg/kg) in guinea pigs. Liquid chromatography with postcolumn derivatization was used for quantitative determination of the drug. The distribution of cisplatin to CSF was fast; at 10 min after drug administration the concentration was 7 μg/ml and the CSF:plasma ratio was 0.37. Cisplatin seems to distribute more slowly to the perilymphatic compartment. The highest concentration measured was 4 μg/ml at 20 min after the injection, and the perilymph:plasma ratio was 0.40 at that time. The concentration-time curves generated for cisplatin in perilymph and CSF were similar. No accumulation in the perilymphatic compartment or CSF was observed.

Noise level, inner hair cell damage, audiometric features, and equal‐energy hypothesis

Rabbits were exposed to 2- to 7-kHz noise either for a short duration at a high sound-pressure level (15 or 30 min at 115 dB SPL), or a long duration at a low level (512 h at 85 dB SPL). The high-level exposure produced a hearing loss in the frequency range 2-6 kHz, whereas the low-level exposure gave maximum hearing loss at 12-20 kHz. The 115-dB exposure caused significantly more damage to inner hair cells than the 85-dB exposure. The implications of the present results for evaluating audiograms, equal-energy hypothesis, risk criteria, and subjective auditory features are pointed out.

The Effect of Topical Application of Vasodilating Agents on Cochlear Electrophysiology

The aim of this investigation was to study whether increased blood flow has beneficial effects on the ear or whether it is damaging to the auditory function, expressed as the auditory gross neural response. Four vasodilating agents were examined after topical application with respect to their influence on cochlear blood flow (CBF), blood pressure, and auditory function in the normal guinea pig. CBF was recorded with laser-Doppler. The drugs used were sodium nitroprusside, hydralazine, nicotinic acid and histamine. Sodium nitroprusside and hydralazine increased CBF and induced concentration dependent loss of auditory function. Neither nicotinic acid nor histamine had any effect on CBF. Nicotinic acid had varying effects: in some cases a negative influence on threshold shifts was seen, and in others a positive one. In most cases histamine caused improvement of the auditory function. The data indicate that topical administration of drugs to the inner ear is effective to influence both CBF and auditory function.

Cochlear morphology in relation to loss of behavioural, electrophysiological, and middle ear reflex thresholds after exposure to noise

Loss of auditory function was correlated with different pathological findings in the inner ear of the rabbit after 15 or 30 min exposure to high level broad band (2-7 kHz) noise. The ears from animals with post-exposure times ranging from 1 to 23 months were analysed by scanning electron microscopy (SEM). Complete cochleograms with quantification of loss of hair cells and damage to stereocilia were produced. Loss of function was defined by determining behavioural threshold, threshold of auditory brainstem response (ABR) to narrow-band stimuli and threshold of the middle ear muscle reflex (MER). A small scattered loss of OHCs and slight disarray of stereocilia were found in non-exposed ears of young animals, but fusion of IHC cilia was not observed. Normal auditory function was not found in any noise exposed animal with abnormal morphology. A loss of threshold sensitivity of up to about 30-40 dB was noted without loss of hair cells in the corresponding region of the cochlea. The mildest structural damage that correlated to a functional alteration consisted of damage to stereocilia of IHC. This correlated well to the MER threshold shift. In two animals a shift of MER threshold of about 20 dB was the only functional abnormality. In ears with more extensive IHC damage loss of OHCs was also found and these animals had primarily an increase in auditory threshold shift with only a small additional change in MER threshold. It is concluded that in the rabbit and with the methods used the IHC stereocilia are the structures most susceptible to damage by the noise used and that the degree of injury can be fairly well assessed by functional tests of a type that is used also routinely in the audiological clinic.

The combined effect of cisplatin and furosemide on hearing function in guinea pigs

The effect of the combined administration of cisplatin and furosemide on the electrophysiological hearing thresholds and endocochlear DC potential (EP) was studied in guinea pigs. A lack of interaction was found in animals given repeated intraperitoneal injections of a low dose of cisplatin with a pharmacological dose of furosemide. An ototoxic interaction occurred when a moderately high dose of cisplatin was administered intravenously at a time when the strial function was most affected by a very high dose of furosemide. The interaction was seen both as a decreased EP and a pronounced shift of auditory thresholds. It is concluded that the stria vascularis plays a role in the ototoxic mechanism of cisplatin.

An Ultrastructural and Functional Study of the Inner Ear after Administration of Hyaluronan into the Middle Ear of the Guinea Pig

A single dose of hyaluronan, 19 mg/ml was administered into the right middle ear cavity of guinea pigs. The auditory function of the right ear was tested by recording the gross neural action potential (N1) before, directly after, and 28 days after the administration of hyaluronan. In a control group the right ear was sham-operated and the gross neural action potential (N1) was recorded twice; on the day of the sham operation and 28 days later. All animals were killed 28 days after the operation. All treated as well as sham-operated ears and every second intact ear were studied by scanning electron microscopy (SEM.) No ear had signs of hearing deterioration. Macroscopically, most of the hyaluronan was eliminated from the middle ear after 28 days. In the histological examination, pathological stereocilia were found in the apical turn of the cochlea in the ears to which hyaluronan was administered, the sham operated and the intact ears.

Freeze fracturing of the human stria vascularis.

The stria vascularis is an important functional element in the mammalian cochlea. This special tissue is considered to be the source of the endocochlear potential and thus the driving force for the production of a receptor response to the auditory stimulus. In order to maintain its function, the stria vascularis needs to be separated from the endolymphatic space by a tight seal. This seal is comprised of tight junctions in the marginal cell layer. The junctional arrangement in the stria vascularis is described, utilizing the freeze-fracturing technique which allows the visualization of large expansions of plasma membrane. The marginal cells are generally separated by tight junctions of the moderately tight to tight type. In places, however, even so-called leaky junctions with only a few sealing strands are present. Whereas the intermediate cell layer seems to lack tight junctions, the basal cells are connected by extensive tight junctions more or less covering the entire cell. These junctions seem to form an extremely tight barrier against the spiral ligament. Gap junctions are also present in the tissue. Intermediate cells as well as the basal cells are coupled by gap junctions. In the basal cell layer, gap junctional elements may also be found inside the large tight junctions comprising so-called mixed junctions.

Selected pathological findings in the human cochlea.

Out of a material of 45 patients with known audiograms where the inner ears had been fixed with an aldehyde within 7 h after death, 4 cases were chosen for detailed morphological examination. The general findings in the ageing human cochlea are presented as well as the findings in the 4 specific cases.