A putative role of p53 pathway against impulse noise induced damage as demonstrated by protection with pifithrin-alpha and a Src inhibitor

• Published in: Neuroscience research 2014-04, Vol.81-82, p.30-37
• Main Authors: Fetoni, Anna R., Bielefeld, Eric C., Paludetti, Gaetano, Nicotera, Thomas, Henderson, Donald
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Auditory Threshold - drug effects; Benzothiazoles - pharmacology; Chinchilla; Cochlea - injuries; Cochlea - metabolism; Hearing Loss, Noise-Induced - metabolism; Indoles - pharmacology; Noise; p53; Pifithrin alpha; Rodentia; Signal Transduction - drug effects; Src inhibitor; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - metabolism; Toluene - analogs & derivatives; Toluene - pharmacology; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - metabolism; Tyrosine kinase proteins
• ISSN: 0168-0102; 1872-8111
• DOI: 10.1016/j.neures.2014.01.006

•Impulse noise leads to OHC pathology within 24h after exposure.•In the normal cochlea phospho-p53 (Ser 15) was lightly expressed in the cochlea.•P53 is overexpressed in both OHC and Hensen cells in the early stage of damage.•OHC damage could be reduced by PFT, a p53 inhibitor; or by KX1-004.•A greater protection by KX1-004 suggests a role of Src-dependent pathway in noise. Exposure to high-level noise leads to oxidative stress and triggers apoptosis of the hair cells. This study examined whether p53, a tumor suppressor protein, is activated in the cochlea following impulse noise exposure. Inhibition of p53 with pifithrin alpha, a specific p53 inhibitor, or KX1-004, a Src-protein tyrosine kinase inhibitor, was tested to determine if p53 inhibition could reduce noise-induced hearing loss and cochlear damage. Chinchillas were pre-treated with a local administration of pifithrin alpha or KX1-004 and exposed to impulse noise. The chinchillas were assessed for threshold shift at 1 and 24h after the noise. At 4 or 24h post noise, the cochleae were removed and organs of Corti were examined to assess the damage to the cells and upregulation of p53 by the noise. Apoptosis was evident in both outer hair cells and supporting cells. Phospho-p53 (Ser 15) was upregulated 4h and 24h after the noise. KX1-004 and pifithrin alpha both decreased threshold shift and the number of missing outer hair cells. These results indicate that p53 is involved in the early stages of noise-induced cell death and inhibition of this signaling pathway is a potential protective strategy against noise-induced hearing loss.