Cisplatin-induced neuropathic pain is mediated by upregulation of N-type voltage-gated calcium channels in dorsal root ganglion neurons
Cisplatin-induced neuropathic pain is mediated by upregulation of N-type voltage-gated calcium channels in dorsal root ganglion neurons
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DOI：
10.1016/j.expneurol.2016.11.003
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发表时间：
2017-02-01
影响因子：
5.3
通讯作者：
Hagenacker, Tim
中科院分区：
文献类型：
--
作者：
Leo, Markus;Schmitt, Linda-Isabell;Hagenacker, Tim
顺铂在治疗各种类型的癌症中很重要。虽然它非常有效，但也有严重的副作用，其中背根神经节（DRG）神经元的神经毒性是最常见的副作用之一。神经毒性的关键机制仍有争议的讨论，但是，在DRG神经元钙稳态的干扰已被建议介导顺铂的神经毒性。采用全细胞膜片钳技术、免疫组化染色和行为学实验，观察了顺铂（DDP）对大鼠背根神经节（DRG）小神经元电压门控钙通道（VGCC）电流（伊卡（v））的影响。体外暴露于顺铂以浓度依赖性方式降低I-Ca（V）（0.01-50 μ M; 13.8-77.3%; IC 50 5.07 μ M）。VGCC的亚型特异性测量显示对I-Ca（V）的不同影响。除极至0 mV时，P/Q型、L型和T型VGCC的I-Ca（V）均降低，而N型VGCC的I-Ca（V）增加了30.3%。DRG神经元暴露于顺铂（0.5或5 μ M）24-48小时在体外显着增加CaMK H-介导的I-Ca（V）电流密度。免疫组化和蛋白质印迹分析显示，N-型VGCC蛋白水平的增加，在DRG神经元顺铂暴露后24小时。使用芋螺毒素MVIIA抑制N型VGCCs可阻止顺铂介导的caspase-3活化。行为实验表明，芋螺毒素MVIIA治疗预防神经病综合征在体内通过抑制上调的N型蛋白质水平。在这里，我们首次证明了N型VGCC在顺铂诱导的多发性神经病的发生中的关键作用。(C)2016 Elsevier Inc. All rights reserved.
Cisplatin is important in the treatment of various types of cancer. Although it is highly effective, it also has severe side effects, with neurotoxicity in dorsal root ganglion (DRG) neurons being one of the most common. The key mechanisms of neurotoxicity are still controversially discussed; however, disturbances of the calcium homeostasis in DRG neurons have been suggested to mediate cisplatin neurotoxicity. By using the whole-cell patch-clamp technique, immunostaining and behavioral experiments with Sprague-Dawley rats, we examined the influence of short- and long-term exposure to cisplatin on voltage-gated calcium channel (VGCC) currents (Ica(v)) in small DRG neurons. In vitro exposure to cisplatin reduced I-Ca(V) in a concentration-dependent manner (0.01-50 mu M; 13.8-77.3%; IC50 5.07 mu M). Subtype-specific measurements of VGCCs showed differential effects on I-Ca(V). While the I-Ca(V) of P/Q-, L- and T-type VGCCs were reduced, I-Ca(V) of N-type VGCCs were increased by 30.3% during depolarization to 0 mV. Exposure of DRG neurons to cisplatin (0.5 or 5 mu M) for 24-48 h in vitro significantly increased a CaMK H-mediated I-Ca(V) current density. Immunostaining and western blot analysis revealed an increase of N-type VGCC protein level in DRG neurons 24 h after cisplatin exposure. Cisplatin-mediated activation of caspase-3 was prevented by inhibition of N-type VGCCs using-conotoxin MVIIA. Behavioral experiments showed that-conotoxin MVIIA treatment prevented neuropathic syndromes in vivo by inhibiting upregulation of the N-type protein level. Here we show evidence for the first time for a crucial role of N-type VGCC in the genesis of cisplatin-induced polyneuropathy. (C) 2016 Elsevier Inc. All rights reserved.