title: E2F1-CDK1 pathway activation in kanamycin-induced spiral ganglion cell apoptosis and the protective effect of CR8.
abstract: Cochlear hair cell loss results in the secondary loss of spiral ganglion cells (SGCs). The death of these SGCs is due to apoptosis. The E2F1-cyclin dependent kinase 1 (CDK1) pathway is believed to represent an important mechanism of neuronal cell death. However, the role of this pathway in spiral ganglion neuronal apoptosis has not yet been reported. In this study, we deafened guinea pigs with a subcutaneous injection of kanamycin followed by an intravenous infusion of furosemide and then assayed the expression levels of cleaved caspase-3, E2F1, CDK1 and cleaved caspase-9 during the induced SGC apoptosis. Our results revealed that co-administration of kanamycin and furosemide rapidly induced hair cell loss in the guinea pigs and then resulted in a progressive loss of SGCs. Expression levels of E2F1 and CDK1 were obviously up-regulated at 1 and 3 days after deafening. Cleaved caspase-9 also increased robustly 1 or 2 weeks after the deafening procedure. The up-regulation of E2F1, CDK1 and cleaved caspase-9 was significantly attenuated by the systemic injection of CR8 (1mg/kg/day, intraperitoneally) starting at 5min after deafening. These findings indicate that the activation of the E2F1-CDK1 pathway and cell cycle re-entry contributes to the apoptosis of SGCs and that the selective inhibition of this signaling cascade may represent an attractive therapeutic strategy. CR8 has the potential to protect SGCs from apoptosis.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China; Department of Otolaryngology-Head and Neck Surgery, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai 200080, China.
authors.forename: Yu-ying
authors.initials: YY
authors.lastname: Liu
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
authors.forename: Guo-peng
authors.initials: GP
authors.lastname: Wang
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Peng
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
authors.forename: Jing-ying
authors.initials: JY
authors.lastname: Guo
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xie
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China. Electronic address: gongss1962@163.com.
authors.forename: Shu-sheng
authors.initials: SS
authors.lastname: Gong
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism; D003638:Deafness / Q000378:metabolism / Q000473:pathology; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D006168:Guinea Pigs; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000473:pathology; D007612:Kanamycin / Q000494:pharmacology*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D015398:Signal Transduction; D013136:Spiral Ganglion / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D000900:Anti-Bacterial Agents; C532131:CR8 compound; D050687:E2F1 Transcription Factor; D018696:Neuroprotective Agents; D011687:Purines; D011725:Pyridines; D007612:Kanamycin; D016203:CDC2 Protein Kinase; D053453:Caspase 9
keywords: Apoptosis; CDK1; CR8; Cochlear; E2F1; Spiral ganglion cells