Blocking c-Jun-N-terminal kinase signaling can prevent hearing loss induced by both electrode insertion trauma and neomycin ototoxicity

Eshraghi, Adrien A.; Wang, Jing; Adil, Eelam; He, Jianbin; Zine, Azel; Bublik, Michael; Bonny, Christophe; Puel, Jean–Luc; Bałkany, Thomas J.; Water, Thomas R. Van De

doi:10.1016/j.heares.2006.09.008

Cited by 103 publications

(75 citation statements)

References 44 publications

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“…A rat model of cochlear implant trauma, created by the insertion and immediate withdrawal of a 'model' cochlear implant electrode, is characterized by an immediate followed by a progressive hearing loss [Eshraghi et al, 2005]. With this model, both the immediate and the delayed hearing loss were diminished by hypothermia, and in a guinea pig model the delayed hearing loss was reduced by a week-long perfusion of the scala tympani with the antiapoptotic agent D-JNKI-1 [Eshraghi et al, , 2007 . While these results are encouraging, certain characteristics of this model might limit its translation and relevance to the clinical arena.…”

Section: Introductionmentioning

confidence: 99%

Effects of Round Window Dexamethasone on Residual Hearing in a Guinea Pig Model of Cochlear Implantation

James

Eastwood²,

Richardson³

et al. 2007

Audiol Neurotol

131

152

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To study electric acoustic stimulation, we have developed a model of guinea pig cochlear implantation via a cochleostomy. Thirty minutes prior to implantation, a hyaluronic acid/carboxymethylcellulose bead, loaded with either dexamethasone or normal saline, was placed upon the round window membrane. Animals that did not receive beads acted as controls. Pure-tone auditory brainstem response thresholds were estimated before and after electrode insertion, and 1 and 4 weeks later. Selected cochlear histology was performed. Results: Dexamethasone could be detected in the cochlea for 24 h after cochlear implantation. Thresholds were elevated across frequencies in all animals immediately after surgery. These thresholds recovered completely at and below 2 kHz, and partially at higher frequencies by 1 week after implantation. At 32 kHz, but not the lower frequencies, the presence of dexamethasone had a significant protective effect upon hearing, which increased in magnitude over time. The protection was greatest in difficult implantations where an intractable resistance to electrode insertion was met. There was a persistent foreign body reaction at the site of implantation of saline-treated implanted ears but not in the dexamethasone-treated implanted ears. Conclusion: Short-term preoperative delivery of dexamethasone through the round window can protect residual hearing during cochlear implantation, especially during technically difficult surgery.

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Section: Introductionmentioning

confidence: 99%

Effects of Round Window Dexamethasone on Residual Hearing in a Guinea Pig Model of Cochlear Implantation

James

Eastwood²,

Richardson³

et al. 2007

Audiol Neurotol

131

152

View full text Add to dashboard Cite

show abstract

“…In addition, aminoglycoside-induced hair cell apoptosis is mediated by c-Jun N-terminal kinase (JNK), a member of the mitogenactivated protein kinase family. Inhibition of JNK using a variety of methods inhibits aminoglycoside-induced hair cell death both in vitro and in vivo (Pirvola et al 2000;Ylikoski et al 2002;Sugahara et al 2006;Eshraghi et al 2007). Furthermore, aminoglycoside exposure results in cytochrome c release from the mitochondria and caspase activation in hair cells Cunningham et al 2002;Sugahara et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Hsp70 inhibits aminoglycoside-induced hearing loss and cochlear hair cell death

Taleb

Brandon

Lee

et al. 2009

Cell Stress and Chaperones

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Sensory hair cells of the inner ear are sensitive to death from aging, noise trauma, and ototoxic drugs. Ototoxic drugs include the aminoglycoside antibiotics and the antineoplastic agent cisplatin. Exposure to aminoglycosides results in hair cell death that is mediated by specific apoptotic proteins, including c-Jun N-terminal kinase (JNK) and caspases. Induction of heat shock proteins (Hsps) can inhibit JNK-and caspase-dependent apoptosis in a variety of systems. We have previously shown that heat shock results in robust upregulation of Hsps in the hair cells of the adult mouse utricle in vitro. In addition, heat shock results in significant inhibition of both cisplatin-and aminoglycoside-induced hair cell death. In this system, Hsp70 is the most strongly induced Hsp, which is upregulated over 250-fold at the level of mRNA 2 h after heat shock. Hsp70 overexpression inhibits aminoglycoside-induced hair cell death in vitro. In this study, we utilized Hsp70-overexpressing mice to determine whether Hsp70 is protective in vivo. Both Hsp70-overexpressing mice and their wildtype littermates were treated with systemic kanamycin (700 mg/kg body weight) twice daily for 14 days. While kanamycin treatment resulted in significant hearing loss and hair cell death in wild-type mice, Hsp70-overexpressing mice were significantly protected against aminoglycosideinduced hearing loss and hair cell death. These data indicate that Hsp70 is protective against aminoglycoside-induced ototoxicity in vivo.

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“…As there is increasing interest in the possibility of implanting patients with high-frequency hearing loss but good low-frequency hearing, it has become an important goal to perform the implantation with minimal damage to residual hearing [72,73,74]. Other drug candidates include the use of neurotrophins to preserve spiral ganglion cells [75] and apoptosis inhibitors to minimize insertion trauma [76]. There are several possible strategies of intracochlear drug delivery in combination with cochlear implants, including applications to the RWM prior to surgery [77], one-shot injections into the ST at the time of implantation [78,79], ‘bathing’ the electrode in drug solution or a gel preparation prior to insertion into the cochlea, drug release from the electrode carrier itself which also functions as a scaffold, drug release from a reservoir in the electrode carrier, drug injection through an incorporated channel attached to a pump [80,81], or by surface coating of the electrode carrier with a controlled-release formulation [82].…”

Section: Delivery Systems and Protocolsmentioning

confidence: 99%

Principles of Local Drug Delivery to the Inner Ear

2009

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As more and more substances have been shown in preclinical studies to be capable of preventing damage to the inner ear from exposure to noise, ototoxic drugs, ischemia, infection, inflammation, mechanical trauma and other insults, it is becoming very important to develop feasible and safe methods for the targeted delivery of drugs to specific regions in the inner ear. Recently developed methods for sampling perilymph from the cochlea have overcome major technical problems that have distorted previous pharmacokinetic studies of the ear. These measurements show that drug distribution in perilymph is dominated by passive diffusion, resulting in large gradients along the cochlea when drugs are applied intratympanically. Therefore, in order to direct drugs to specific regions of the ear, a variety of delivery strategies are required. To target drugs to the basal cochlear turn and vestibular system while minimizing exposure of the apical cochlear turns, single one-shot intratympanic applications are effective. To increase the amount of drug reaching the apical cochlear turns, repeated intratympanic injections or controlled-release drug delivery systems, such as biodegradable biopolymers or catheters and pumps, are more effective. However, if the applied substance does not easily pass through the round window membrane, or if a more widespread distribution of drug in the ear is required, then intralabyrinthine injections of the substance may be required. Intralabyrinthine injection procedures, which are currently in development in animals, have not yet been proven safe enough for human use.

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Blocking c-Jun-N-terminal kinase signaling can prevent hearing loss induced by both electrode insertion trauma and neomycin ototoxicity

Cited by 103 publications

References 44 publications

Effects of Round Window Dexamethasone on Residual Hearing in a Guinea Pig Model of Cochlear Implantation

Effects of Round Window Dexamethasone on Residual Hearing in a Guinea Pig Model of Cochlear Implantation

Hsp70 inhibits aminoglycoside-induced hearing loss and cochlear hair cell death

Principles of Local Drug Delivery to the Inner Ear

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