The effects of oxaliplatin, an anticancer drug, on potassium channels of the peripheral myelinated nerve fibres of the adult rat
The effects of oxaliplatin, an anticancer drug, on potassium channels of the peripheral myelinated nerve fibres of the adult rat
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DOI：
10.1016/j.neuro.2008.09.005
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发表时间：
2008-11-01
期刊：
影响因子：
3.4
通讯作者：
Theophilidis, George
中科院分区：
文献类型：
--
作者：
Kagiava, Alexia;Tsingotjidou, Anastasia;Theophilidis, George
奥沙利铂是一种新型的化疗药物，对晚期结直肠癌有效，但同时会引起周围神经纤维的严重神经病变，主要影响电压门控钠（Na+）通道（VGNaCs）。本研究利用离体成年大鼠坐骨神经体外观察奥沙利铂对外周髓鞘神经纤维（pmnf）的影响。这种神经准备的优点是可以记录稳定的振幅诱发复合动作电位（CAP）超过1000分钟。坐骨神经纤维在25、100和500 μ M奥沙利铂中孵育300-700 min，引起CAP波形的剧烈畸变，即复极相变宽、重复放电和后超极化（AHP），与电压门控钾（K+）通道（VGKCs）功能障碍有关。在浓度为5 μ M时，奥沙利铂仅引起CAP复极化相展宽，而未观察到的效应浓度估计为1 μ M。这些发现表明奥沙利铂对VGKCs有严重的影响。相比之下，CAP去极化的振幅和上升时间没有明显变化，这清楚地表明特定神经制剂的VGNaCs不受奥沙利铂的影响。奥沙利铂对pmnf的作用与4-氨基吡啶（4-AP）相似，4-氨基吡啶是一种经典的VGKCs拮抗剂。奥沙利铂和4-AP在作用模式上的相似之处，以及奥沙利铂在较低浓度下作用更明显和发展的事实表明，奥沙利铂是一种有效的VGKCs拮抗剂。(c) 2008爱思唯尔公司版权所有。
Oxaliplatin is a novel chemotherapeutic agent which is effective against advanced colorectal cancer, but at the same time causes severe neuropathy in the peripheral nerve fibres, affecting mainly the voltage-gated sodium (Na+) channels (VGNaCs), according to literature. In this study the effects of oxaliplatin on the peripheral myelinated nerve fibres (PMNFs) were investigated in vitro using the isolated sciatic nerve of the adult rat. The advantage of this nerve-preparation was that stable in amplitude evoked compound action potentials (CAP) were recorded for over 1000 min. Incubation of the sciatic nerve fibres in 25, 100 and 500 mu M oxaliplatin, for 300-700 min caused dramatic distortion of the waveform of the CAP, namely broadening the repolarization phase, repetitive firing and afterhyperpolarization (AHP), related to the malfunction of voltage-gated potassium (K+) channels (VGKCs). At a concentration of 5 mu M, oxaliplatin caused broadening of the repolarization phase of the CAP only, while the no observed effect concentration was estimated to be 1 mu M. These findings are indicative of severe effects of oxaliplatin on the VGKCs. In contrast, the amplitude and the rise-time of the depolarization of the CAP did not change significantly, a clear indication that the VGNaCs of the particular nerve preparation were not affected by oxaliplatin. The effects of oxaliplatin on the PMNFs were similar to those of 4-aminopyridine (4-AP), a classical antagonist of VGKCs. These similarities in the pattern of action between oxaliplatin and 4-AP combined with the fact that the effects of oxaliplatin were more pronounced and developed at lower concentrations suggest that oxaliplatin acts as a potent VGKCs antagonist. (c) 2008 Elsevier Inc. All rights reserved.