Protection from impulse noise-induced hearing loss with novel Src-protein tyrosine kinase inhibitors

• Published in: Neuroscience research 2011-12, Vol.71 (4), p.348-354
• Main Authors: Bielefeld, Eric C., Hangauer, David, Henderson, Donald
• Format: Article
• Language: English
• Subjects: Acetamides - pharmacology; Animals; Apoptosis; Apoptosis - drug effects; Benzodioxoles - pharmacology; Chinchilla; Cochlea; Cochlea - drug effects; Evoked Potentials, Auditory; Female; Hearing Loss, Noise-Induced - prevention & control; Indoles - pharmacology; Male; Noise; Outer hair cell; Protein Kinase Inhibitors - pharmacology; Pyridines - pharmacology; Quinazolines - pharmacology; Rodentia; Src; src-Family Kinases - antagonists & inhibitors; Tubulin
• ISSN: 0168-0102; 1872-8111
• DOI: 10.1016/j.neures.2011.07.1836

► Src inhibitors used to protect against acoustic trauma to the inner ear. ► Biaryl-based Src inhibitor, KX2-329, protected hearing and sensory cells. ► Indole-based Src inhibitor did not provide statistically significant protection. ► KX2-329 inhibits Src and inhibits tubulin polymerization. ► Inhibiting tubulin polymerization is a novel mechanism to protect the ear from noise. Apoptosis is a significant mechanism of cochlear hair cell loss from noise. Molecules that inhibit apoptotic intracellular signaling reduce cochlear damage and hearing loss from noise. The current study is an extension of a previous study of the protective value of Src-protein tyrosine kinase inhibitors against noise ( Harris et al., 2005). The current study tested three Src-inhibitors: the indole-based KX1-141, the biaryl-based KX2-329, and the ATP-competitive KX2-328. Each of the three drugs was delivered into the chinchillas’ cochleae by allowing the solutions to diffuse across the round window membrane thirty minutes prior to exposure to impulse noise. Hearing thresholds were measured using auditory evoked responses from electrodes in the inferior colliculi. Ears treated with KX2-329 showed significantly lower threshold shifts and outer hair cell losses than the control group. The cochleae treated with KX1-141 and KX2-328 did not show statistically significant protection from the impulse noise. The finding of protection with KX2-329 demonstrates that a biaryl-based Src inhibitor has protective capacity against noise-induced hearing loss that is as good as that demonstrated by KX1-004, a Src inhibitor drug that has been studied extensively as an otoprotectant against noise, and suggests that KX2-329 could be useful for protection against noise.