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.

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.

Chronotolerance for cisplatin ototoxicity in the rat.

Cisplatin is a potent chemotherapeutic compound for which ototoxicity is a significant side effect. Cisplatin has shown sensitivity to circadian time, in that cisplatin is most effective as an anti-tumor compound, and least nephrotoxic, when given in the active (dark) period of the light-dark cycle in rodents. The objective of the study was to determine the sensitivity of cisplatin ototoxicity to circadian time. Fifty-seven Fischer 344/NHsd rats were exposed to 12 mg/kg cisplatin by intra-peritoneal injection at one of six time points on a 12 h light-12 h dark cycle: 2, 6, or 10 h after light onset or 2, 6, or 10 h after light offset. Cochlear injury was evaluated using auditory brainstem response threshold shifts and postmortem outer hair cell counts. All animals experienced threshold shift in the highest frequencies tested (30 and 40 kHz). The animals exposed to cisplatin at 6 h after light onset (the inactive period) had significantly higher mid-frequency threshold shifts and outer hair cell losses than the groups exposed during the dark hours. The results indicate that cisplatin is less likely to cause ototoxicity in the Fischer 344/NHsd rat when given during the active period. This finding is consistent with the lower nephrotoxicity that has been detected in cisplatin-exposed animals treated during the dark hours, and the magnitude of differences in threshold shifts between the light and dark exposure indicates that circadian timing has a significant impact on susceptibility to cisplatin ototoxicity.

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.

A putative role of p53 pathway against impulse noise induced damage as demonstrated by protection with pifithrin-alpha and a Src inhibitor.

Exposure to high-level noise leads to oxidative stress and triggers apoptosis of the hair cells. This study examined whether p53, a tumor suppressor protein, is activated in the cochlea following impulse noise exposure. Inhibition of p53 with pifithrin alpha, a specific p53 inhibitor, or KX1-004, a Src-protein tyrosine kinase inhibitor, was tested to determine if p53 inhibition could reduce noise-induced hearing loss and cochlear damage. Chinchillas were pre-treated with a local administration of pifithrin alpha or KX1-004 and exposed to impulse noise. The chinchillas were assessed for threshold shift at 1 and 24h after the noise. At 4 or 24h post noise, the cochleae were removed and organs of Corti were examined to assess the damage to the cells and upregulation of p53 by the noise. Apoptosis was evident in both outer hair cells and supporting cells. Phospho-p53 (Ser 15) was upregulated 4h and 24h after the noise. KX1-004 and pifithrin alpha both decreased threshold shift and the number of missing outer hair cells. These results indicate that p53 is involved in the early stages of noise-induced cell death and inhibition of this signaling pathway is a potential protective strategy against noise-induced hearing loss.

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.

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.

[L-NAC protect hair cells in the rat cochlea from injury of exposure to styrene].

OBJECTIVE: To observe the effects of N-acetyl-L-cysteine (L-NAC) protect hair cells in the rat cochlea from injury of exposure to styrene. METHOD: Seventeen adult Long Evans rats were used in present study. The animals were randomly assigned into test group (n=9) and control group (n=8). The animals were exposed to styrene by gavage at 400 mg/kg (2 g styrene was mixed with 1 ml olive oil). Test group animals received styrene exposure plus L-NAC 325 mg/kg (L-NAC was dissolved in physiological saline solution) by intraperitoneal injection. Treatment was performed once a day, 5 days per week for 3 weeks. Control group animals received the same volume of saline injection on an identical time schedule used for the test group. The auditory brainstem response (ABR) thresholds of both ears elicited with clicks were measured before and at the end of the 3-week styrene or styrene plus L-NAC treatment. After hearing was re-assessed, animals were sacrificed and cochleae were quickly removed from the skull. Following fixation, whole specimens comprising the basilar membrane with Corti's organ were separated from the modiolus. The organs of Corti were stained with propidium iodide (PI) and the TUNEL assay to visualize the morphologic viability of hair cell nuclei, FITC-labeled phalloidin, a F-actin intercalating fluorescent probe used to visualize the morphologic viability of cuticular plate and the stereocilia in the hair cells. Each organ of Corti was thoroughly examined using fluorescence microscopy. The numbers of damaged OHCs (apoptotic, necrotic and missing OHCs) were documented. RESULT: There was a statistically significant decrease in ABR threshold shift (P<0.05) in the styrene-plus-L-NAC treated animals. The average percentage of damaged OHCs in the styrene-treated animals was 28.3%. In contrast, the average percentage of OHC damage in the styrene-plus-L-NAC treated group was only 10.6% (P<0.01). The percentage of reduction in the number of apoptotic cells in styrene-plus-L-NAC treated group was 78% (P<0.01). However, the mean reduction of necrotic cells was only 23% (P>0.05). CONCLUSION: The results indicate that the treatment with L-NAC may effectively protect against the styrene-induced hair cells damage and preferably reduce the number of apoptotic OHCs.

The effects of acoustic environment after traumatic noise exposure on hearing and outer hair cells.

Previous studies reported that exposure to non-traumatic level sounds after traumatic noise exposure reduced the degree of noise-induced hearing loss and hair cell stereocilia damage. The current study investigated the effects of a 3-day post-noise acoustic environment on the degree of noise-induced hearing loss and cochlear damage. Female chinchillas were exposed to traumatic continuous noise (4 kHz octave-band noise) at 107 dB SPL for 1h and then placed in either an augmented acoustic environment (AAE) or deprived acoustic environment (DAE) for 3 days. The AAE group was exposed to a broad-band noise (4-20 kHz) at 80 dB SPL and the DAE animals were fit with conventional earplugs to minimize the level of acoustic stimulation. Auditory brainstem responses (ABRs) were recorded before and 3 days after the traumatic noise exposure. The AAE group showed a significantly lower average threshold shift at the frequencies of 4 and 8 kHz (p<0.01). Correspondingly, significantly fewer missing and dying outer hair cells (OHCs) were observed in the AAE group than in the DAE group. Although the cochlear reduced and oxidized glutathione levels (GSH and GSSG, respectively) were essentially the same in two groups at day 3, significant correlations were found between GSSG levels and mean ABR threshold shift (1-16 kHz) in the AAE group; as well as GSSG and percentage of total OHC loss in the DAE group. The results suggest that post-noise acoustic environment influenced the degree of hearing loss and OHC deterioration after traumatic noise exposure.

Protective effect of N-acetyl-L-cysteine (L-NAC) against styrene-induced cochlear injuries.

CONCLUSION: Styrene exposure causes hair cell death through both apoptotic and necrotic pathways and treatment with N-acetyl-L-cysteine (L-NAC) reduces styrene ototoxicity. OBJECTIVE: Exposure to styrene causes hearing loss and hair cell death in the middle frequency region in the cochlea. The current study was designed to examine the cell death pathways and the protective effect of L-NAC against styrene-induced cochlear injuries. MATERIALS AND METHODS: Seventeen rats were exposed to styrene by gavage at 400 mg/kg 5 days per week for 3 weeks. Nine of the styrene-treated rats received L-NAC by intraperitoneal injection (325 mg/kg), and the remaining eight rats received saline injections as controls. The styrene-induced hearing loss was assessed by auditory brainstem responses (ABRs). Apoptotic, necrotic, and missing hair cells were quantified using combined methods, including nuclear staining with propidium iodide, F-actin staining with FITC-phalloidin, and the TUNEL assay. RESULTS: The styrene exposure caused a threshold shift of 15±4.3 dB. Both apoptosis and necrosis were involved in the pathogenesis of the cochlear lesion, but apoptosis appeared to be the major cell death pathway leading to the styrene ototoxicity. Treatment with L-NAC reduced the number of missing and dying outer hair cells (OHCs) and reduced the styrene-induced hearing loss.

Noise protection with N-acetyl-l-cysteine (NAC) using a variety of noise exposures, NAC doses, and routes of administration.

CONCLUSION: These studies extend previous work on N-acetyl-l-cysteine (NAC) and noise, showing protection with NAC against a high-kurtosis noise, showing protection with NAC at low doses, as well as protection by oral gavage. The studies further reveal the potential for the use of NAC in a clinical population exposed to noise. OBJECTIVE: To extend previous work on NAC protection from noise, the current study examined the effectiveness of NAC against a high-kurtosis noise that combined continuous and impact noise, tested the effectiveness of NAC at varying doses, and tested NAC when administered by gavage. MATERIALS AND METHODS: Chinchillas were tested for auditory brainstem responses (ABRs) at five frequencies before and at three time points after one of three noise exposures: high-kurtosis (2 h, 108 dB L(eq)), impulse (75 pairs of 155 dB pSPL impulses), or continuous (4 kHz octave band, 105 dB SPL for 6 h). Animals were treated with NAC or saline vehicle before and after noise. RESULTS: The NAC was protective against the high-kurtosis noise both at low doses and when given orally by gavage.

NAC for noise: from the bench top to the clinic.

Noise-induced hearing loss (NIHL) is an important etiology of deafness worldwide. Hearing conservation programs are in place and have reduced the prevalence of NIHL, but this disorder is still far too common. Occupational and recreational pursuits expose people to loud noise and ten million persons in the US have some degree of noise-induced hearing impairment. It is estimated that 50 million in the US and 600 million people worldwide are exposed to noise hazards occupationally. Noise deafness is still an important and frequent cause of battlefield injury in the US military. A mainstay of hearing conservation programs is personal mechanical hearing protection devices which are helpful but have inherent limitations. Research has shown that oxidative stress plays an important role in noise-induced cochlear injury resulting in the discovery that a number of antioxidant and cell death inhibiting compounds can ameliorate deafness associated with acoustic trauma. This article reviews one such compound, N-acetylcysteine (NAC), in terms of its efficacy in reducing hearing loss in a variety of animal models of acute acoustic trauma and hypothesizes what its therapeutic mechanisms of action might be based on the known actions of NAC. Early clinical trials with NAC are mentioned.

A comparison of the protective effects of systemic administration of a pro-glutathione drug and a Src-PTK inhibitor against noise-induced hearing loss.

Both the antioxidant, n-l-acetyl cysteine (L-NAC) and the Src inhibitor, KX1-004, have been used to protect the cochlea from hazardous noise. To date, KX1-004 has only been used locally on the round window. In the current study, the two drugs were administered systemically. LNAC was delivered intraperitoneally at a dose of 325 mg/kg while KX1-004 was administered subcutaneously at a dose of 50 mg/kg. The noise exposure consisted of a 4 kHz octave band of noise at 100 dB SPL for 6 hours/day for 4 days. The drugs were administered once each day, 30 minutes prior to the onset of the noise exposure. The animals' hearing was estimated using the evoked response records from surgically-implanted chronic electrodes in the inferior colliculi. Animals treated with LNAC and KX1-004 had from 10 to 20 dB less temporary threshold shift at day 1 and an average 10 dB less permanent threshold shift by day 21 when compared to control saline treated animals. There were no significant side effects (i.e.: appetite loss, weight loss, lethargy, etc.) related to either of the drug treatments. KX1-004 produced at least as much protection as L-NAC, but at a significantly lower concentration.