Extracellular divalent cations modulate aminoglycoside-induced hair cell death in the zebrafish lateral line.
Extracellular divalent cations modulate aminoglycoside-induced hair cell death in the zebrafish lateral line.
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DOI：
10.1016/j.heares.2009.03.004
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发表时间：
2009-07
期刊：
影响因子：
2.8
通讯作者：
Rubel, Edwin W.
中科院分区：
文献类型：
--
作者：
Coffin, Allison B.;Reinhart, Katherine E.;Owens, Kelly N.;Raible, David W.;Rubel, Edwin W.
氨基糖苷类抗生素导致感觉毛细胞死亡。过去十年的研究已经确定了细胞内级联反应中的几个关键参与者。然而，细胞外环境在氨基糖苷类药物耳毒性中的作用受到的关注相对较少。本研究使用斑马鱼侧线证明，细胞外钙和镁离子调节毛细胞死亡的新霉素和庆大霉素在体内，与高水平的二价阳离子提供显着的保护。荧光标记庆大霉素的成像实验表明，在高钙条件下药物摄取减少。用毛细胞转导阻断剂阿米洛利治疗鱼类也会减少氨基糖苷类的摄取，防止毒性，并且用可变钙和阿米洛利浓度的实验表明两种保护剂之间的互补作用。相比之下，镁的升高似乎不会显著减弱药物的摄取，这表明两种二价阳离子可能通过不同的机制保护毛细胞免受氨基糖苷类药物的损伤。这些结果为钙依赖性和转导依赖性氨基糖苷类摄取提供了额外的证据。二价阳离子对新霉素和庆大霉素提供了不同的保护，高浓度的阳离子几乎完全保护毛细胞免受新霉素和急性庆大霉素毒性的影响，但对连续（6小时）庆大霉素暴露的保护作用降低。这些实验进一步支持氨基糖苷类药物毒性通过多种途径以药物和时间过程特异性方式发生的假设。
Aminoglycoside antibiotics cause death of sensory hair cells. Research over the past decade has identified several key players in the intracellular cascade. However, the role of the extracellular environment in aminoglycoside ototoxicity has received comparatively little attention. The present study uses the zebrafish lateral line to demonstrate that extracellular calcium and magnesium ions modulate hair cell death from neomycin and gentamicin in vivo, with high levels of either divalent cation providing significant protection. Imaging experiments with fluorescently tagged gentamicin show that drug uptake is reduced under high calcium conditions. Treating fish with the hair cell transduction blocker amiloride also reduces aminoglycoside uptake, preventing the toxicity, and experiments with variable calcium and amiloride concentrations suggest complementary effects between the two protectants. Elevated magnesium, in contrast, does not appear to significantly attenuate drug uptake, suggesting that the two divalent cations may protect hair cells from aminoglycoside damage through different mechanisms. These results provide additional evidence for calcium- and transduction-dependent aminoglycoside uptake. Divalent cations provided differential protection from neomycin and gentamicin, with high cation concentrations almost completely protecting hair cells from neomycin and acute gentamicin toxicity, but offering reduced protection from continuous (6 hr) gentamicin exposure. These experiments lend further support to the hypothesis that aminoglycoside toxicity occurs via multiple pathways in a both a drug and time course-specific manner.
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影响因子：
82.9
作者：
Basile, AS;Huang, JM;Skolnick, P
通讯作者：
Skolnick, P
DOI：
10.1007/s10162-006-0043-x
发表时间：
2006-09-01
影响因子：
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作者：
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作者：
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影响因子：
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作者：
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通讯作者：
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