Addition of exogenous NAD+ prevents mefloquine-induced neuroaxonal and hair cell degeneration through reduction of caspase-3-mediated apoptosis in cochlear organotypic cultures.
Addition of exogenous NAD+ prevents mefloquine-induced neuroaxonal and hair cell degeneration through reduction of caspase-3-mediated apoptosis in cochlear organotypic cultures.
复制标题
DOI：
10.1371/journal.pone.0079817
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Someya S
中科院分区：
文献类型：
--
作者：
Ding D;Qi W;Yu D;Jiang H;Han C;Kim MJ;Katsuno K;Hsieh YH;Miyakawa T;Salvi R;Tanokura M;Someya S
甲氟喹广泛用于治疗疟疾。然而，这种药物已知会引起神经系统副作用，包括抑郁症，焦虑症，平衡障碍和感觉神经性听力损失。然而，目前还没有治疗这些副作用的方法。在这项研究中，我们表明，辅酶NAD+，已知在维持适当的细胞氧化还原环境中发挥关键作用，保护耳蜗轴突和感觉毛细胞从甲氟喹诱导的退化培养大鼠耳蜗。甲氟喹单独破坏大鼠耳蜗器官型培养物中的毛细胞和神经纤维轴突，呈剂量依赖性，而NAD+治疗保护轴突和毛细胞免受甲氟喹诱导的变性。此外，用甲氟喹处理的耳蜗器官显示出增加的氧化应激标志物水平，包括超氧化物和蛋白质羰基，以及增加的凋亡标志物水平，包括TUNEL阳性核和半胱天冬酶-3。用NAD+处理降低了这些氧化应激和凋亡标志物的水平。两者合计，我们的研究结果表明，甲氟喹破坏细胞的氧化还原环境，诱导耳蜗毛细胞和神经纤维的氧化应激，导致半胱天冬酶-3介导的这些结构的凋亡。外源性NAD+抑制甲氟喹诱导的氧化应激，并防止甲氟喹治疗引起的耳蜗轴突和感觉毛细胞的变性。
Mefloquine is widely used for the treatment of malaria. However, this drug is known to induce neurological side effects including depression, anxiety, balance disorder, and sensorineural hearing loss. Yet, there is currently no treatment for these side effects. In this study, we show that the coenzyme NAD+, known to play a critical role in maintaining the appropriate cellular redox environment, protects cochlear axons and sensory hair cells from mefloquine-induced degeneration in cultured rat cochleae. Mefloquine alone destroyed hair cells and nerve fiber axons in rat cochlear organotypics cultures in a dose-dependent manner, while treatment with NAD+ protected axons and hair cells from mefloquine-induced degeneration. Furthermore, cochlear organs treated with mefloquine showed increased oxidative stress marker levels, including superoxide and protein carbonyl, and increased apoptosis marker levels, including TUNEL-positive nuclei and caspases-3. Treatment with NAD+ reduced the levels of these oxidative stress and apoptosis markers. Taken together, our findings suggest that that mefloquine disrupts the cellular redox environment and induces oxidative stress in cochlear hair cells and nerve fibers leading to caspases-3-mediated apoptosis of these structures. Exogenous NAD+ suppresses mefloquine-induced oxidative stress and prevents the degeneration of cochlear axons and sensory hair cells caused by mefloquine treatment.
登录
查看更多内容
影响因子：
5.3
作者：
Fischer, LR;Culver, DG;Glass, JD
通讯作者：
Glass, JD
影响因子：
2.8
作者：
Ding, DL;Stracher, A;Salvi, RJ
通讯作者：
Salvi, RJ
影响因子：
56.9
作者：
Brunet, A;Sweeney, LB;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
3.4
作者：
Hood, Jonathan E.;Jenkins, Jerry W.;Aschner, Michael
通讯作者：
Aschner, Michael
影响因子：
2.8
作者：
Ding, Dalian;Jiang, Haiyan;Salvi, Richard
通讯作者：
Salvi, Richard