EFFECT OF CISPLATIN AND ACTH(4-9) ON NEURAL TRANSPORT IN CISPLATIN-INDUCED NEUROTOXICITY
EFFECT OF CISPLATIN AND ACTH(4-9) ON NEURAL TRANSPORT IN CISPLATIN-INDUCED NEUROTOXICITY
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DOI：
10.1016/0006-8993(95)00100-5
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发表时间：
1995-04-10
期刊：
影响因子：
2.9
通讯作者：
BRIMIJOIN, WS
中科院分区：
文献类型：
--
作者：
RUSSELL, JW;WINDEBANK, AJ;BRIMIJOIN, WS
顺铂引起剂量限制性周围神经病变，然而，其发生的生物学机制尚不清楚。小鼠N1E.115神经母细胞瘤细胞和神经嵴衍生的色素细胞具有与人神经细胞相似的转运机制，并用于研究顺铂对细胞转运的影响。与对照细胞相比，顺铂减少了细胞器在顺行和逆行方向上移动的数量和速度。顺铂诱导的转运抑制可通过同时给予ACTH来预防（4-9）。这种类似物单独对N1E.115细胞器或红细胞颗粒运动没有影响。在N1E.115和色素细胞中，顺铂在暴露于药物的1小时内抑制转运。与急性暴露相比，如果色素细胞在顺铂中孵育48 h，抑制程度并没有显著增加。色素细胞和N1E.115神经突中的微管保留了其结构完整性，这表明总微管形态变化以外的因素是顺铂神经毒性的原因。顺铂在孵育48小时后减少N1E.115神经突生长，但这可以通过同时使用ACTH来预防（4-9）。本研究首次证明顺铂和ACTH（4-9）通过特定机制影响快速轴突运输，这些机制似乎分别与观察到的神经毒性和神经保护作用相关。
Cisplatin causes a dose limiting peripheral neuropathy, however, the biological mechanism by which this occurs is unknown. Murine N1E.115 neuroblastoma cells and neural crest derived pigment cells have similar transport mechanisms to human neural cells and were used to study the effect of cisplatin on cellular transport. Cisplatin reduced both the number and velocity of organelles moving in the anterograde and retrograde direction, compared to control cells. Cisplatin induced inhibition of transport was prevented by the simultaneous administration of ACTH(4-9). This analog alone had no effect on N1E.115 organelle, or erythrophore granule, movement. In both N1E.115 and pigment cells cisplatin inhibited transport within 1 h of exposure to the drug. The degree of inhibition did not increase significantly if pigment cells were incubated in cisplatin for 48 h compared to acute exposure. Microtubules in both pigment cells and N1E.115 neurites retained their structural integrity suggesting that factors other than changes in gross microtubule morphology are responsible for cisplatin neurotoxicity. Cisplatin reduces N1E.115 neurite growth after 48 h incubation but this can be prevented by simultaneous use of ACTH(4-9). This study demonstrates for the first time that cisplatin and ACTH(4-9) affect fast axonal transport by specific mechanisms which appear related to their observed neurotoxic and neuroprotective roles, respectively.