No full-text available
To read the full-text of this research,
you can request a copy directly from the author.
Oral pharmacologic otoprotective agents to prevent Noise-Induced Hearing Loss (NIHL): When dietary concentration isn't enough
Abstract
In summary, several agents are going through the FDA approval process for clinical trials to prevent noise-induced hearing loss. Currently D-met and ebselen are in or approaching FDA approved clinical trials. They both have an extensive body of consistently positive animal data supporting their development. Hopefully one or more agents will be FDA approved for use in the next few years. As discussed in Dr. LePrell's paper, a number of nutraceuticals also show excellent promise. While nutraceuticals do not generally go through the FDA approval process, some compounds like ACE Mg are promising and are undergoing rigorous clinical trials to also ensure safety and efficacy. In the future the incidence and severity of noise-induced hearing loss may be reduced.
Noise-induced hearing loss (NIHL) still remains a problem in developed countries, despite reduced occupational noise exposure, strict standards for hearing protection and extensive public health awareness campaigns. Therefore NIHL continues to be the focus of noise research activities. This paper summarizes progress achieved recently in our knowledge of NIHL. It includes papers published between the years 2008-2011 (in English), which were identified by a literature search of accessible medical and other relevant databases. A substantial part of this research has been concerned with the risk of NIHL in the entertainment sector, particularly in professional, orchestral musicians. There are also constant concerns regarding noise exposure and hearing risk in "hard to control" occupations, such as farming and construction work. Although occupational noise has decreased since the early 1980s, the number of young people subject to social noise exposure has tripled. If the exposure limits from the Noise at Work Regulations are applied, discotheque music, rock concerts, as well as music from personal music players are associated with the risk of hearing loss in teenagers and young adults. Several recent research studies have increased the understanding of the pathomechanisms of acoustic trauma, the genetics of NIHL, as well as possible dietary and pharmacologic otoprotection in acoustic trauma. The results of these studies are very promising and offer grounds to expect that targeted therapies might help prevent the loss of sensory hair cells and protect the hearing of noise-exposed individuals. These studies emphasize the need to launch an improved noise exposure policy for hearing protection along with developing more efficient norms of NIHL risk assessment.
Purpose: A previous study reported radiation protection from mucosal injury with D-methionine (D-met) in preclinical evaluation; therefore, the pharmacokinetics, safety, and utility of D-met were evaluated clinically.
Experimental Design: The pharmacokinetics of D-met following oral administration of a bioavailable formulation (MRX-1024) was evaluated in normal volunteers. Subsequently, 25 patients were enrolled on a phase 1 study of MRX-1024 concurrent with radiation therapy (RT) with or without weekly cisplatinum. Toxicity and mucosal events were evaluated weekly.
Results: Oral MRX-1024 resulted in rapid and dose-dependent increases in plasma D-met concentrations with a half-life of 3 hours. When administered concurrent with RT without chemotherapy, it was associated with a modest increase in grade 2 (two of six patients) and grade 3 (one of six patients) emesis. In those treated with MRX-1024 along with RT and weekly cisplatinum, there was no appreciable increase in emesis. Overall, five patients withdrew from the study due to emesis (four grade 2 and one grade 3). Only one incidence of dose-limiting toxicity (grade 3 emesis) was identified in 25 patients (4%). Finally, in 18 evaluable patients treated with MRX-1024 at 100 mg/kg twice daily (BID), the incidence of severe (grade 3) oral mucositis was 6% (1 of 18) with no grade 4 mucositis.
Conclusions: There is a dose-dependent increase in D-met exposure following MRX-1024 administration at 50 and 100 mg/kg, and MRX-1024 is safe for use concurrent with combined radiation and chemotherapy. The observed rate of mucositis seems less than that for similar treatment regimens within the published literature. Clin Cancer Res; 16(9); 2666–76. ©2010 AACR.
The cellular mechanisms leading to noise-induced hearing loss (NIHL) involve the generation of reactive oxygen species (ROS). Recent studies on glutathione (GSH) and N-acetylcysteine (NAC) show that they can protect the cochlea from ROS-derived damage, increasing the levels of endogenous cellular defences. The purpose of this study was to verify NAC's oto-protective efficacy and determine if drug administration timing influences the degree of oto-protection.
Forty male Sprague Dawley albino rats were divided in four groups exposed to 8-kHz 105-dB SPL continuous noise. The groups were treated with diverse NAC administration modalities: group A received 4 injections during 48 hours (pre- and post-noise exposure), group B 1 injection prior to exposure, group C 1 injection 24 h after exposure, and group D served as untreated controls. The single injection dosage was 375 mg/kg; the controls received an equal volume of saline solution. Cochlear function was assessed by pre- and post-noise (after 168 hours) recordings of distortion product otoacoustic emissions (DPOAEs) and auditory brainstem responses (ABR). DPOAEs were obtained by three different asymmetric protocols (P1=60-50, P2=50-40, P3=40-30 dB SPL) for frequencies of 4-16 kHz. ABR responses were elicited by tone-bursts at 8 and 16 kHz.
The most important outcome of the study was that the administration of NAC significantly reduced the threshold shifts in the treated animals. NAC provided different degrees of threshold reduction according to the timing of the drug injection.
The role played by the timing of NAC injection was important for the OHC protection index. From a DPOAE perspective, the best protection scheme was observed in the group receiving NAC after noise exposure, but full recovery of cochlear function was not observed in any of the tested groups.
Three groups of chinchillas were exposed to a nonGaussian continuous broadband noise at an Leq=10 5dB SPL, 8h/d for 5d. One group (N=6) received only the noise. A second group (N=6) received the noise and was additionally treated with L-NAC (325 mg/kg, i.p.). Treatment was administered twice daily for 2d prior to exposure and for 2d following the exposure. During exposure the animals received the L-NAC just prior to and immediately after each daily exposure. The third group (N=4) was exposed to the noise and received saline injections on the same schedule as the L-NAC treated animals. Auditory evoked potential recordings from the inferior colliculus were used to estimate pure tone thresholds and surface preparations of the organ of Corti quantified the sensory cell population. In all three groups PTS exceeded 50 dB at 2.0k Hz and above with severe sensory cell loss in the basal half of the cochlea. There was no statistically significant difference among the three groups in all measures of noise-induced trauma. Treatment with L-NAC did not reduce the trauma produced by a high-level, long duration, broadband noise exposure.
D-Methionine (D-met) protects against cisplatin (CDDP)-induced hearing loss and outer hair cell loss (Campbell et al., 1996). However, D-met’s protective effects on the stria vascularis has not been previously investigated. The purpose of this study was to examine, using semi-quantitative analysis, whether D-met also protects the stria vascularis. We removed a basal turn section of the stria vascularis from five groups of five male Wistar rats each: (1) a CDDP-treated control group receiving a 30 min i.p. infusion of 16 mg/kg CDDP, (2) a saline-injected control group receiving an equivalent volume of saline, and (3) three groups injected with either 75, 150, or 300 mg/kg D-methionine (D-met) i.p. 30 min prior to receiving the 16 mg/kg CDDP dosing. Using transmission electron microscopy and light microscopy, we analyzed strial volume (i.e. edema), marginal cell damage classification (bulging and/or compression), and relative optical density (ROD) ratios (i.e. depletion of marginal cell cytoplasmic organelles). All three levels of D-met provided complete protection against marginal cell bulging and/or compression but only partial protection against strial edema. At 300 mg/kg, D-met significantly reduced ROD ratio degradation in the spiral prominence and middle stria vascularis regions. In Reissner’s membrane region, values from the D-met pretreated group were not significantly different from either the treated or untreated control groups suggesting only partial protection for that area. Protection of marginal cell cytoplasmic organelles was also noted. In summary, D-met partially or fully protects the stria vascularis from several types of CDDP-induced damage.
Apoptosis is an important process, both for normal development of the inner ear and for removal of oxidative-stress damaged sensory cells from the cochlea. Oxidative-stressors of auditory sensory cells include: loss of trophic factor support, ischemia-reperfusion, and ototoxins. Loss of trophic factor support and cisplatin ototoxicity, both initiate the intracellular production of reactive oxygen species and free radicals. The interaction of reactive oxygen species and free radicals with membrane phospholipids of auditory sensory cells creates aldehydic lipid peroxidation products. One of these aldehydes, 4-hydroxynonenal, functions as a mediator of apoptosis for both auditory neurons and hair cells. We present several approaches for the prevention of auditory sensory loss from reactive oxygen species-induced apoptosis: 1) preventing the formation of reactive oxygen species; (2) neutralizing the toxic products of membrane lipid peroxidation; and 3) blocking the damaged sensory cells' apoptotic pathway.
Cisplatin is a widely used, very effective chemotherapeutic agent that can cause severe ototoxicity. In this study, D-methionine was tested as an otoprotectant via round window membrane (RWM) application in the chinchilla.
A minute amount of cisplatin alone, or D-methionine followed by cisplatin, was applied topically directly to the intact RWM of anesthetized adult chinchillas. Auditory brainstem responses were measured before and 1 week after topical round window application. Animals were killed, and the cochleas were examined.
The ears pretreated with D-methionine were completely protected from hearing loss and hair cell loss in the organ of Corti compared with controls. The ears receiving cisplatin without D-methionine protection sustained nearly complete hearing loss with threshold shifts of >60 dB, with extensive outer hair cell loss throughout the organ of Corti but particularly in the basal turn.
These results demonstrate that topical D-methionine provides excellent otoprotection against cisplatin-induced ototoxicity both electrophysiologically and structurally.
To investigate the effects of salicylate on noise-induced hearing loss (NIHL) in guinea pigs.
The animals were allocated into four groups (salicylate + noise, saline + noise, noise only and salicylate only) and were exposed to a 4 kHz octave band noise at 105 dB SPL for 2 hours for 5 consecutive days. Dynamic changes of ABR thresholds evoked by clicks were monitored. After physiological examination, the cochleae were processed for the morphological examination by light microscopy.
Mean thresholds of ABRs in the experimental group obtained on 5th day of the noise exposure was positively lower than the control groups (P < 0.05). The similar trends of ABR changes were found during other exposure days and after exposure, but the differences were not statistically significant. In the experimental group, there were 37.00 +/- 8.89 hair cell loses as assessed by nucleus staining, and 3.20 +/- 1.07 hair cells with nuclear deformation. The noise group had 74.11 +/- 10.28 hair cell loses and 10.43 +/- 9.71 hair cells with nuclear deformation, whereas the saline group had 63.60 +/- 7.97 hair cell loses and 20.80 +/- 15.48 hair cells with nuclear deformation. The difference between two groups was significant (P < 0.05).
The results suggest that administration of salicylate facilitates the recovery of cochlear hearing and reduces damage to hair cells after noise exposure.
Cell proliferation in the cochleae of guinea pigs and rats was investigated after systemic application of kanamycin sulfate (KM) and ethacrynic acid (EA). Bromodeoxyuridine (BrdU) was injected daily for 10 days, after which the number of BrdU-positive cells was counted in paraffin sections of the cochlea. Only a few BrdU-positive cells were present in the spiral ligament and among the acoustic nerve fibers in the non-deafened control animals. Animals treated with KM and EA had profound hearing loss and significant increases in the number of BrdU-positive cells in the spiral ligament and among the acoustic nerve fibers. No BrdU-positive cells were found in the auditory sensory epithelium of any animal. These findings suggest that in the mature mammalian cochlea cell proliferation increases in nonsensory regions after ototoxic damage but may not occur in the auditory sensory epithelium.
Noise-induced hearing loss is one of the most common causes of hearing disability, and at present there is no effective biological protection or cure. Firearms and some industrial equipment can generate very high levels of impulse noise, which is known to cause sensorineural hearing loss. It has been shown that antioxidants such as N-L-acetylcysteine (NAC) can protect the inner ear from oxidative damage. The present study investigates whether NAC (i.p.) can protect the cochlea from impulse noise trauma. Rats were exposed to 50 noise pulses at 160 dB SPL peak value. Electrophysiological hearing thresholds were assessed with auditory brainstem response (ABR) up to 4 weeks after noise exposure. Animals exposed to impulse noise, without treatment of NAC, had larger threshold shifts in the frequency range 4-40 kHz than animals injected with NAC. Hair cell loss was significantly reduced using a schedule of three NAC injections in the rats. These results suggest that NAC can partially protect the cochlea against impulse noise trauma.
Previous studies indicate that noise induced hearing loss (NIHL) involves a decrease in glutathione peroxidase (GPx) activity and a subsequent loss of outer hair cells (OHC). However, the cellular localization of this GPx decrease and the link to OHC loss are still poorly understood. In this report, we examined the cellular localization of GPx (GPx1, GPx 3 and GPx 4) in F-344 rat before and after noise exposure and after oral treatment with ebselen, a small molecule mimic of GPx activity. Results indicate that GPx1 is the major isoform within the cochlea and is highly expressed in cells of the organ of Corti, spiral ganglia, stria vascularis, and spiral ligament. Within 5h of noise exposure (4h at 113 dB, 4-16 kHz), significant OHC loss was already apparent in regions coincident with the 8-16 kHz region of the cochlea. In addition, the stria vascularis exhibited significant edema or swelling and a decrease in GPx1 immunoreactivity or fluorescent intensity. Treatment with ebselen (4 mg/kg p.o.) before and immediately after noise exposure reduced both OHC loss and the swelling of the stria vascularis typically observed within 5h post-noise exposure. Interestingly, GPx1 levels increased in the stria vascularis after noise and ebselen treatment vs noise and vehicle-only treatment, and exceeded baseline no noise control levels. These data indicate that ebselen acts to prevent the acute loss of OHCs and reduces the acute swelling of the stria vascularis by two potential mechanisms: one, as a ROS/RNS scavenger through its intrinsic GPx activity, and two, as a stimulator of GPx1 expression or activity. This latter mechanism may be due to the preservation of endogenous GPx1 from ROS/RNS induced degradation and/or the stimulation of GPx1 expression or activity.
Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), a seleno-organic compound, mimics glutathione peroxidase and reacts with peroxynitrite. It is reported to protect against gentamicin- and cisplatin-induced ototoxicity. We investigated whether it protects the cochlea from acoustic trauma. Male pigmented guinea pigs (250-300 g) with normal auditory brainstem response (ABR) thresholds were exposed for 5 h to 125 dB sound pressure level octave band noise centered at 4 kHz. One hour before and 18 h after exposure, they received orally 0.25 ml chloroform solution containing 0, 10, or 30 mg/kg ebselen (n=6, 5 and 5, respectively). The protective effect of ebselen was evaluated by ABR measurement and quantitative hair cell assessment. Treatment significantly (P<0.01) reduced the extent of permanent threshold shifts and outer hair cell loss. Interestingly, the protective effect of a 30 mg/kg dose was less than that of a 10 mg/kg dose. There were no adverse systemic or auditory function effects in three unexposed control subjects given 30 mg/kg ebselen. These findings indicate that ebselen attenuates noise-induced cochlear damage. The concentration that provides optimal protection against such damage has now to be determined.
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.
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.
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.
The NAC was protective against the high-kurtosis noise both at low doses and when given orally by gavage.
The present study was designed to test whether noise-induced temporary threshold shift (TTS) could be attenuated by D-methionine and its possible relation to the biochemical changes of cochlear lateral walls such as ATPase activities and oxidative stress in guinea pigs.
Thirty-two normal-hearing male guinea pigs were randomly divided into saline-treated and D-methionine-treated (300 mg/kg) experimental groups. One hour after treatment, they were exposed to a continuous broadband white noise at 105 +/- 2 dB sound pressure level for 10 min, causing TTS. Each group was then divided into four subgroups based on the number of survival days after noise exposure (0, 1, 2, and 7 days). Each subgroup had four animals and eight ears included. By means of click-evoked auditory brain stem responses (ABR), auditory thresholds of guinea pigs were measured before noise exposure, immediately after noise exposure, and before killing. After animals were killed, cochlear lateral walls were immediately harvested and assayed for enzyme-specific activities of Na+, K+-ATPase and Ca2+-ATPase, lipid peroxidation, and nitric oxide.
A 15.31 +/- 3.80 dB threshold shift was found immediately after noise exposure in saline-pretreated guinea pigs. In contrast, ABR threshold shift was significantly attenuated to 4.06 +/- 2.35 dB in D-methionine-treated animals. Furthermore, D-methionine enhanced the restoration of ABR threshold to baseline level by 1 day. In addition, noise significantly decreased Na+, K+-ATPase, and Ca2+-ATPase activities and increased lipid peroxidation and nitric oxide levels of the cochlear lateral walls. D-methionine significantly protected against all of these changes.
Noise not only induced TTS but also inhibited ATPase activities as well as increased oxidative stress in guinea-pig cochlear lateral walls; all of these changes could be attenuated by d-methionine through its antioxidative property. These results suggest the potential usefulness of d-methionine in protecting from noise-induced ototoxicity.