Mild hearing loss in C57BL6/J mice after exposure to antiretroviral compounds during gestation and nursing.

OBJECTIVE: There is evidence of ototoxicity from antiretrovirals (ARVs), and ARV therapy in pregnant/nursing mothers can expose offspring to these compounds. The current work modelled whether exposure to ARVs in utero and during nursing altered the functioning of the auditory system in offspring mice. DESIGN: The females of seven breeding pairs of C57BL6/J mice were given daily doses of ARVs lamivudine and tenofovir disoproxil fumarate by oral gavage during gestation and nursing. Three breeder females were given equivalent volumes of water as controls. At wean age (3 weeks after birth), the offspring mice were tested with auditory brainstem responses (ABRs). At the conclusion of the experiment, the offspring mice's cochleae were examined for hair cell counts. STUDY SAMPLE: Ten breeder female C57BL6/J mice and 69 offspring mice. RESULTS: The offspring mice exposed to ARVs during development showed higher ABR thresholds than the control offspring. No differences were found in supra-threshold ABRs. There was no evidence of missing hair cells. CONCLUSIONS: Hearing impairment may be a possible consequence of exposure to ARVs during gestation and development. Because the threshold differences were not large, if they are occurring in humans, it is unlikely they would be identified in any hearing screening tests.

Pharmaceutical otoprotection strategies to prevent impulse noise-induced hearing loss.

One of the ongoing challenges for hearing researchers is successful protection of the ear from noise injury. For decades, the most effective methods have been based on modifying the acoustic properties of the noise, either by reducing noise output from various sources, interfering in the acoustic exposure path with environmental controls, or altering the noise dose for the individual with personal hearing protection devices. Because of the inefficiencies of some of the acoustic modification procedures, pharmaceutical otoprotection is targeted at making the cochlea less susceptible to injury. Short-duration, high-level impulse noises, typically caused by small-scale explosions, cause different sets of injuries in the ear than long-duration, low-variance noise exposures. Therefore, the expectation is that the ears exposed to impulse noise may need different pharmaceutical interventions, both in type of compounds used and the time course of administration of the compounds. The current review discusses four different classes of compounds that have been tested as impulse noise otoprotectants. In the process of describing those experiments, particular emphasis is placed on the acoustic properties of the impulses used, with the goal of providing context for evaluating the relevance of these different models to human impulse noise-induced hearing loss.

Long-Term Synergistic Interaction of Cisplatin- and Noise-Induced Hearing Losses.

OBJECTIVE: Past experiments in the literature have shown that cisplatin interacts synergistically with noise to create hearing loss. Much of the previous work on the synergistic interaction of noise and cisplatin tested exposures that occurred very close together in time. The present study assessed whether rats that have been exposed to cisplatin continue to show increased susceptibility to noise-induced hearing loss months after conclusion of the cisplatin exposure. DESIGN: Thirty-two Fischer 344/NHsd rats were exposed to one of five conditions: (1) cisplatin exposure followed by immediate cochlear tissue harvest, (2) cisplatin exposure and a 20-week monitoring period before tissue harvest, (3) cisplatin exposure followed immediately by noise exposure, (4) cisplatin exposure followed by noise exposure 16 weeks later, and (5) noise exposure without cisplatin exposure. The cisplatin exposure was an 8-week interval in which cisplatin was given every 2 weeks. Cochlear injury was evaluated using auditory brainstem response thresholds, P1 wave amplitudes, and postmortem outer hair cell counts. RESULTS: The 8-week cisplatin exposure induced little threshold shift or P1 amplitude loss, and a small lesion of missing outer hair cells in the basal half of the cochlea. The rats exposed to noise immediately after the cisplatin exposure interval showed a synergistic interaction of cisplatin and noise. The group exposed to noise 16 weeks after the cisplatin exposure interval also showed more severe threshold shift and outer hair cell loss than control subjects. The controls exposed to cisplatin and monitored for 20 weeks showed little threshold shift or outer hair cell loss, but did show P1 wave amplitude changes over the 20-week monitoring period. CONCLUSIONS: The results from the groups exposed to cisplatin followed by noise, combined with the findings from the cisplatin- and noise-only groups, suggest that the cisplatin induced cochlear injuries that were not severe enough to result in threshold shift, but left the cochlea in a state of heightened susceptibility to future injury. The heightened susceptibility to noise injury was still present 16 weeks after the conclusion of the cisplatin exposure.

Ototoxicity of 12 mg/kg cisplatin in the Fischer 344/NHsd rat using multiple dosing strategies.

Ototoxicity continues to be a major dose-limiting side effect of cis-diamminedichloroplatinum(II) (cisplatin). With an ongoing need to develop pharmaceutical protection strategies for cisplatin's ototoxicity, there is also a need to develop stable in-vivo mammalian models of cisplatin ototoxicity. The current study examined the difference in ototoxicity of a cumulative 12 mg/kg dose of cisplatin in the Fischer 344/NHsd rat when administered over four different dosing protocols. Hearing sensitivity was measured using free-field auditory brainstem response thresholds under anesthesia. Rats were divided into four groups. The first group was administered 12 mg/kg of cisplatin in a single bolus infusion. The second group was administered two 6 mg/kg infusions separated by 7 days. The third group was administered 3 mg/kg injections once per day for 4 consecutive days. The fourth group was administered 3 mg/kg injections in four injections separated by 3 days each. Hearing thresholds and body weights were measured at 3 and 7 days after the final cisplatin exposure. Postmortem sensory cell counts were used to confirm injury to the auditory system. The 4 consecutive days of 3 mg/kg induced a greater mortality rate and greater hearing loss at day 3 than the other experimental protocols. The 3 mg/kg administered every 3 days induced less sensory cell loss than the other conditions. The findings indicate that 4 consecutive days of 3 mg/kg cisplatin is not a viable ototoxicity model in the Fischer 344/NHsd rat, but that the other models are all effective in inducing comparable cochlear injuries.

Utility of the Vivosonic Integrity™ auditory brainstem response system as a hearing screening device for difficult-to-test children.

OBJECTIVE: Inability to complete a behavioral hearing screening is a challenge for children with developmental disorders or who are otherwise difficult to test, defined here as unable or unwilling to complete a behavioral screening. The study compared referral rates from screenings that used behavioral methods alone, with screenings that added a screen with the Vivosonic Integrity™ auditory brainstem response (ABR) device. DESIGN: Behavioral screening was performed first. Those children who failed were re-screened with the Vivosonic Integrity ABR device. Changes in referral and screening completion rates after the second screening were calculated and analysed. STUDY SAMPLE: The participant population (n = 43) consisted of children with diagnosed developmental disorders. RESULTS: Adding the Vivosonic Integrity to the screening protocol significantly increased the proportion of children who completed the screening, from 57% after behavioral screening to 81% after behavioral and ABR screening. The addition of the ABR screen did not change that overall pass/refer rate, in part because four participants who did not complete the behavioral screen received a 'Refer' outcome on the ABR screen. CONCLUSIONS: The results indicate that the Vivosonic Integrity device could be a useful tool for hearing screening of children who are difficult to screen using behavioral procedures.

Influence of dose and duration of isoflurane anesthesia on the auditory brainstem response in the rat.

OBJECTIVE: Isoflurane anesthesia can have significant effects on processing of sounds at the peripheral and central levels, manifesting in changes in auditory-evoked potentials. The current study tested whether duration of isoflurane anesthesia changes thresholds, amplitudes, and latencies of the auditory brainstem response (ABR). DESIGN: The study tested ABRs in a rat animal model under isoflurane anesthesia. Study variables were duration of isoflurane anesthesia, stimulus frequency, stimulus level, and the dose of isoflurane. Rats were anesthetized with 1.5% or 2% isoflurane. ABRs were collected from 90 to 5 dB SPL at 5-40 kHz. Three full ABR series were collected over a 105-minute period. Thresholds were assigned, and ABR wave amplitudes and latencies were measured at each stimulus frequency and level. STUDY SAMPLE: Ten Sprague-Dawley rats were tested in a repeated measures design. RESULTS: Statistical analyses revealed no significant effects of dose or duration on threshold, but a series of significant interactions between test variables for the amplitude and latency measurements. CONCLUSIONS: In the rat, dose and duration of isoflurane anesthesia induced inconsistent changes in latency and amplitude of the ABR. At 40 kHz, isoflurane dose had more powerful effects on latency and amplitude than occurred at other frequencies.

An Src-protein tyrosine kinase inhibitor to reduce cisplatin ototoxicity while preserving its antitumor effect.

Ototoxicity remains a major dose-limiting side effect of cisplatin. The current studies were carried out to evaluate the effectiveness of a novel Src-protein tyrosine kinase inhibitor in protecting the ear from cisplatin ototoxicity without compromising cisplatin's antitumor effects. The Src inhibitor has been shown to be effective in protecting the ear from noise-induced hearing loss. Three studies were carried out to determine whether this compound has otoprotective activity in rats treated with cisplatin. The first two studies used the Src inhibitor as a cotreatment with single doses of cisplatin in Fischer 344/NHsd rats and nude rats, respectively. Cochlear damage was assessed by auditory brainstem response threshold shifts and outer hair cell loss. The third study was carried out in nude rats with implanted HT-29 tumors, and the Src inhibitor was administered as a cotreatment with a lower dose of cisplatin. Cochlear damage and changes in tumor volume were assessed in the third study. In the first two studies, cotreatment with the Src inhibitor reduced cisplatin-induced hearing loss significantly. In the third study, little hearing loss was induced because of the use of a lower dose of cisplatin. However, cotreatment with the Src inhibitor did not exert a negative effect on cisplatin's slowing of tumor growth in the treated rats. The findings suggest that the Src inhibitor may provide an effective cotreatment with cisplatin to reduce cisplatin's ototoxicity, without compromising its antitumor capability.

Reduction in impulse noise-induced permanent threshold shift with intracochlear application of an NADPH oxidase inhibitor.

BACKGROUND: Toxic levels of reactive oxygen species are key contributors to the lesion of dead outer hair cells (OHCs) seen in the cochlea after noise exposure. The current study follows previous work in which paraquat was used to demonstrate that NADPH oxidase is active in the cochlea and can contribute to cochlear reactive oxygen species formation and hair cell loss. PURPOSE: The current study was undertaken to test whether pharmacological blockade of NADPH oxidase in the cochlea would lead to reduced noise-induced hearing loss and OHC death. STUDY SAMPLE: A total of 18 chinchillas (36 ears) were assessed in the study. INTERVENTION: AEBSF (4-[2-aminoethyl]benzenesulfonyl fluoride), an inhibitor of NADPH oxidase activation, was dissolved in distilled water and delivered into the cochlea via diffusion across the round window membrane. The contralateral ears received distilled water as a vehicle control. Following treatment, chinchillas were exposed to one of two noises: a 4 kHz octave band noise at 106 dB SPL for 6 hr or an impulse noise that consisted of 75 pairs of 155 dB pSPL impulses. DATA COLLECTION AND ANALYSIS: Pre- and post-noise exposure, thresholds of the auditory brainstem response at 2-8 kHz were measured. Postmortem OHC counts were conducted at the conclusion of the study. Two- and three-factor ANOVAs were used for statistical analysis of the OHC losses and ABR threshold shifts induced by the noise exposures. RESULTS: Permanent threshold shift from the impulse noise was reduced in the ears treated with the NADPH oxidase inhibitor, but no differences were found in the groups exposed to the continuous noise. OHC losses were not statistically different between the treated and untreated ears for either noise exposure. CONCLUSIONS: The results suggest that NADPH oxidase-mediated superoxide has a role in cochlear damage from impulse noise, and pharmacologic inhibition of NADPH oxidase can reduce cochlear susceptibility to noise damage. The lack of protection from the longer-duration continuous noise can be attributed to a number of possibilities related to dose level and delivery schedule.

Music as a unique source of noise-induced hearing loss.

Music is among the most important artistic, cultural, and entertainment modalities in any society. With the proliferation of music genres and the technological advances that allow people to consume music in any location and at any time, music over-exposure has become a significant public health issue. Music-induced hearing loss has a great deal in common with noise-induced hearing loss. However, there are important differences that make music a unique insult to the auditory system and a unique threat to public health. Its unique properties also make it a potentially valuable asset in sound conditioning paradigms. This review discusses hearing loss from noise and music, comparing and contrasting the two. Recent research on music-induced hearing loss is reviewed, followed by discussion of the differences in music-induced hearing loss between performers and consumers. The review concludes with a discussion of the potential of music as a sound conditioning stimulus to protect against acquired hearing loss.

Hearing Loss in Offspring Exposed to Antiretrovirals During Pregnancy and Breastfeeding.

Over 27 million people worldwide currently receive daily antiretroviral therapy for the management of HIV/AIDS. In order to prevent the continued spread of HIV, the World Health Organization (WHO) recommends the use of highly active antiretroviral therapy by pregnant and nursing women. There is currently little research into the auditory effects of this therapy on children exposed during pregnancy and breastfeeding, and research to date on the direct effects of antiretroviral exposure on the auditory system is inconclusive. The current study examined the effects of WHO-recommended first-line antiretrovirals in a well-controlled animal model to evaluate the potential for auditory damage and dysfunction following these exposures. Female breeding mice were each exposed to one of four antiretroviral cocktails or a vehicle control once daily during pregnancy and breastfeeding. Offspring of these mice had their auditory status evaluated after weaning using auditory brainstem responses and distortion-product otoacoustic emissions (DPOAEs). Auditory brainstem response thresholds following antiretroviral exposure during gestation and breastfeeding showed elevated thresholds and increased wave latencies in offspring of exposed mice when compared to unexposed controls, but no corresponding decrease in DPOAE amplitude. These differences in threshold were small and so may explain the lack of identified hearing loss in antiretroviral-exposed children during hearing screenings at birth. Minimal degrees of hearing impairment in children have been correlated with decreased academic performance and impaired auditory processing, and so these findings, if also seen in human children, suggest significant implications for children exposed to antiretrovirals during development despite passing hearing screenings at birth.

Cochlear Preconditioning as a Modulator of Susceptibility to Hearing Loss.

Significance: Acquired sensorineural hearing loss is a major public health problem worldwide. The leading causes of sensorineural hearing loss are noise, aging, and ototoxic medications, with the key underlying pathology being damage to the cochlea. The review focuses on the phenomenon of preconditioning, in which the susceptibility to cochlear injury is reduced by exposing the ear to a stressful stimulus. Recent Advances: Cochlear conditioning has focused on the use of mono-modal conditioning, specifically conditioning the cochlea with moderate noise exposures before a traumatic exposure that causes permanent hearing loss. Recently, cross-modal conditioning has been explored more thoroughly, to prevent not only noise-induced hearing loss, but also age-related and drug-induced hearing losses. Critical Issues: Noise exposures that cause only temporary threshold shifts (TTSs) can cause long-term synaptopathy, injury to the synapses between the inner hair cells and spiral ganglion cells. This discovery has the potential to significantly alter the field of cochlear preconditioning with noise. Further, cochlear preconditioning can be the gateway to the development of clinically deployable therapeutics. Therefore, understanding the underlying mechanisms of conditioning is crucial for optimizing clinical protection against sensorineural hearing loss. Future Directions: Before the discovery of synaptopathy, noise exposures that caused only TTSs were believed to be either harmless or potentially beneficial. Any considerations of preconditioning with noise must consider the potential for injury to the synapses. Further, the discovery of different methods to precondition the cochlea against injury will yield new avenues for protection against hearing loss in the vulnerable populations. Antioxid. Redox Signal. 36, 1215-1228.

Postexposure treatment with a Src-PTK inhibitor in combination with N-l-acetyl cysteine to reduce noise-induced hearing loss.

Both the antioxidant, N-l-acetyl cysteine (NAC), and the Src inhibitor, KX1-004, have been used to protect the cochlea from hazardous noise. In order to extend our previous work on KX1-004 with noise exposure, the current studies were undertaken with two goals: (1) to test the effectiveness of NAC and KX1-004 in combination with one another when given in a protection paradigm, and (2) to test the NAC+KX1-004 combination in a postexposure rescue paradigm. The noise exposure for the first experiment consisted of a 4-kHz octave band of noise at 107 dB SPL for 2 hours. The combination of NAC and KX1-004 were administered either prior to the noise exposure or post exposure (rescue). The second experiment was undertaken to extend the findings of the first experiment's rescue paradigm. The 4 kHz octave band noise was delivered at 112 dB SPL for 1 hour, with the experimental drugs delivered only in a rescue paradigm. In Experiment 1, animals treated before the 2-hour noise exposure with the combination of NAC and KX1-004 had from 12 to 17 dB less permanent threshold shift when compared to control saline treated animals. Treatment in the rescue paradigm did not produce any reductions in threshold shift from the 2-hour exposure. In the second experiment, with the 1-hour noise, rescue with KX1-004 or KX1-004 plus NAC yielded small, but significant, reductions in threshold shift. There was no additional benefit from the combination of NAC and KX1-004 over KX1-004 by itself.

Changing the time intervals between cisplatin cycles alter its ototoxic side effect.

Various methods have been tested and deployed clinically to identify and minimize cisplatin ototoxicity. Upon early identification of hearing loss, one of the possible approaches to reducing future ototoxicity is to increase the gaps or breaks between cycles or doses of cisplatin. However, recent findings about the retention of cisplatin in the cochlea and the potential for its long-term ototoxic effects call into question whether such an approach is effective in reducing hearing loss. The current study was undertaken to determine whether increasing the rest intervals between cycles of cisplatin altered the resulting ototoxicity. CBA/CaJ mice were exposed to a cumulative dose of 48 mg/kg cisplatin delivered in three cycles of 16 mg/kg (4 mg/kg per day for 4 consecutive days). The cycles were separated by either 10, 17, or 87 days to determine if the inter-cycle rest intervals affected resulting ototoxicity. Ototoxicity was measured using auditory brainstem response threshold shifts and hair cell losses. Results indicated that longer intervals between cycles of cisplatin led to lower threshold shifts and outer hair cell lesions. The results support the principle that 'slowing down' cisplatin dosing by increasing rest intervals between doses can reduce the ototoxic side effect. Further testing is needed to optimize the timing and to determine the impact of longer inter-cycle intervals on cisplatin's anti-tumor efficacy.

Early Physiological and Cellular Indicators of Cisplatin-Induced Ototoxicity.

Cisplatin chemotherapy often causes permanent hearing loss, which leads to a multifaceted decrease in quality of life. Identification of early cisplatin-induced cochlear damage would greatly improve clinical diagnosis and provide potential drug targets to prevent cisplatin's ototoxicity. With improved functional and immunocytochemical assays, a recent seminal discovery revealed that synaptic loss between inner hair cells and spiral ganglion neurons is a major form of early cochlear damage induced by noise exposure or aging. This breakthrough discovery prompted the current study to determine early functional, cellular, and molecular changes for cisplatin-induced hearing loss, in part to determine if synapse injury is caused by cisplatin exposure. Cisplatin was delivered in one to three treatment cycles to both male and female mice. After the cisplatin treatment of three cycles, threshold shift was observed across frequencies tested like previous studies. After the treatment of two cycles, beside loss of outer hair cells and an increase in high-frequency hearing thresholds, a significant latency delay of auditory brainstem response wave 1 was observed, including at a frequency region where there were no changes in hearing thresholds. The wave 1 latency delay was detected as early cisplatin-induced ototoxicity after only one cycle of treatment, in which no significant threshold shift was found. In the same mice, mitochondrial loss in the base of the cochlea and declining mitochondrial morphometric health were observed. Thus, we have identified early spiral ganglion-associated functional and cellular changes after cisplatin treatment that precede significant threshold shift.

Cisplatin-induced threshold shift in the CBA/CaJ, C57BL/6J, BALB/cJ mouse models of hearing loss.

The development of a clinically-relevant rodent model of cisplatin-induced hearing loss presents the challenges of finding the cumulative dose, dosing schedule, and rodent strain to induce a consistent level of threshold shift with low mortality. This study was undertaken to model hearing loss at 16, 32, and 48 mg/kg cumulative doses of cisplatin in the CBA/CaJ, C57BL/6J, and BALB/cJ mouse strains. Mice were exposed to three cycles of 16 mg/kg cisplatin, for a cumulative dose of 48 mg/kg. Equal numbers of male and female mice were used in each strain, and the cisplatin was delivered in three different dosing schedules: a single bolus dose of 16 mg/kg followed by 20 days of recovery, 8 mg/kg doses delivered every ten days, and 4 mg/kg delivered daily for four consecutive days followed by 17 days of recovery. Auditory brainstem response threshold shifts indicated increased hearing loss with increasing cumulative dose in all strains and dosing schedules. The BALB/cJ experienced the largest threshold shifts, and the C57BL/6J the smallest. However, the BALB/cJ mice had the lowest mortality (0%) of the strains. The dosing schedule had minimal effects on threshold shift, but did affect mortality, with the 16 mg/kg single dose inducing more mortality than the other two schedules. In the BALB/cJ mice, the males experienced more threshold shift than the females. The results mirror past work comparing the three strains' susceptibility to kanamycin ototoxicity, with highest pigmentation showing the lowest acute susceptibility to cisplatin-induced hearing loss, and the albino strain showing the highest susceptibility.

Advances and Challenges in Pharmaceutical Therapies to Prevent and Repair Cochlear Injuries From Noise.

Noise induces a broad spectrum of pathological injuries to the cochlea, reflecting both mechanical damage to the delicate architecture of the structures of the organ of Corti and metabolic damage within the organ of Corti and lateral wall tissues. Unlike ototoxic medications, the blood-labyrinth barrier does not offer protection against noise injury. The blood-labyrinth barrier is a target of noise injury, and can be weakened as part of the metabolic pathologies in the cochlea. However, it also offers a potential for therapeutic intervention with oto-protective compounds. Because the blood-labyrinth barrier is weakened by noise, penetration of blood-borne oto-protective compounds could be higher. However, systemic dosing for cochlear protection from noise offers other significant challenges. An alternative option to systemic dosing is local administration to the cochlea through the round window membrane using a variety of drug delivery techniques. The review will discuss noise-induced cochlear pathology, including alterations to the blood-labyrinth barrier, and then transition into discussing approaches for delivery of oto-protective compounds to reduce cochlear injury from noise.

Assessing Hidden Hearing Loss After Impulse Noise in a Mouse Model.

INTRODUCTION: There are several key differences between impulse and continuous noise: the nature of the noise itself, the cochlear and neuronal structures affected, the severity to which they damage the auditory system, and the period of time in which damage occurs. Notably, no work on hidden hearing loss after impulse noise exposure has been done to this point, though it has been extensively studied after continuous noise. Hidden hearing loss manifests physiologically with reductions in suprathreshold amplitudes of the first wave of the auditory brainstem response, while auditory thresholds can remain relatively normal. OBJECTIVE: This study aimed to assess the extent to which, if at all, hidden hearing loss is present after exposure to impulse noise in C57BL6/J mice. METHODS: Thirty-one C57BL6/J mice were used in the experiment, in accordance with IACUC protocols. Auditory brainstem responses were recorded before and after noise exposures. The noise exposures consisted of 500 impulses at 137 dB peSPL. RESULTS: Suprathreshold amplitude reductions in the P1 wave of the mouse auditory brainstem response were seen, but only at frequencies with significant threshold shift. CONCLUSION: These amplitude changes were consistent with hidden hearing loss, and we conclude that impulse noise can cause hidden hearing loss, but future studies are required to determine the specific mechanisms involved and if they parallel those of hidden hearing loss after continuous noise.

Apoptotic outer hair cell death in the cochleae of aging Fischer 344/NHsd rats.

Apoptotic cell death has been implicated in cochlear degeneration during aging. To better understand the impact and the biological process of outer hair cell (OHC) apoptosis, we investigated the contribution of apoptotic cell death to the formation of the OHC lesions, and observed the temporal patterns of the occurrence of apoptotic events associated with the mitochondrial pathway in Fischer 344/NHsd rats, with ages ranging from 20 to 27 months. The results showed that the ratio of apoptotic to necrotic OHCs was 8:1. During the process of cell degeneration, the onset of Bax expression, cytochrome c release, and nuclear DNA fragmentation preceded the onset of nuclear condensation. In contrast, the activation of caspases-3 and -9, as well as the degradation of F-actin, took place after the onset of nuclear condensation. The results of this study suggest that the initiation of nuclear degradation is a caspase-3-independent process. Moreover, the study revealed that OHCs with Bax expression or cytochrome c release could enter either the apoptotic or necrotic pathway, suggesting the presence of a regulatory mechanism that guides degenerating OHCs to die via either the apoptotic or necrotic pathway.

Age-related hearing loss in the Fischer 344/NHsd rat substrain.

Studies of the F344 rat have shown a variety of age-related auditory anatomy and physiology changes. The current study was undertaken to clarify the ARHL in the F344 rat, by examining the auditory pathway of the F344/NHsd substrain that is distributed by Harlan Laboratories for research in the United States. The F344/NHsd rat begins to lose its hearing at about 12 months, and by 24 months, there are 50-60 dB auditory brainstem response threshold shifts at 20 and 40 kHz and 20 dB losses at 5-10 kHz. Distortion product otoacoustic emissions (DPOAE) amplitudes at 1.8-12 kHz stimuli were depressed in the older (18-24 months) rats. Amplitude input-output functions of the compound action potential (CAP) were also depressed across frequency. The endocochlear potential (EP) was 90-100 mV in the 3 month old rats. All but one of the 24 month old rats' EPs were in the +75-85 mV range. Tympanometry revealed no differences in middle ear function between the young and older rats. Collectively, these findings suggest damage to the outer hair cells, but anatomical examination of the outer hair cells revealed a relative lack of cell loss compared to the magnitude of the hearing and DPOAE loss.

Multiple dosing strategies with acetyl L-carnitine (ALCAR) fail to alter age-related hearing loss in the Fischer 344/NHsd rat.

BACKGROUND: The Fischer 344/NHsd rat undergoes age-related, progressive, high-frequency hearing loss beginning at age 12 months. The loss has been linked to defects/death in the outer hair cells related to oxidative stress originating in the mitochondria. Acetyl L-carnitine (ALCAR) is known to enhance mitochondrial bioenergetics and membrane efficiency. Therefore, ALCAR was targeted as a possible pharmacologic intervention to prevent, or even restore, hearing loss from aging. METHODS: Three different paradigms were used to deliver ALCAR to aging Fischer 344/NHsd rats. Rats in each condition had their hearing evaluated by auditory brainstem responses before, during, and after treatment. First, 24-month-old rats were given ALCAR (100 mg/kg dissolved 25 mg/ml in saline) by IP injection daily for one month. Second, 18-month-old rats were given ALCAR (100 mg/kg) by oral gavage for 90 days. Third, 15-month-old rats were given ALCAR (100 mg/kg) by oral gavage for 90 days. Control rats in each condition received saline by i.p. injection or gavage. RESULTS: Hearing thresholds of the three sets of ALCAR-treated animals were never significantly different from their matched controls before, during, or after the treatments at any of the five test stimuli (5, 10, 20, and 40 kHz tone bursts and a click). CONCLUSION: The current study does not provide evidence that age-related hearing loss in the Fischer 344/NHsd rat can be altered with systemic administration of ALCAR.