title: Lysine-specific demethylase 1 inhibitors protect cochlear spiral ganglion neurons against cisplatin-induced damage.
abstract: Cisplatin is a widely used chemotherapeutic drug, but one of its side effects is ototoxicity. Epigenetic-related drugs, such as lysine-specific demethylase 1 (LSD1) inhibitors, have been reported to protect against cisplatin-induced hair cell loss by preventing demethylation of histone H3K4 (H3K4me2). However, the protective effect of LSD1 inhibitors in spiral ganglion neurons (SGNs) remains unclear. To investigate whether LSD1 inhibitors exert similar protective effects on SGNs, we treated mouse cochlear explant cultures with LSD1 inhibitors (2PCPA, S2101, or CBB1007) together with cisplatin. Low concentrations of cisplatin damaged SGNs much more than high concentrations, and blocking the demethylation of H3K4me2 with LSD1 inhibitors prevented the SGNs from injury. Reactive oxygen species are also involved in the injury process, and LSD1 inhibitors protected SGNs by increasing the expression level of the antioxidant gene Slc7a11 and decreasing the level of the pro-oxidant gene lactoperoxidase (Lpo). Our findings show that LSD1 inhibitors prevent cisplatin-induced SGN loss by regulating the demethylation of H3K4 and preventing increases of reactive oxygen species levels, which might provide a potential therapeutic strategy for cisplatin-induced hearing loss.
authors.affiliation: aDepartment of Otorhinolaryngology, Research Center, Key Laboratory of Hearing Science, Ministry of Health, Affiliated Eye and ENT Hospital; State Key Laboratory of Medical Neurobiology; Institute of Stem Cell and Regeneration Medicine, Institutes of Biomedical Science, Fudan University, Shanghai bDepartment of Otolaryngology Head and Neck Surgery, the First Affiliated Hospital, Xiamen University, Xiamen, Fujian, China.
authors.forename: Ao
authors.initials: A
authors.lastname: Li
authors.forename: Yingzi
authors.initials: Y
authors.lastname: He
authors.forename: Shan
authors.initials: S
authors.lastname: Sun
authors.forename: Chengfu
authors.initials: C
authors.lastname: Cai
authors.forename: Huawei
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001550:Benzamidines / Q000494:pharmacology*; D002945:Cisplatin / Q000633:toxicity*; D003521:Cyclopropanes / Q000494:pharmacology*; D005260:Female; D056466:Histone Demethylases / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010647:Phenyl Ethers / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D055493:Spiral Ligament of Cochlea / Q000187:drug effects* / Q000473:pathology; D014191:Tranylcypromine / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001550:Benzamidines; C000604717:CBB1007; D003521:Cyclopropanes; D018696:Neuroprotective Agents; D010647:Phenyl Ethers; D010879:Piperazines; C000604718:S2101 compound; D014191:Tranylcypromine; D056466:Histone Demethylases; C504076:KDM1a protein, mouse; D002945:Cisplatin