TRPA1 and TRPV4 mediate paclitaxel-induced peripheral neuropathy in mice via a glutathione-sensitive mechanism
TRPA1 and TRPV4 mediate paclitaxel-induced peripheral neuropathy in mice via a glutathione-sensitive mechanism
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DOI：
10.1007/s00424-011-1071-x
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发表时间：
2012-04-01
影响因子：
4.5
通讯作者：
Nassini, Romina
中科院分区：
文献类型：
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作者：
Materazzi, Serena;Fusi, Camilla;Nassini, Romina
Paclitaxel产生感觉神经病变，其特征在于机械和冷超敏反应，其通过抗氧化剂减轻。瞬时受体电位香草酸4（TRPV 4）通道已被报道有助于紫杉醇诱发的啮齿动物异常性疼痛。我们最近发现TRP锚蛋白1（TRPA 1）通道介导奥沙利铂诱发的冷和机械异常性疼痛，药物通过产生氧化应激靶向TRPA 1。在这里，我们探讨了TRPA 1激活是否有助于紫杉醇诱导的机械和冷超敏反应，以及这种激活是否是由氧化应激产生介导的。TRPA 1拮抗剂HC-030031和TRPV 4拮抗剂HC-067047可部分减轻紫杉醇诱发的机械性异常性疼痛，两种拮抗剂联合使用可完全减轻。在TRPA 1缺陷小鼠中观察到的紫杉醇诱发的机械性异常性疼痛减少，在小鼠接受HC-067047给药时完全消除。HC-030031和TRPA 1缺陷小鼠的冷异常性疼痛完全减轻。紫杉醇暴露于小鼠食管切片释放感觉神经肽降钙素基因相关肽（CGRP）。辣椒素脱敏和无钙培养基（表明感觉神经末梢的神经分泌）可消除该效应，HC-030031或HC-067047可部分降低该效应，谷胱甘肽（GSH）可完全消除该效应。最后，减少CGRP的释放，观察TRPA 1缺陷小鼠的食管切片，进一步抑制GSH。起搏通过氧自由基形成靶向TRPA 1和TRPV 4，这两个通道是延迟机械性异常性疼痛发展的关键。然而，冷异常性疼痛完全依赖于TRPA 1。
Paclitaxel produces a sensory neuropathy, characterized by mechanical and cold hypersensitivity, which are abated by antioxidants. The transient receptor potential vanilloid 4 (TRPV4) channel has been reported to contribute to paclitaxel-evoked allodynia in rodents. We recently showed that TRP ankyrin 1 (TRPA1) channel mediates oxaliplatin-evoked cold and mechanical allodynia, and the drug targets TRPA1 via generation of oxidative stress. Here, we have explored whether TRPA1 activation contributes to paclitaxel-induced mechanical and cold hypersensitivity and whether this activation is mediated by oxidative stress generation. Paclitaxel-evoked mechanical allodynia was reduced partially by the TRPA1 antagonist, HC-030031, and the TRPV4 antagonist, HC-067047, and was completely abated by the combination of the two antagonists. The reduced paclitaxel-evoked mechanical allodynia, observed in TRPA1-deficient mice, was completely abolished when mice were treated with HC-067047. Cold allodynia was abated completely by HC-030031 and in TRPA1-deficient mice. Exposure to paclitaxel of slices of mouse esophagus released the sensory neuropeptide, calcitonin gene-related peptide (CGRP). This effect was abolished by capsaicin desensitization and in calcium-free medium (indicating neurosecretion from sensory nerve terminals), partially reduced by either HC-030031 or HC-067047, and completely abated in the presence of glutathione (GSH). Finally, the reduced CGRP release, observed in esophageal slices of TRPA1-deficient mice, was further inhibited by GSH. Paclitaxel via oxygen radical formation targets TRPA1 and TRPV4, and both channels are key for the delayed development of mechanical allodynia. Cold allodynia is, however, entirely dependent on TRPA1.