d-jnki-1 and Hearing-Loss

As the current trend in cochlear implantation is to prescribe cochlear implants for patients with residual hearing and to use electroacoustic stimulation, cochlear implant damage must be prevented. This article summarizes current research endeavors to prevent electrode insertion trauma and resulting hearing loss.. Alteration in surgical technique is necessary with each new electrode design. Nontraumatic surgical technique also requires minimizing acoustic trauma due to drilling the cochleostomy, mechanical damage from electrode insertion, potential infection, and fibrosis of the cochlea. The pattern of hearing loss following electrode insertion trauma is an immediate loss that results from direct trauma to the macroscopic elements of the cochlea and a delayed loss that may reflect the activation of inflammatory and cell death pathways. Therapies under investigation include glucocorticoids, inhibitors of cell death pathways, and hypothermia.. Electrode insertion trauma-induced hearing loss involves multiple mechanisms ranging from mechanical insertion trauma to activation of inflammatory and cell death pathways. The macroscopic mechanical damage to the cochlea may be prevented by improvement of electrode design and surgical technique. The molecular damage needs further studies to assess the efficacy of novel therapeutic strategies in preserving functional residual hearing.

Topics: Animals; Auditory Threshold; Cochlear Implantation; Electrodes, Implanted; Equipment Design; Glucocorticoids; Hearing Loss; Humans; Hypothermia, Induced; MAP Kinase Kinase 4; Models, Animal; Organ of Corti; Peptides; Wounds and Injuries

Topics: Animals; Clinical Trials as Topic; Hearing Loss; Humans; Peptides

AM-111, a cell-permeable peptide inhibitor of c-Jun N-terminal kinase, was investigated for its protective effects against ischemic damage of the cochlea in gerbils.. Transient cochlear ischemia was introduced in animals by occluding the bilateral vertebral arteries for l5 minutes. Then, 10 μl of AM-111 at a concentration of l, 10, or 100 μM in hyaluronic acid gel formulation was applied onto the round window 30 minutes after the insult. Gel without active substance was used in a control group. Treatment effects were evaluated by auditory brainstem response (ABR) and histology of the inner ear.. In controls, transient cochlear ischemia caused a 25.0 ± 5.0 dB increase in the ABR threshold at 8 kHz and a decrease of 13.3 ± 2.3% in inner hair cells at the basal turn on Day 7. Ischemic damage was mild at 2 and 4 kHz. When the animals were treated with AM-111 at 100 μM, cochlear damage was significantly reduced: the increase in ABR threshold was 3.3 ± 2.4 dB at 8 kHz, and the inner hair cell loss was 3.1 ± 0.6% at the basal turn on Day 7. The effects of AM-111 were concentration dependent: 100 μM was more effective than 1 or 10 μM.. Direct application of AM-111 in gel formulation on the round window was effective in preventing acute hearing loss because of transient cochlear ischemia.

Topics: Animals; Cochlea; Evoked Potentials, Auditory, Brain Stem; Gerbillinae; Hair Cells, Auditory; Hearing Loss; Ischemia; Peptides

Iatrogenic semicircular canal (SC) transection during mastoidectomy for chronic otitis media often leads to profound hearing loss. AM-111, an apoptosis inhibitor, has been shown to mitigate hearing loss resulting from a variety of inner ear injuries. The goal of this study was to determine if round window application of AM-111 following SC transection in the presence of Pseudomonas aeruginosa otitis media (PA-OM) may reduce the associated hearing loss.. Prospective, randomized, controlled study in an animal model.. PA-OM was induced bilaterally in 34 guinea pigs. After 3 days, both bullae were opened and the lateral SC of one ear was transected. AM-111 or vehicle was applied topically to the round window of the ear that had undergone SC transection. Hearing was assessed with auditory brainstem responses.. The mean change in hearing thresholds was significantly less in transected ears treated with AM-111 than those receiving vehicle alone when testing with clicks (22.1 dB vs. 35.0 dB; P = .019) and at 4kHz (11.3 dB vs. 40.0 dB; P = .021). A similar trend was shown with 16 kHz tone pips (27.7 dB vs. 41.1 dB; P = .119).. AM-111 prevents hearing loss from SC transection in the guinea pig model of PA-OM.

Topics: Administration, Topical; Animals; Apoptosis; Guinea Pigs; Hearing Loss; Otitis Media; Peptides; Prospective Studies; Pseudomonas aeruginosa; Pseudomonas Infections; Random Allocation; Semicircular Canals

This study investigated the otoprotective properties of AM-111, an inhibitor of c-Jun N-terminal kinase-mediated apoptosis and inflammation.. A controlled, prospective animal study using a guinea pig model of acute labyrinthitis.. Acute labyrinthitis was generated by injection of antigen into the scala tympani of sensitized guinea pigs. Treatment groups received 100 microL of AM-111 at concentrations of 100 micromol/L, 10 micromol/L, and 1 micromol/L in a hyaluronic acid gel formulation delivered over the round window niche within 1 hour of antigen challenge. Cochlear function was monitored over 21 days with serial auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) measurements followed by histologic analysis.. The ABR results on day 21 demonstrated that untreated control ears for acute labyrinthitis had a mean hearing loss (HL) of 68 +/- 12 dB. In contrast, ears treated with AM-111 (100 micromol/L) had a mean HL of 39 +/- 31 dB. These two groups were statistically different (one-way analysis of variance, P = .03). Secondary outcomes, including DPOAE shift, inner hair cell survival, inflammatory cell counts, and spiral ganglion density, were also statistically significant in favor of an otoprotective effect of AM-111. Lower doses of AM-111 did not produce a statistically significant reduction in HL over controls.. AM-111 delivered over the round window membrane in a 100 microL hyaluronic acid formulation at a 100 micromol/L concentration immediately after induction of acute labyrinthitis in the guinea pig cochlea protects hearing, reduces hair cell loss, and reduces the number of inflammatory cells at 21 days after treatment.

Topics: Animals; Apoptosis; Cell Count; Disease Models, Animal; Evoked Potentials, Auditory, Brain Stem; Female; Follow-Up Studies; Guinea Pigs; Hearing Loss; Labyrinthitis; Peptides; Prospective Studies; Spiral Ganglion; Treatment Outcome

1) Hearing loss caused by electrode insertion trauma has both acute and delayed components; and 2) the delayed component of trauma-initiated hearing loss can be prevented by a direct delivery of a peptide inhibitor of the c-Jun N-terminal kinase cell death signal cascade, that is, D-JNKI-1, immediately after the electrode insertion within the cochlea.. Acute trauma to the macroscopic elements of the cochlea from electrode insertion is well known. The impact of trauma-induced oxidative stress within injured cochlear tissues and the efficacy of drugs (e.g., D-JNKI-1) to prevent apoptosis of damaged hair cells is not well defined.. Hearing function was tested by pure-tone evoked auditory brainstem responses (ABRs) and distortion products of otoacoustic emissions (DPOAEs). D-JNKI-1 in artificial perilymph (AP) or AP alone was delivered into the scala tympani immediately after electrode trauma and for 7 days. Controls were nontreated contralateral and D-JNKI-1-treated ears without electrode insertion trauma.. There was no increase in the hearing thresholds of either the contralateral control ears or in the D-JNKI-1 without trauma animals. There was a progressive increase in ABR thresholds and decrease in DPOAE amplitudes after electrode insertion trauma in untreated and in AP-treated cochleae. Treatment with D-JNKI-1 prevented the progressive increase in ABR thresholds and decrease in DPOAE amplitudes that occur after electrode insertion trauma.. Hearing loss caused by cochlear implant electrode insertion trauma in guinea pigs has both acute and delayed components. The delayed component can be prevented by treating the cochlea with D-JNKI-1.

Topics: Analysis of Variance; Animals; Audiometry, Pure-Tone; Auditory Threshold; Cell Death; Cochlea; Cochlear Implantation; Electrodes; Evoked Potentials, Auditory, Brain Stem; Guinea Pigs; Hearing Loss; JNK Mitogen-Activated Protein Kinases; Organ of Corti; Otoacoustic Emissions, Spontaneous; Peptides; Random Allocation; Time Factors; Treatment Outcome

Recent advances in molecular pharmacology of the cochlea have lead to a much better understanding of the physiology, and especially the pathophysiology, of the sensorineural structures of the organ of Corti. Knowledge of the intimate molecular mechanisms of cellular dysfunction is of considerable use in the development of new therapeutic strategies. Herein, we summarize the mechanisms of sensory hair cell death after various injuries. Based on these molecular mechanisms, we propose novel therapeutic strategies to restore hearing. In addition to permanent hearing loss, exposure to noise or ototoxic drugs also induces tinnitus. We thus review recent findings obtained from a behavioral model of tinnitus in rats. In addition to providing evidence for the site and mechanism of generation of tinnitus induced by salicylate, these results support the idea that targeting cochlear N-methyl-D-aspartate receptors may represent a promising therapeutic strategy for treating tinnitus.

Topics: Animals; Apoptosis; Disease Models, Animal; Hair Cells, Auditory; Hearing Loss; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase 4; Mitogen-Activated Protein Kinase Kinases; Neuroprotective Agents; Peptides; Riluzole; Salicylates; Signal Transduction; Tinnitus

Hearing loss can be caused by a variety of insults, including acoustic trauma and exposure to ototoxins, that principally effect the viability of sensory hair cells via the MAP kinase (MAPK) cell death signaling pathway that incorporates c-Jun N-terminal kinase (JNK). We evaluated the otoprotective efficacy of D-JNKI-1, a cell permeable peptide that blocks the MAPK-JNK signal pathway. The experimental studies included organ cultures of neonatal mouse cochlea exposed to an ototoxic drug and cochleae of adult guinea pigs that were exposed to either an ototoxic drug or acoustic trauma. Results obtained from the organ of Corti explants demonstrated that the MAPK-JNK signal pathway is associated with injury and that blocking of this signal pathway prevented apoptosis in areas of aminoglycoside damage. Treatment of the neomycin-exposed organ of Corti explants with D-JNKI-1 completely prevented hair cell death initiated by this ototoxin. Results from in vivo studies showed that direct application of D-JNKI-1 into the scala tympani of the guinea pig cochlea prevented nearly all hair cell death and permanent hearing loss induced by neomycin ototoxicity. Local delivery of D-JNKI-1 also prevented acoustic trauma-induced permanent hearing loss in a dose-dependent manner. These results indicate that the MAPK-JNK signal pathway is involved in both ototoxicity and acoustic trauma-induced hair cell loss and permanent hearing loss. Blocking this signal pathway with D-JNKI-1 is of potential therapeutic value for long-term protection of both the morphological integrity and physiological function of the organ of Corti during times of oxidative stress.

Topics: Acoustic Stimulation; Aminoglycosides; Animals; Cell Death; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Evaluation, Preclinical; Enzyme Inhibitors; Guinea Pigs; Hair Cells, Auditory; Hearing Loss; Hearing Loss, Noise-Induced; Hearing Tests; In Vitro Techniques; JNK Mitogen-Activated Protein Kinases; Ligands; Mice; Mitogen-Activated Protein Kinases; Neuroprotective Agents; Organ of Corti; Peptides; Proto-Oncogene Proteins c-fos; Signal Transduction