Department of Otolaryngology Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu Provincial Key Medical Discipline (Laboratory), No.321 Zhongshan Road,Nanjing 210008, China.
ENT institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China.
Neurobiol Dis. 2023 Jul;183:106176. doi: 10.1016/j.nbd.2023.106176. Epub 2023 May 31.
Aminoglycoside antibiotics (AGAs) are widely used in life-threatening infections, but they accumulate in cochlear hair cells (HCs) and result in hearing loss. Increases in adenosine triphosphate (ATP) concentrations and P2X7 receptor expression were observed after neomycin treatment. Here, we demonstrated that P2X7 receptor, which is a non-selective cation channel that is activated by high ATP concentrations, may participate in the process through which AGAs enter hair cells. Using transgenic knockout mice, we found that P2X7 receptor deficiency protects HCs against neomycin-induced injury in vitro and in vivo. Subsequently, we used fluorescent gentamicin-Fluor 594 to study the uptake of AGAs and found fluorescence labeling in wild-type mice but not in P2rx7-/- mice in vitro. In addition, knocking-out P2rx7 did not significantly alter the HC count and auditory signal transduction, but it did inhibit mitochondria-dependent oxidative stress and apoptosis in the cochlea after neomycin exposure. We thus conclude that the P2X7 receptor may be linked to the entry of AGAs into HCs and is likely to be a therapeutic target for auditory HC protection.
氨基糖苷类抗生素（AGAs）被广泛应用于危及生命的感染，但它们在耳蜗毛细胞（HCs）中积累，导致听力损失。新霉素处理后，观察到三磷酸腺苷（ATP）浓度和 P2X7 受体表达增加。在这里，我们证明 P2X7 受体是一种非选择性阳离子通道，可被高浓度 ATP 激活，可能参与 AGAs 进入毛细胞的过程。使用转基因敲除小鼠，我们发现 P2X7 受体缺失可保护 HCs 免受新霉素诱导的体外和体内损伤。随后，我们使用荧光庆大霉素-Fluor 594 研究 AGAs 的摄取，发现体外野生型小鼠有荧光标记，但 P2rx7-/- 小鼠没有。此外，敲除 P2rx7 并没有显著改变 HC 计数和听觉信号转导，但它抑制了新霉素暴露后耳蜗中线粒体依赖性氧化应激和细胞凋亡。因此，我们得出结论，P2X7 受体可能与 AGAs 进入 HCs 有关，可能是听觉 HC 保护的治疗靶点。
