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ARTICLES Table of Contents   
Year : 2005  |  Volume : 7  |  Issue : 29  |  Page : 24-30
A comparison of the protective effects of systemic administration of a pro-glutathione drug and a Src-PTK inhibitor against noise-induced hearing loss

1 Center for Hearing and Deafness, Department of Communicative Disorders and Sciences, State University of New York at Buffalo, Buffalo, NY 14214, USA
2 Department of Defense Spatial Orientation Center, Department of Otolaryngology, Naval Medical Center San Diego, San Diego, CA 92134-2200, USA

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  Abstract 

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 from10 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.

Keywords: Apoptosis, cochlea, glutathione, noise, reactive oxygen species, Srch

How to cite this article:
Bielefeld EC, Hynes S, Pryznosch D, Liu J, Coleman JK, Henderson D. A comparison of the protective effects of systemic administration of a pro-glutathione drug and a Src-PTK inhibitor against noise-induced hearing loss. Noise Health 2005;7:24-30

How to cite this URL:
Bielefeld EC, Hynes S, Pryznosch D, Liu J, Coleman JK, Henderson D. A comparison of the protective effects of systemic administration of a pro-glutathione drug and a Src-PTK inhibitor against noise-induced hearing loss. Noise Health [serial online] 2005 [cited 2020 May 26];7:24-30. Available from: http://www.noiseandhealth.org/text.asp?2005/7/29/24/31875

  Introduction Top


Recent investigations into the cellular processes that underlie noise-induced cochlear damage and hearing loss have revealed two important mechanisms involved in noise-induced hair cell death. The first of those mechanisms is reactive oxygen species (ROS) as a cause of cochlear pathology, including hair cell loss. ROS include oxygen-based molecules with an unpaired electron (free radicals, including superoxide, the hydroxyl radical and peroxynitrite), as well as oxygen-based molecules that will readily react to form free radicals (including hydrogen peroxide). [1] Several studies have shown increases in ROS [2],[3] and ROS activity [4],[5] in the cochlea after noise exposure. Pretreatment of the cochlea with antioxidants (which scavenge ROS or convert them to less harmful molecules) or pro-antioxidant drugs can attenuate noise damage and hearing loss. [6],[7],[8],[9],[10],[11],[12]

The second important mechanism in noise-induced cochlear damage is that noise-exposed hair cells die through apoptosis. [14],[15],[16] Contrasted with necrotic cell death, which is a passive process, apoptosis is an active, regulated cell death process that consumes energy. [17] Through the activation of a family of specific cysteine proteases called caspases, the cell systematically disassembles. [18] Throughout the process of apoptosis, the cell membrane remains intact and the cell condenses and pulls away from neighboring cells resulting in minimal damage to surrounding tissue. Apoptosis can be initiated by a number of triggers including mechanical stress [19],[20],[21],[20] and ROS, [21] both of which occur in the cochlea as a result of noise exposure.

The classification of apoptosis or necrosis is dependent on the observation of morphological and/or biochemical markers. Morphologically, apoptotic cells exhibit shrunken nuclei and subsequently break into apoptotic bodies or broken off fragments of the cell. Markers of apoptosis were found in the cochlea following noise exposure v apoptosis was implicated as a driving factor contributing to the growth of the hair cell lesion after cessation of the noise exposure. Pharmacological interruption of apoptotic cellular signaling pathways has been shown to reduce noise-induced hearing loss (NIHL). [13],[22]

The current study is an extension of two previous studies that used pharmacological interventions to protect against noise damage. One of the studies used N-acetyl-l-cysteine (LNAC) to protect the cochlea by neutralizing ROS [10] and the other used KX1-004 to protect the cochlea through inhibition of the formation of ROS and inhibition of apoptosis. [22] LNAC is an FDA-approved compound that enhances the supply of glutathione, a major antioxidant molecule that scavenges some of the most dangerous ROS, the hydroxyl radical (OH●) and peroxynitrite (ONOO-). Kopke et al [10] used systemic injections of LNAC dissolved in saline (along with salicylate dissolved in saline) before a six-hour noise exposure to reduce the amount of threshold shift and outer hair cell (OHC) loss that resulted.

KX1-004 is non-ATP competitive Src protein tyrosine kinase inhibitor. The Src signaling pathway is thought to be involved in the initiation of apoptosis from mechanical stress. The Src pathway may also be involved in the generation of superoxide and other downstream ROS through a complex pathway involving the activation of NADPH oxidase, an enzyme shown to be active in the cochlea. [23],[24],[25] Since the Src pathway was thought to be involved in both mechanical stress-induced apoptosis and involved in the generation of ROS, interruption of that pathway was targeted as a possible protective strategy to prevent NIHL. Harris et al [22] used KX1-004 (30 mM) dissolved in DMSO and delivered it to the cochleae of chinchillas via diffusion across the round window membrane. The drug was found to significantly reduce temporary threshold shift (TTS), permanent threshold shift (PTS) and OHC loss resulting from a noise exposure.

The purpose of the current study was to examine the protective effects of LNAC and KX1-004 delivered systemically. The two drugs were compared to each other and to a group of vehicle controls. The groups were measured for TTS, PTS and OHC loss that resulted from a long duration noise exposure of six hours per day for four days. Previous studies of Src inhibition before noise focused on single-day noise exposures of either four hours or 75 seconds duration. [22] Observation of possible protection from a longer-term noise exposure with the Src inhibitor would provide additional insight into the involvement of Src-mediated apoptosis in cochlear damage from long-term exposures. Because the Src inhibitor may be capable of preventing the generation of ROS, rather than scavenging and eliminating ROS that have already formed, KX1-004 was thought to be effective in much lower doses than antioxidants. To test this hypothesis, KX1-004 was given at a lower dose (50 mg/kg) than the LNAC (325 mg/kg).


  Materials and Methods Top


Seventeen adult chinchillas weighing between 400 and 700 g were divided into three different experimental groups. Prior to surgical procedures and between test times, the animals were housed in a quiet colony. All procedures involving use and care of the animals were reviewed and approved by the State University of New York at Buffalo Institutional Animal Care and Use Committee.

Inferior colliculus (IC) electrode implantation

To test hearing sensitivity, all animals were implanted with IC electrodes. The animals were intramuscularly injected with ketamine (60 mg/kg) and acepromazine (0.5 mg/kg) to achieve a deep plane of anesthesia. The animals were then placed in a stereotaxic apparatus. The electrodes were inserted bilaterally into the region of the IC. A ground electrode was placed in the rostral cranium. [26] The animals were allowed to recover for two weeks prior to evoked potential testing.

Evoked potential testing

During evoked potential threshold testing, the chinchillas were awake and secured in a restraint tube. [27] Test stimuli consisted of alternating phase tone bursts at frequencies of 0.5, 1, 2, 4 and 8 kHz. Signals were generated using Tucker Davis Technologies (TDT) SigGen software. Each tone burst had a 2 msec rise/fall time, a 1 ms plateau with a cosine ramp and were presented at a 21/sec rate. Signals were generated digitally with a TDT D/A converter at a 50 kHz sampling rate and were 20 kHz low-pass filtered. Signals were routed to an earphone (Etymotic ER-1) that was inserted into the canal of the test ear. Acoustic stimuli were calibrated prior to each testing session. The evoked responses were amplified by 20,000 times by a TDT Headstage-4 bioamplifier and bandpass filtered at a range of 100-3000 Hz. One hundred samples were taken at each stimulus level. Averaged responses were displayed on a PC monitor using TDT BioSig software. The level of the signal was decreased in 5-dB steps from 90 to a point at which no response was detectable. Threshold was determined as the midpoint between the level at which a clear response was elicited and the next lowest level.

Drug preparation and administration

L-NAC (Sigma Chemicals A7250) was dissolved in physiological saline at a concentration of 81.25 mg/ml. The solution was then brought up to physiological ph with the addition of sodium hydroxide. Animals were given the LNAC solution at a level of 325 mg/kg (equal to 4.0 ml of the solution per kg) by intraperitoneal injection one hour before each of the four days of the noise exposure. KX1-004, the Src-PTK inhibitor, was obtained through collaboration with Dr. David Hangauer, Senior Vice President for Research and Development, Kinex Pharmaceuticals (www.kinexpharma.com). The drug was put into suspension in sterile, highly refined, low acidity olive oil (Sigma 01514). The suspension was delivered at 50 mg/kg (approximately 4.0 ml of the suspension per kg) by subcutaneous injection one hour before each of the four days of the noise exposure. Control animals were given one of the two drug vehicles (physiological saline by intraperitoneal injection or olive oil by subcutaneous injection) on the same schedule as the drug groups.

Noise exposure

The noise exposure was a continuous octave-band noise centered at 4 kHz of 100 dB SPL for six hours/day for four days. The noise was generated by a D/A converter on a signal processing board in a personal computer. The noise was routed through an attenuator (HP 350 D), a filter (Krohn-Hite 3550R) and an amplifier (NAD 2200 PE). The acoustic horn (JBL 2360) was suspended directly above the chinchillas' cages. Prior to each day of the exposure, the noise level was calibrated with a Larson Davis 800B sound level meter.

Assessment of threshold shift

To assess noise-induced threshold shift in the animals, IC evoked potential testing was performed before the noise exposure and four time points following the final day of the exposure: 24 hours post exposure (day 1), four days post (day 4), eight days post (day 8) and twenty-one days post (day 21). Pre-exposure thresholds were subtracted from the four threshold measurements to calculate threshold shift at each time point. The 21-day measurement provided the data for calculation of PTS.

Histology

After the final physiological measurements were obtained, the animals were rapidly sacrificed using inhalation of CO2. Both auditory bullae were removed from each animal. The stapes were removed from each cochlea and the cochleae were then perfused with 10% buffered formalin. For counts of the missing cells, the cochleae were perfused with a solution of 0.2 M sodium succinate and 0.1% nitrotetrazolium blue in 0.2 M phosphate buffer. The cochleae were rinsed and fixed 4% paraformaldehyde for 24 hours. The organs of Corti were then dissected from the cochleae and mounted as surface preparations. Missing OHCs were counted along the length of the organ of Corti that was affected by the noise exposure (60-90% from the apex). The frequency-place map for cochleograms was derived from Greenwood [28] and has been used in previous noise protection studies with the chinchilla. [10],[11]

Statistical analysis

A 3-factor ANOVA (Drug Group X Frequency X Time) was used to analyze differences between the means of the three experimental groups (LNAC, KX1-004, Vehicle Controls) across the five different test frequencies at the four different time points post noise exposure. Group and Frequency were analyzed as between-subjects variables and time (days post noise) was analyzed as a repeated measure. If a significant main effect occurred for group or frequency, post hoc testing with Tukeys A tests was performed to delineate the nature of the differences. If a significant main effect of day occurred, the different days were compared with paired-subjects t-tests. For comparing differences between drug groups with respect to OHC loss, a two-way ANOVA (concentration X distance along cochlea from the apex) was used, with post-hoc Tukeys A tests to delineate any main Group effect.


  Results Top


Pre-exposure thresholds

The two experimental groups had six animals each and the control group had five animals. Statistical analysis (Two-way ANOVA with Tukeys post-hoc test) revealed a significant main effect of frequency, but no main effect of Group or group X frequency interaction. The absence of differences between groups prior to noise exposure gave confidence that the differences observed in threshold shift between groups were a result of the protective drug administrations the groups received before each day of the noise exposure.

Threshold shifts induced by noise

Threshold shifts for the three groups at the five frequencies tested are shown for day 1 [Figure - 1], day 4 [Figure - 2], day 8 [Figure - 3] and day 21 [Figure - 4]. At day 1, substantial threshold shifts occurred at 2-8 kHz, with minimal shifts at 0.5-1 kHz. Such a pattern of threshold shifts was expected with a 4 kHz octave band noise exposure. All groups exhibited recovery (10-35 dB) at 2-8 kHz over the period of time from day 1 to day 21. The three-way ANOVA showed significant main effects of Group, Day and Frequency, as well as significant two-way interactions of group X frequency and frequency X day. The frequency X day interaction was expected since there was little recovery over time at 0.5 and 1 kHz due to the small threshold shifts induced at those frequencies. The group X frequency interaction was broken down with a series of one-way ANOVAs at each frequency comparing the three groups collapsed across days. One-way ANOVAs found no differences between groups at 0.5 and 1 kHz. At 2 kHz, the KX1-004 Group had significantly lower threshold shift than the vehicle controls (P=0.018). No significant differences were found at 4 kHz. At 8 kHz, both the LNAC and KX1-004 groups were lower than the vehicle control group (ps=0.001 and 0.005, respectively).

OHC loss

OHC loss cytocochleograms for the three groups are plotted in [Figure - 5]. Mean OHC losses were averaged and analyzed for the region along the basilar membrane corresponding to the 2-8 kHz region of hearing. Mean OHC losses for the Control group were 29-41% in the 2-8 kHz range. The LNAC and KX1-004 groups had mean OHC losses of less than 10% across the same region. The two-way ANOVA revealed a significant main effect of Group ( P <0.001), with no two-way interaction. Tukeys A post hoc testing revealed that both the LNAC and KX1-004 treated groups had lower OHC loss than the control group, but that the LNAC and KX1-004 groups were not different from each other.


  Discussion Top


Consistent with past findings, both LNAC and KX1-004 were able to reduce TTS and PTS compared to the vehicle controls. KX1-004 was more effective than LNAC at the 2 kHz test frequency, but the drugs were equally effective at 8 kHz. Additionally, both drugs afforded nearly complete protection from OHC loss across the range affected by the 4 kHz octave band noise exposure. The current findings extend the protection studies with LNAC and KX1-004 to a longer-term noise exposure of six hours per day for four days. Additionally, the current study demonstrates the effectiveness of KX1-004 when delivered systemically, via subcutaneous injections. While the finding of protection against noise with systemic administration of a Src inhibitor is novel, the finding is consistent with past studies that confirmed the efficacy of protection from noise with anti-apoptotic agents that inhibit the c-Jun N-terminal kinase (JNK) pathway, both those delivered directly into the cochlea [29] and those administered systemically. [13],[30]

KX1-004 demonstrated greater effectiveness than LNAC at a lower dose (50 mg/kg of KX1-004 compared to 325 mg/kg of LNAC). Although strict comparison cannot be made since KX1-004 was delivered in suspension compared to solution for LNAC, the effectiveness of KX1-004 at a lower dose may be attributed to the fact that Src inhibition may be protecting hair cells from noise in a number of ways. Reduction of mechanical stress-induced apoptosis may be a significant intervention to restrict the growth of the hair cell lesion over time following the noise exposure. [15] Additionally, Src inhibition may be limiting the noise-induced generation of superoxide and subsequent downstream toxic ROS. [16] Superoxide alone has been shown to trigger hair cell death. [24] and can also be converted into the hazardous hydroxyl radical through contact with superoxide dismutase and transition metal ions or converted into peroxynitrite through contact with nitric oxide. [1] Restriction of the generation of superoxide, rather than scavenging and neutralizing ROS with antioxidant treatments, may help explain why KX1-004 was effective at a low dose. Further study of the two drugs at various dosages is warranted before stronger conclusions about the relative effectiveness of the two drugs can be made.

There is uncertainty of exactly how much of either drug enters the cochlea when delivered via systemic injection. Therefore, ongoing investigations will sample cochlear fluid levels to determine the levels of the drug in perilymph when delivered systemically. Differential cochlear uptake of the drugs could be an influencing factor in determining the relative effectiveness of each drug and the potential individual protective benefit any subject could receive from them. Additionally, since the current study uses one specific type of noise exposure, further studies of systemic LNAC and KX1-004 injections as protective strategies are warranted using various other noise exposures with different durations and intensities. Also, since the two drugs were effective separately as protective strategies and they act against potentially different mechanisms, using the two drugs in combination is worthy of future exploration, since the protective effect of the combination may be even greater than either drug alone.

Side effects from the drugs were minimal. None of the three groups' mean weights changed significantly (not shown). Overall, the findings of the current study extend the findings of Harris et al [22] that the Src inhibitor, KX1-004, has significant potential as an otoprotective drug against noise exposure when delivered systemically. The effective use of the drug systemically is a step forward from the round window membrane mode of delivery in terms of applying the drug practically. The study also confirmed the effectiveness of LNAC when delivered systemically for a prolonged, four-day exposure. [10]


  Acknowledgements Top


The authors thank Dr. Bohua Hu, Dr. David Hangauer and his laboratory and the Kinex Corporation for their contributions to the design and execution of the project, including the supply of KX1-004. We would also like to thank Drs. Ronald Jackson and Richard Kopke for their collaboration. Additionally we would like to thank Jawaad Sheriff for his assistance with data collection. The views expressed in this article are those of the authors and do not reflect the official policy or position of the Departments of the Navy, Army or Defense or the United States Government. Research was supported by the NIDCD Grant (1 P01 DC03600-01A1) to D.H.

 
  References Top

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Correspondence Address:
Eric C Bielefeld
Center for Hearing and Deafness, State University of New York at Buffalo , Buffalo, NY 14214
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1463-1741.31875

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