Journal
DRUG DELIVERY
Volume 25, Issue 1, Pages 1033-1043Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/10717544.2018.1461277
Keywords
Apoptosis; gentamycin; H3K4me2; hair cell; compounds
Categories
Funding
- National Key R&D Program of China [2017YFA0103900, 2016YFC0905200, 2015CB965000]
- National Natural Science Foundation of China [81620108005, 81570913, 81500801, 81622013, 81470692 31500852]
- Pujiang Talents Plan from the Shanghai Municipal Committee of Science and Technology
- Natural Science Foundation from Jiangsu Province [BK20150022]
- Nanjing Medical Science and Technique Development Foundation [YKK17064]
- Fundamental Research Funds for the Central Universities
- Boehringer Ingelheim Pharma GmbH
- Yingdong Huo Education Foundation
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Aminoglycoside-induced hair cell (HC) loss is a major cause of hearing impairment, and the effective prevention of HC loss remains an unmet medical need. Epigenetic mechanisms have been reported to be involved in protecting cochlear cells against ototoxic drug injury, and in this study we developed new bioactive compounds that have similar chemical structures as the epigenetics-related lysine-specific demethylase 1 (LSD1) inhibitors. LSD1 inhibitors have been reported to protect cochlear cells by preventing demethylation of dimethylated histone H3K4 (H3K4me2). To determine whether these new compounds exert similar protective effects on HCs, we treated mouse cochlear explant cultures with the new compounds together with gentamycin. There was a severe loss of HCs in the organ of Corti after gentamycin exposure, while co-treatment with the new compounds significantly protected against gentamycin-induced HC loss. H3K4me2 levels in the nuclei of HCs decreased after exposure to gentamycin, but H3K4me2 levels were maintained in the presence of the new compounds. Apoptosis is also involved in the injury process, and the new compounds protected the inner ear HCs against apoptosis by reducing caspase-3 activation. Together, our findings demonstrate that our new compounds prevent gentamycin-induced HC loss by preventing the demethylation of H3K4me2 and by inhibiting apoptosis, and these results might provide the theoretical basis for novel drug development for hearing protection.
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