title: AM-111 protects against permanent hearing loss from impulse noise trauma.
abstract: The otoprotective peptide AM-111, a cell-permeable inhibitor of JNK mediated apoptosis, was tested for its efficacy as a rescue agent following impulse noise trauma. Single dose administrations of AM-111 at 1h or 4h post-impulse noise exposure (155 dB peak SPL) via systemic or local routes were evaluated with a total of 48 chinchillas. The animals received the compound either by IP injection or locally onto the round window membrane (hyaluronic acid gel formulation or osmotic mini-pump). Efficacy was determined by auditory brainstem responses (ABR) as well as cytocochleograms. Three weeks after impulse noise exposure, permanent threshold shifts (PTS) were significantly lower for AM-111 treated ears compared to controls, regardless of the drug administration route and the time point of drug delivery. Even the treatments which started 4h post-noise exposure, reduced hearing loss in the 2-8 kHz range compared to controls by up to 16-25 dB to a PTS as low as 6-17 dB, demonstrating significant protection against permanent hearing loss from impulse noise trauma. These findings suggest a key role for JNK mediated cochlear sensory cell death from oxidative stress.
authors.affiliation: Naval Medical Center Spatial Orientation Center, 34800 Bob Wilson Dr. Suite 200, Naval Medical Center San Diego, San Diego, CA 92134-5000, USA.
authors.forename: John K M
authors.initials: JK
authors.lastname: Coleman
authors.forename: Cherllynn
authors.initials: C
authors.lastname: Littlesunday
authors.forename: Ronald
authors.initials: R
authors.lastname: Jackson
authors.forename: Thomas
authors.initials: T
authors.lastname: Meyer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002682:Chinchilla; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D005260:Female; D005782:Gels; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000473:pathology; D006317:Hearing Loss, Noise-Induced / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015918:Infusion Pumps, Implantable; D007274:Injections, Intraperitoneal; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D005782:Gels; D010455:Peptides; D048031:JNK Mitogen-Activated Protein Kinases