BDNF protection of auditory neurons from cisplatin involves changes in intracellular levels of both reactive oxygen species and glutathione
BDNF protection of auditory neurons from cisplatin involves changes in intracellular levels of both reactive oxygen species and glutathione
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DOI：
10.1016/s0169-328x(97)00173-3
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发表时间：
1997-10-15
期刊：
影响因子：
--
通讯作者：
VandeWater, TR
中科院分区：
文献类型：
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作者：
Gabaizadeh, R;Staecker, H;VandeWater, TR
以往的研究表明，脑源性神经营养因子（BDNF）在体外可保护听神经元免受顺铂的毒性。为了探讨BDNF介导的神经元保护机制，连续共聚焦显微镜取样的听觉神经元测定细胞内活性氧（ROS）水平的反应，在正常和氧化应激状态下的BDNF补充，顺铂暴露和BDNF保护顺铂损伤。此外，我们研究了神经元内的自由基清除剂谷胱甘肽（GSH）的水平，以响应撤销的BDNF。BDNF的撤回导致ROS的产生增加和听觉神经元的存活减少。在BDNF撤除后，神经元内GSH的水平增加，并且这种增加被证明滞后于ROS的产生。与未受保护的顺铂暴露培养物中的神经元相比，补充BDNF并暴露于顺铂的培养物中的听觉神经元显示出显著较低的ROS水平和增加的存活率。与暴露于顺铂的补充BDNF的培养物中的神经元相比，用buthivine sulfoximine（GSH合成的抑制剂）补充BDNF并暴露于顺铂处理的神经元显示出显著更高的细胞内ROS水平。这些结果表明，细胞内的ROS水平在顺铂诱导的听神经元细胞死亡中起着重要作用，并且可以通过补充BDNF来改善ROS的产生。GSH似乎介导BDNF保护这些神经元免受顺铂诱导的ROS和随后的损伤。(C)1997年Elsevier Science B.V.
Previous studies have shown that brain derived neurotrophic factor (BDNF) can protect auditory neurons from cisplatin toxicity in vitro. To explore the mechanism of BDNF mediated neuronal protection sequential confocal microscopic sampling of auditory neurons measured intracellular levels of reactive oxygen species (ROS) in response to withdrawal of BDNF supplementation, cisplatin exposure, and BDNF protection from cisplatin damage in normal and oxidative stress states. Additionally, we examined intraneuronal levels of the free radical scavenger glutathione (GSH) in response to withdrawal of BDNF. Withdrawal of BDNF resulted in increased production of ROS and decreased survival of auditory neurons. Levels of GSH within neurons increased after BDNF withdrawal, and this increase was shown to lag behind the production of ROS. Auditory neurons in cultures supplemented with BDNF and exposed to cisplatin showed significantly lower levels of ROS and increased survival compared to neurons in unprotected, cisplatin exposed cultures. Neurons treated with buthionine sulfoximine (an inhibitor of GSH synthesis), supplemented with BDNF, and exposed to cisplatin showed significantly higher intracellular levels of ROS compared to the neurons in BDNF supplemented cultures exposed to cisplatin. These results suggest that intracellular levels of ROS play an important role in cisplatin induced cell death of auditory neurons and that production of ROS can be ameliorated through supplementation with BDNF. GSH appears to mediate BDNF protection of these neurons from cisplatin induced ROS and subsequent damage. (C) 1997 Elsevier Science B.V.