d-jnki-1 and Hearing-Loss--Noise-Induced

Cochlear implantation trauma and noise-induced hearing loss both involve a physical disruption of the organ of Corti and may involve several mechanisms of cell death at the molecular level, i.e., necrosis, necrosis-like programmed cell death (PCD; type 2 PCD), and apoptosis (type 1 PCD). This article reviews several promising therapeutic strategies that are currently being developed. One of these promising new strategies involves the use of a highly effective peptide inhibitor of the c-Jun N-terminal kinase cell death signal cascade (i.e., D-JNKI-1) to prevent apoptosis of injured auditory hair cells. Our recent studies showed prevention of cochlear implantation-induced hearing loss by infusing this peptide into the cochlea of guinea pigs. Another otoprotective therapy under investigation is the application of mild hypothermia to protect the cochlea from the development of a hearing loss that follows exposure to a physical trauma, e.g., electrode array insertional trauma. These forward-looking strategies have the potential of improving hearing outcomes after cochlear implantation and providing novel means of otoprotection from noise-induced trauma.

Topics: Animals; Apoptosis; Cochlear Implantation; Electrophysiology; Hearing Loss, Noise-Induced; Humans; Hypothermia; JNK Mitogen-Activated Protein Kinases; Organ of Corti; Peptides

Intratympanic administration of a cell-permeable JNK ligand has been shown to prevent hearing loss after acute acoustic trauma in animal models.. Functional and morphological analysis of the treated ears revealed that AM-111 had an excellent otoprotective effect, even when administered hours after the noise exposure. Blocking the signal pathway with D-JNKI-1 is therefore a promising way to protect the morphological integrity and physiological function of the inner ear in various conditions involving acute sensorineural hearing loss.. For the first application of AM-111 in humans, we organized a clinical phase I/II trial in patients with acute acoustic trauma after exposure to firecrackers in Berlin and Munich on New Year's Eve 2005/2006. We randomly selected 11 patients for intratympanic treatment with AM-111 at a concentration of 0.4 mg/ml or 2 mg/ml within 24 h after noise exposure. Pure tone audiometry and otoacoustic emissions were assessed before treatment and on days 3 and 30 thereafter.. Based on clinical experience and on a calculation using an empirically derived exponential hearing recovery function AM-111 seems to have had a therapeutic effect. A total of 13 adverse events were reported in 5 study participants. None of the adverse events were serious or severe.

Topics: Acute Disease; Adult; Audiometry, Pure-Tone; Double-Blind Method; Enzyme Inhibitors; Female; Hearing Loss, Noise-Induced; Humans; JNK Mitogen-Activated Protein Kinases; Male; Middle Aged; Peptides; Prospective Studies; Recovery of Function

Hearing loss is the most prevalent sensory disability worldwide and may be caused by age, drugs or exposure to excessive noise. We have previously developed a minimally-invasive nanohydrogel drug delivery system that successfully delivers nanoparticles into the inner ear. We have substantially extended this technique by functionalizing the nanoparticles and introducing a targeting peptide which recognizes prestin, a transmembrane electromotile protein uniquely expressed in outer hair cells (OHCs) of the inner ear. We demonstrate the successful delivery of molecules and plasmids specifically to OHCs. When compared to untargeted nanoparticles, the delivery of a c-Jun N-terminal kinase (JNK) inhibitor, D-JNKi-1, to OHCs by targeted nanoparticles improved protection from noise induced hearing loss (NIHL). This is the first demonstration of a protection from NIHL using a novel safe and controllable delivery system which is minimally-invasive to the inner ear and, as such, is an extremely appealing technique for use in many clinical applications.

Topics: Animals; Cell Line; CHO Cells; Cricetulus; Drug Delivery Systems; Ear, Inner; Female; Hair Cells, Auditory, Outer; Hearing Loss, Noise-Induced; Humans; JNK Mitogen-Activated Protein Kinases; Mice; Mice, Inbred CBA; Nanoparticles; Neuroprotective Agents; Peptides

We tested and characterized the therapeutic value of round window membrane-delivered (RWM) d-JNKI-1 peptide (Bonny et al., 2001) against sound trauma-induced hearing loss. Morphological characteristics of sound-damaged hair cell nuclei labeled by Hoechst staining show that apoptosis is the predominant mode of cell death after sound trauma. Analysis of the events occurring after sound trauma demonstrates that c-Jun N-terminal kinase (JNK)/stress-activated protein kinase activates a mitochondrial cell death pathway (i.e., activation of Bax, release of cytochrome c, activation of procaspases, and cleavage of fodrin). Fluorescein isothiocyanate (FITC)-conjugated d-JNKI-1 peptide applied onto an intact cochlear RWM diffuses through this membrane and penetrates cochlear tissues with the exception of the stria vascularis. A time sequence of fluorescence measurements demonstrates that FITC-labeled d-JNKI-1 remains in cochlear tissues for as long as 3 weeks. In addition to blocking JNK-mediated activation of a mitochondrial cell death pathway, RWM-delivered d-JNKI-1 prevents hair cell death and development of a permanent shift in hearing threshold that is caused by sound trauma in a dose-dependent manner (EC50 = 2.05 microM). The therapeutic window for protection of the cochlea from sound trauma with RWM delivery of d-JNKI-1 extended out to 12 h after sound exposure. These results show that the mitogen-activated protein kinase/JNK signaling pathway plays a crucial role in sound trauma-initiated hair cell death. Blocking this signaling pathway with RWM delivery of d-JNKI-1 may have significant therapeutic value as a therapeutic intervention to protect the human cochlea from the effects of sound trauma.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Carrier Proteins; Caspases; Cytochromes c; Guinea Pigs; Hair Cells, Auditory; Hearing Loss, Noise-Induced; JNK Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; Microfilament Proteins; Mitochondria; Necrosis; Peptides; Phosphorylation; Protein Transport; Proto-Oncogene Proteins c-jun; Round Window, Ear

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