Auditory Brainstem Response Threshold Shifts Research Articles

Effects of delayed and extended antioxidant treatment on acute acoustic trauma

Objective: Hair cell death caused by acute acoustic trauma (AAT) reaches a secondary maximum at 7–10 days after noise exposure due to a second oxidative stress. Therefore, this study tested the effects of a combination of hydroxylated alpha-phenyl-tert-butylnitrone (4-OHPBN), N-acetyl-L-cysteine (NAC) and acetyl-L-carnitine (ALCAR) on AAT when the duration of treatment was extended over the period of 7–10 days after noise exposure as well as when the initial treatment was delayed 24 to 48 h after noise exposure. Methods: Thirty chinchilla were exposed to a 105 dB octave-band noise centred at 4 kHz for 6 h and received the following treatments: (1) noise + saline (2–5) 4-OHPBN (20 mg/kg) + NAC (50 mg/kg) + ALCAR (20 mg/kg) intraperitoneally injected beginning 24 or 48 h after noise exposure twice daily for the next 2, 8 or 9 days. Auditory brainstem response (ABR) threshold shifts, outer hair cell (OHC) counts and organ of Corti immunohistochemistry were analyzed. Results: The combination administration decreased ABR threshold shifts, inhibited OHC loss and reduced 4-hydroxynonenal (4-HNE) immunostaining. Significant decreases in the threshold shifts and reduction in OHC loss were observed with a shorter delay before starting treatment (24 h) and longer duration (9 days) treatment. Conclusions: These results demonstrate that the administration of antioxidant drugs extended up to 10 days after noise exposure can effectively treat AAT in a chinchilla model. This may provide significant and potentially clinically important information about the effective therapeutic window for AAT treatment.

Adenosine kinase inhibition in the cochlea delays the onset of age-related hearing loss

This study was undertaken to determine the role of adenosine signalling in the development of age-related hearing loss (ARHL). We and others have shown previously that adenosine signalling via A 1 receptors is involved in cochlear protection from noise-induced cochlear injury. Here we demonstrate that enhanced adenosine signalling in the cochlea provides partial protection from ARHL in C57BL/6J mice. We targeted adenosine kinase (ADK), the key enzyme in adenosine metabolism, using a treatment regime with the selective ADK inhibitor ABT-702 (1.5 mg/kg intraperitoneally twice a week) commencing at the age of three months or six months. This treatment, intended to increase free adenosine levels in the cochlea, was maintained until the age of nine months and hearing thresholds were evaluated monthly using auditory brainstem responses (ABR). At nine months, when C57BL/6J mice normally exhibit significant ARHL, both groups treated with ABT-702 showed lower ABR threshold shifts at 10 and 16 kHz compared to control animals receiving the vehicle solution. The better thresholds of the ABT-702-treated mice at these frequencies were supported by increased survival of hair cells in the apical region of the cochlea. This study provides the first evidence that ARHL can be mitigated by enhancing adenosine signalling in the cochlea.

Systemic Erdosteine against Cisplatin‐Induced Ototoxicity

Objective: Cisplatin is a commonly used chemotherapeutic agent. One of its major dose limiting side effects is ototoxicity. No treatment has yet been approved for this condition. The objective of this study was to determine the potential protective effect of a systemic administration of erdosteine against cisplatin-induced ototoxicity. Method: Guinea pigs were assigned to 4 groups, each receiving a different concentration of intraperitoneal erdosteine: 0, 100, 200, and 500 mg/kg/d for 4 days. All of the animals received 12 mg/kg/d of intraperitoneal cisplatin. Auditory brainstem response (ABR), scanning electron microscopy, and outer hair cell counts were performed. Results: Significant otoprotection was observed in groups receiving 200 and 500 mg/kg/d of erdosteine as demonstrated by high frequency (25 kHz) ABR threshold shifts. These findings are supported by outer hair cell counts by scanning electron microscopy. Guinea pigs receiving 100 mg/kg/d did not present otoprotection. Conclusion: A systemic administration of erdosteine appears to provide a significant otoprotective effect at the basal area of the cochlea for cisplatin-induced ototoxicity in a guinea pig model.

Micellization of cisplatin (NC-6004) reduces its ototoxicity in guinea pigs

Nanocarriers potentially reduce or prevent chemotherapy-induced side effects, facilitating the translation of nanocarrier formulation into the clinic. To date, organ-specific toxicity by nanocarriers remains to be clarified. Here, we studied the potential of polymeric micelle nanocarriers to prevent the ototoxicity, which is a common side effect of high-dose cisplatin (CDDP) therapy. In this study, we evaluated the ototoxicity of CDDP-incorporating polymeric micelles (NC-6004) in guinea pigs in comparison with that of cisplatin. Their auditory brainstem responses (ABRs) to 2, 6, 12, 20, and 30 kHz sound stimulation were measured before and 5 days after the drug administration. Groups treated with NC-6004 showed no apparent ABR threshold shifts, whereas groups treated with CDDP showed dose-dependent threshold shifts particularly at the higher frequencies. Consistent with the ABR results, groups treated with NC-6004 showed excellent hair-cell preservation, whereas groups treated with CDDP exhibited significant hair-cell loss ( P < 0.05). Synchrotron radiation-induced X-ray fluorescence spectrometry imaging demonstrated that the platinum distribution and concentration in the organ of Corti were significantly reduced ( P < 0.01) in guinea pigs treated with NC-6004 compared with guinea pigs treated with CDDP. These findings indicate that micellization of CDDP reduces its ototoxicity by circumventing the vulnerable cells in the inner ear.

Therapeutic efficacy of topical application of dexamethasone to the round window niche after acoustic trauma caused by intensive impulse noise in guinea pigs

To assess the therapeutic efficacy of dexamethasone administered topically to the round window niche, following acoustic trauma induced by intensive impulse noise, in guinea pigs. Adult, male, albino guinea pigs with a normal Preyer's reflex were exposed to 80 impulse noises (peak value 167 dB, duration 0.5 ms, interval 2 s). Dexamethasone (40 mg/ml) or saline was then topically applied to the round window niche. Each animal's auditory brainstem response was measured before and one day after exposure, and three weeks after topical treatment. Cochlear morphology was examined to assess hair cell loss and spiral ganglion cell damage. To assess oxidative activity, cochlear malondialdehyde and superoxide dismutase concentrations were determined three weeks post-treatment. Following topical application, the pharmacokinetic characteristics of dexamethasone in cochlear perilymph were analysed using high-performance liquid chromatography. Animals receiving dexamethasone showed reduced noise-induced outer hair cell loss (three weeks post-treatment), and significant attenuation of noise-induced auditory brainstem response threshold shifts (one day post-exposure and three weeks post-treatment), compared with controls. There was no difference in spiral ganglion morphology. Animals receiving dexamethasone also showed a significantly lower malondialdehyde concentration and a higher superoxide dismutase concentration, post-exposure. Following topical application, the perilymph dexamethasone level peaked at 5330.522 µg/ml (15 minutes post-treatment), and was 299.797 µg/ml 360 minutes later. Topical application of dexamethasone to the round window niche has protective effects against intensive impulse noise induced trauma in the guinea pig cochlea. This drug can diffuse into the inner ear through the round window membrane and persist in the perilymph for a relatively long period. The mechanism of protection may involve an anti-oxidant effect.

Oxidative stress in spiral ganglion cells of pigmented and albino guinea pigs exposed to impulse noise

Conclusions: The results suggest that melanin inhibits formation of reactive oxygen species (ROS) and prevents apoptosis in spiral ganglion cells (SGCs) of pigmented guinea pigs following impulse noise. Objective: The stria vascularis of pigmented guinea pig cochlea contains melanocytes that produce melanin, which has a protective effect on noise-induced hair cell damage through its antioxidant property. ROS are involved in cochlear damage induced by impulse noise trauma. The purpose of the present study was to investigate the oxidative stress in SGCs of pigmented and albino guinea pigs after exposure to impulse noise. Methods: Pigmented and albino guinea pigs were exposed to impulse noise. Auditory thresholds were assessed by sound-evoked auditory brainstem response (ABR) before impulse noise exposure and 72 h after impulse noise exposure. 4-Hydroxynonenal (HNE) was used as a histochemical marker of ROS formation, and active-caspase-3 (cas-3) served as a marker for apoptosis. 4-HNE and cas-3 were determined immunohistochemically. Hair cell damage was analyzed by scanning electron microscopy. Results: The rates of 4-HNE-positive and cas-3-positive SGCs in pigmented guinea pigs were much less than those for albino guinea pigs. Correspondingly, there was less hair cell damage and reduced ABR threshold shifts in pigmented guinea pigs.

Evaluation of the Effect of Acetyl L-Carnitine on Experimental Cisplatin Ototoxicity and Neurotoxicity

Introduction: Cisplatin (CDDP) is an effective and widely used chemotherapeutic agent for pediatric tumors, and ototoxicity is one of the dose-limiting side effects. Objective: It was the aim of our study to investigate the effect of acetyl L-carnitine (ALCAR) on experimental CDDP ototoxicity by audiologic tests, histomorphologic, immunohistochemical and ultrastructural examinations and to investigate the apoptotic pathways. Materials and Methods: Wistar albino rats (n = 28) were studied. Baseline audiological tests were performed in 4 groups: group 1, control; group 2, ALCAR; group 3, CDDP; group 4, CDDP + ALCAR-administered rats. Control audiological tests were performed on the 3rd day, and then the rats were sacrificed. Ear and brain specimens were examined by transmission electron microscopy, and caspase 3, 8 and 9 activities were investigated. Results: The CDDP-administered rats showed significant auditory brainstem response threshold shifts using all stimuli (clicks, 6-kHz and 8-kHz tone burst) compared with the control groups. The CDDP + ALCAR-administered rats showed significant auditory brainstem response threshold shifts by only click stimuli compared with the control groups. In the brain, spiral ganglion and organ of Corti, ultrastructural damage was prominent in group 3; the number of TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling)-positive cells and caspase 3, 8 and 9 immunostaining cells was significantly high in group 3. Conclusion: ALCAR improves CDDP-induced auditory impairment, and also antioxidative and antiapoptotic properties of ALCAR on CDDP ototoxicity were supported by the findings.

Conservation of endocochlear potential in mice with profound hearing loss induced by co-administration of kanamycin and furosemide

Research in mammalian hair cell regeneration is hampered by a lack of in vivo model of adult mouse inner ear injury. In the present study we investigated the effects of a combination of a single dose of aminoglycoside followed by a loop diuretic in adult mice. The auditory brainstem response threshold shift, extent and defining characteristics of the cochlear lesion were assessed and verified at different time points post-treatment. Our data indicated that this drug combination caused the rapid and extensive death of outer hair cells (OHCs). OHC death presented throughout the cochlea that commenced in the basal turn by 24 h and progressed apically. In contrast, inner hair cell (IHC) loss was delayed and mild. Terminal deoxynucleotidyl transferase dUTP nick end labelling-positive nuclei demonstrated that the majority of OHCs died via an apoptotic pathway. Auditory threshold shifts of up to 90 dB SPL indicated a profound hearing loss. In addition, the endocochlear potential (EP) in the drug-treated animals displayed a significant decline at 12 h post-treatment followed by recovery by 48 h post-treatment. Despite this recovery, there was a significant and progressive decrease in strial vascularis thickness, which was predominantly due to atrophy of marginal cells. The present study reproduced an adult mouse model of aminoglycoside-induced hearing loss. The mechanism underlying the recovered EP in the model with extensive hair cell death is discussed.

Differential Effects of Salicylate, Quinine, and Furosemide on Guinea Pig Inner and Outer Hair Cell Function Revealed by the Input–Output Relation of the Auditory Brainstem Response

Sensory hearing loss is predominantly caused by the destruction of cochlear outer hair cells (OHCs), inner hair cells (IHCs), or spiral ganglion cells (SGCs). There have been a number of attempts to differentiate between these etiologies of hearing loss, using various psychoacoustic and physiologic paradigms. Here we investigate the potential of the auditory brainstem response (ABR) input/output function for such differential diagnosis. On the basis of the saturation of the OHC-based cochlear amplifier, it was hypothesized that selective impairment of OHCs would reduce ABR amplitudes at low to moderate but not at high sound levels. Selective impairment of IHCs or SGCs would reduce ABR amplitudes more or less uniformly across sound level. Finally, a mix of OHC and IHC or SGC impairment would reduce ABR amplitudes at all sound levels but less so at high levels depending on the relative contribution of OHC impairment to the hearing loss. To test these hypotheses, normal-hearing adult guinea pigs were intravenously injected with either salicylate, furosemide, or quinine, under ketamine anesthesia. ABRs, as well as distortion-product otoacoustic emissions (DPOAEs), were measured as a function of the sound stimulus level before and after drug injection. Following salicylate injection, ABR amplitudes were reduced only at low-moderate stimulus levels. Following furosemide or quinine injection, ABR amplitudes were reduced at all levels but less so at high ones. This is in accord with the expectation that acute salicylate administration selectively affects the OHCs, while furosemide and quinine affect both OHCs and IHCs/SGCs. Such differential diagnosis was not possible solely on the basis of DPOAE amplitudes, which were unchanged at high stimulus levels after the injection of each of the three drugs. Comparison of ABR and DPOAE threshold shifts could also differentiate the effects of salicylate from those of furosemide and quinine but could not, for example, unequivocally point to salicylate's selective impairment of OHCs. ABR amplitudes appear suitable for differentiating between damage to OHCs and IHCs/SGCs, at least in a controlled experimental setting where pre- and postmanipulation data are available. This could be useful for noninvasively testing the effects of drugs or acoustic overstimulation on the cochlea, at least in the laboratory. Clinical applicability would seem to be limited by the high variability in ABR amplitudes among normal-hearing humans but might be feasible in the future if regular ABR testing entered into routine clinical practice.

Changes in auditory brainstem response (ABR) in Kanamycin-induced auditory disturbance model rats

This study was designed to evaluate changes in auditory brainstem response (ABR) in the course of auditory disturbance in rats induced by Kanamycin (KM). KM was administered subcutaneously to 12 CD (SD) male rats aged 6 weeks for 10 days at a dose of 800 mg/kg. Death was observed in one male on day 8 and 2 males on day 10. It was thought that kidney damage was the cause of death from histopathological findings. ABR was recorded before KM treatment and on days 4, 8, 10 and 11 after KM treatment. The ABR changes after KM treatment in rats were as follows. On day 4, 6 rats showed an increase in amplitude of waves I and/or II and on day 8, among those, 4 rats still showed a high amplitude of waves I and/or II. On day 8, 2 rats showed an elevation of ABR threshold (15-40 dB SPL) and a decrease in amplitude of wave I and increase in amplitude of wave II at the same time. On day 11, 7 rats showed a decrease in amplitude of wave I. In addition, ABR threshold shifts (10-70 dB SPL) were observed in those rats. In ABR recording, KM-induced auditory disturbance model rats showed an increase in amplitude of waves I and/or II earlier than an ABR threshold shift. By analyzing temporal alteration of amplitude of the ABR components, we could detect precursory phenomenon of the auditory disturbance at an early phase of treatment. By following the pathway of click-ABR and tone pip-ABR examination, the auditory disturbance of low- frequency to high-frequency range could be analyzed at an early date in detail.

Protective Effects of α-Tocopherol on ABR Threshold Shift in Rabbits Exposed to Noise and Carbon Monoxide.

Noise induced hearin gloss (NIHL) is one of the most important occupational disease world wide. NIHL has been found potentiate by simultaneous carbon monoxide (CO) exposure. Free radicals have been implicated in cochlear damage resulted from the exposure to noise and due to the CO hypoxia. This study examined whether α-tocopherol administration , as a free radical scavenger, causes the attenuation of auditory brainstem response (ABR) threshold shifts resulting from noise exposure and noise plus CO exposure. Forty-two rabbits were divided in to seven groups including control, noise + saline, noise + CO + saline, noise + α-tocopherol, noise + CO + α-tocopherol , CO + α-tocopherol and α-tocopherol alone. ABR was assessed before exposure, 1 hand 14 days post exposure. The administration of 50 mg/Kg of α-tocopherol prior, following and post exposure to noise or noise plus CO recovered permanent ABR threshold shift at 1 and KHz almost to the baseline and provided significant attenuation in permanent ABR threshold shift at 4 and 8 KHz in subject swhich were exposed to noise but it did not block the potentiating of threshold elevation by CO exposure (extra threshold loss by combined exposure) at 4 and 8 KHz. α Tocopherol provides protective effect against the hearing loss resulting from noise exposure and simultaneous exposure to noise plus CO.

Effect of epithelial stem cell transplantation on noise-induced hearing loss in adult mice

Noise trauma in mammals can result in damage to multiple epithelial cochlear cell types, producing permanent hearing loss. Here we investigate whether epithelial stem cell transplantation can ameliorate noise-induced hearing loss in mice. Epithelial stem/progenitor cells isolated from adult mouse tongue displayed extensive proliferation in vitro as well as positive immunolabelling for the epithelial stem cell marker p63. To examine the functional effects of cochlear transplantation of these cells, mice were exposed to noise trauma and the cells were transplanted via a lateral wall cochleostomy 2 days post-trauma. Changes in auditory function were assessed by determining auditory brainstem response (ABR) threshold shifts 4 weeks after stem cell transplantation or sham surgery. Stem/progenitor cell transplantation resulted in a significantly reduced permanent ABR threshold shift for click stimuli compared to sham-injected mice, as corroborated using two distinct analyses. Cell fate analyses revealed stem/progenitor cell survival and integration into suprastrial regions of the spiral ligament. These results suggest that transplantation of adult epithelial stem/progenitor cells can attenuate the ototoxic effects of noise trauma in a mammalian model of noise-induced hearing loss.

A combination antioxidant therapy prevents age-related hearing loss in C57BL/6 mice

Objective Age-related hearing loss (ARHL) is characterized by gradual, progressive sensorineural hearing loss, which impairs communication, lending to clinical depression and social withdrawal. There are currently no effective treatments for ARHL. The purpose of this study is to evaluate the potential of a combination antioxidant therapy in preventing ARHL. Study Design Randomized controlled trial. Setting Animal study. Subjects and Methods C57BL/6 mice, a recognized animal model of ARHL, were assigned to one of three groups: early treatment (n = 12), late treatment (n = 9), or control group (n = 9). Treatment groups of mice were fed with a combination agent comprising six antioxidant agents that target four sites within the oxidative pathway: L-cysteine-glutathione mixed disulfide, ribose-cysteine, NW-nitro-L-arginine methyl ester, vitamin B12, folate, and ascorbic acid. Auditory brainstem response (ABR) thresholds were recorded at baseline and every three months following initiation of treatment. Results Threshold shifts from baseline were decreased in the treatment groups when compared to the control group at all tested frequencies ( P < 0.001). The ABR threshold shift at 12 months of age for the control group was 34.7 dB with a 95% confidence interval (CI) of ±1.6. The mean threshold shifts for the early and late treatment groups were 7.5 dB (±0.87, 95% CI) and 9.2 dB (±1.6, 95% CI). Conclusion Combination antioxidant therapy effectively decreased threshold shifts on ABR within an animal model of ARHL. Combination antioxidant therapy, with further research and investigation, may provide a safe and cost-effective method of preventing presbycusis in the growing elderly population.

Protective roles of α-lipoic acid in rat model of mitochondrial DNA4834bp deletion in inner ear

The protective roles of alpha-lipoic acid in the rat model of mitochondrial DNA (mtDNA) 4834bp deletion in inner ear were investigated. Forty female Wistar rats at 4 weeks of age were divided into four groups: group A (D-galactose group, n=10), group B (D-galactose+alpha-lipoic acid group, n=10), group C (alpha-lipoic acid group, n=10), and group D (control group, n=10). Auditory brainstem response (ABR) was used to detect the hearing threshold. Colorimetry was used to analyze activity of superoxide dismutase (SOD) and concentration of malondialdehyde (MDA). The percentage of mtDNA4834bp deletion in inner ear was identified by real-time PCR. There was no significant difference in ABR threshold shift among all groups. The percentage of mtDNA4834bp deletion in group A was higher than that in other groups, but there was no significant difference in percentage of mtDNA4834bp deletion among groups B, C, and D. The activity of SOD in group A was lower than that in other groups. The concentration of MDA in group A was higher than that in other groups. It was concluded that there was no significant hearing loss when the percentage of mtDNA4834bp deletion was lower than 12.5%. Alpha-lipoic acid could prevent the reactive oxygen species (ROS)-induced mtDNA4834bp deletion in inner ear of rats.

Pre-Operative Intravenous Dexamethasone Prevents Auditory Threshold Shift in a Guinea Pig Model of Cochlear Implantation

Aim: To protect hearing during cochlear implantation with systemic administration of dexamethasone. Methods: Seventeen normal-hearing guinea pigs were randomly allocated to receive an intravenous injection of either normal saline (control), low- (0.2 mg/kg) or high- (2 mg/kg) dose dexamethasone 60 min prior to cochlear implantation. Auditory brainstem response (ABR) threshold shifts (2–32 kHz) were estimated between pre- and 4-week-postoperative levels. Results: ABR threshold shifts (8–32 kHz) observed in control and low-dose steroid groups were significantly reduced in the high-dose steroid group. Conclusions: A single, high-dose injection of intravenous dexamethasone protected hearing during cochlear implantation.

Protective effects of exogenous GM-1 ganglioside on acoustic injury of the mouse cochlea

GM-1 ganglioside (GM-1), a glycosphingolipid, is embedded in the lipid layer of neuronal membranes and is one of the neuroprotective agents. To the best of our knowledge, the role of GM-1 has never been examined in hair cell injury. The purpose of this study was therefore to evaluate the effects of GM-1 on acoustic injury of the cochlea. Mice were exposed to 4-kHz pure tone of 128 dB SPL (sound pressure level) for 4 h. GM-1 was intraperitoneally administered immediately before the onset of acoustic overexposure. The threshold shift of the auditory brainstem response (ABR) and hair cell loss were then evaluated 2 weeks after acoustic overexposure. Immunostaining for 4-hydroxynonenal (4-HNE), indicative of lipid peroxidation, was also examined in animals subjected to acoustic overexposure. GM-1 treatment significantly decreased the ABR threshold shifts and hair cell loss after acoustic overexposure. And immunostaining for 4-HNE was reduced by GM-1 treatment. These findings suggest that GM-1 is involved in the protection of the cochlea against acoustic injury through inhibiting lipid peroxidation.

Effects of N-Acetylcysteine on Auditory Brainstem Response Threshold Shift in Rabbits Exposed to Noise and Carbon Monoxide

Problem statement: Noise Induced Hearing Loss (NIHL) is one of the most important occupational disease in worldwide. NIHL has been found to be potentiated by simultaneous Carbon monoxide (CO) exposure. Exposure to noise plus CO is common in occupational and environmental settings. Free radicals have been implicated in cochlear damage resulting from exposure to noise and due to CO hypoxia This study examined whether N-Acetylcysteine (NAC) administration cause attenuation of Auditory Brainstem Response (ABR) threshold shifts resulting from noise exposure and noise plus CO exposure. Approach: Forty-two rabbits were divided into seven groups including control, noise+ saline, noise+ CO +saline, noise+ NAC, noise+ CO+ NAC, CO+ NAC and NAC alone. ABR was assessed before exposure, 1 hour and 14 days post exposure. Results: The administration of 325 mg kg-1 of NAC prior, following and post exposure to noise or noise plus CO recovered permanent ABR threshold shift at 1 and 2 kHz almost to the baseline and provided significant attenuation in permanent ABR threshold shift at 4 and 8 kHz in subjects which were exposed to noise but it did not block the potentiating of threshold elevation by CO exposure (extra threshold loss by combined exposure) at 4 and 8 kHz. Conclusion: NAC provides protective effect against hearing loss resulting from noise exposure and simultaneous exposure to noise plus CO.

Cochlear protection from acoustic injury by inhibitors of p38 mitogen-activated protein kinase and sequestosome 1 stress protein

This study evaluated the protective role of p38 mitogen-activated protein kinase (p38 MAPK) inhibitors and sequestosome 1 (Sqstm1/A170/p62), a stress-induced signal modulator, in acoustic injury of the cochlea in mice. Two weeks after the exposure of mice to acoustic stress, threshold shifts of the auditory brainstem response (ABR) from the pre-exposure level and hair cell loss were evaluated. The activation of p38 MAPK was observed in cochlea by immunostaining 4 h after acoustic stress. To examine the role of p38 MAPK in tissue injury, its inhibitors were i.p. injected into male wild-type C57BL mice before the acoustic overexposure. The inhibitors SB202190 and SB203580 but not the inactive analogue SB202474 dose-dependently decreased the auditory threshold shift and outer hair cell loss induced by acoustic overexposure, suggesting the involvement of p38 MAPK in ototoxicity. We found that acoustic overexposure induced the up-regulation of Sqstm1 mRNA expression in the cochlea of wild-type mice and that SQSTM1-deficient mice exhibited an enhanced ABR threshold shift and hair cell loss, suggesting a role of SQSTM1 in the protection of tissue from acoustic stress.

Study of protective effect on rat cochlear spiral ganglion after blast exposure by adenovirus-mediated human β-nerve growth factor gene

Objective To study whether adenovirus-mediated human β-nerve growth factor (Ad-hNGF β) gene has any protective effect on rat cochlear spiral ganglion after blast exposure. Methods Deafness was induced by blast exposure (172.0 dB) in 20 healthy rats. Seven days after blast exposure, Ad-hNGF β was infused into the perilymphatic space of 10 animals as the hNGF β/blast group, and artificial perilymph fluid (APF) was infused into the perilymphatic space of 10 animals as the APF/blast control group. An additional control group consisted of 10 healthy rats which received Ad-hNGF β target gene with no blast exposure (hNGF β/control group). Auditory functions were monitored by thresholds of auditory brain stem responses (ABR). At weeks 1, 4, and 8 postoperatively, the animals were killed, and the cochleae were removed for immunohistochemical, hematoxylin and eosin staining study. Results The ABR threshold shifts in the hNGF β/blast group were significantly smaller than that of APF/blast control group. There were no significant differences of the ABR values between before and after operation in the hNGF β/control group. Expression of Ad-hNGF β protein was detected in each turn of the cochlea in the first week, with almost equal intensity in all turns. In the fourth week, the reactive intensity decreased. In the eighth week, no reaction was detectable. The results of hematoxylin and eosin stain showed that the number of spiral ganglions in the hNGF β/blast group was significantly greater than that of the APF/blast control group in the 4th week ( P < .01). Conclusion Adenovirus-mediated human β-nerve growth factor can be expressed at a high level and for a relatively long period in the blast impaired cochlea, suggesting that Ad-hNGF β has a protective effect on rat cochlear spiral ganglion cells after blast exposure.

Measurement of conductive hearing loss in mice

In order to discriminate conductive hearing loss from sensorineural impairment, quantitative measurements were used to evaluate the effect of artificial conductive pathology on distortion-product otoacoustic emissions (DPOAEs), auditory brainstem responses (ABRs) and laser-Doppler vibrometry (LDV) in mice. The conductive manipulations were created by perforating the pars flaccida of the tympanic membrane, filling or partially filling the middle-ear cavity with saline, fixing the ossicular chain, and interrupting the incudo-stapedial joint. In the saline-filled and ossicular-fixation groups, averaged DPOAE thresholds increased relative to the control state by 20–36 and 25–39dB, respectively with the largest threshold shifts occurring at frequencies less than 20kHz, while averaged ABR thresholds increased 12–19 and 12–25dB, respectively without the predominant low-frequency effect. Both DPOAE and ABR thresholds were elevated by less than 10dB in the half-filled saline condition; no significant change was observed after pars flaccida perforation. Conductive pathology generally produced a change in DPOAE threshold in dB that was 1.5–2.5 times larger than the ABR threshold change at frequencies less than 30kHz; the changes in the two thresholds were nearly equal at the highest frequencies. While mild conductive pathology (ABR threshold shifts of <10dB) produced parallel shifts in DPOAE growth with level functions, manipulations that produced larger conductive hearing losses (ABR threshold shifts >10dB) were associated with significant deceases in DPOAE growth rate. Our LDV measurements are consistent with others and suggest that measurements of umbo velocity are not an accurate indicator of conductive hearing loss produced by ossicular lesions in mice.