Paclitaxel Inhibits KCNQ Channels in Primary Sensory Neurons to Initiate the Development of Painful Peripheral Neuropathy.
Paclitaxel Inhibits KCNQ Channels in Primary Sensory Neurons to Initiate the Development of Painful Peripheral Neuropathy.
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DOI：
10.3390/cells11244067
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发表时间：
2022-12-15
期刊：
影响因子：
6
通讯作者：
Yang, Qing
中科院分区：
文献类型：
--
作者：
Wu, Zizhen;Toro, Gabor;Xu, Guoying;Dang, Danny;Prater, Charmaine;Yang, Qing
接受紫杉醇输注的癌症患者通常经历外周神经变性和称为紫杉醇诱导的外周神经病变（PIPN）的严重神经性疼痛。然而，紫杉醇剂量或治疗方案的改变不能消除PIPN，并且没有可用于PIPN的疗法，尽管许多研究揭示了这种状况的发展/维持的潜在机制。因此，我们的目的是揭示一个新的机制，PIPN的发病机制。临床研究表明，初级感觉神经元的急性过度兴奋与PIPN的发病机制有关。我们发现，紫杉醇诱导的初级感觉神经元的急性超兴奋性的结果从紫杉醇诱导的抑制KCNQ钾通道（主要是KCNQ 2），发现丰富的感觉神经元和轴突。我们发现，重复应用XE-991，一种特定的KCNQ通道阻滞剂，诱导大鼠PIPN样改变，包括机械超敏反应和周围神经变性，如形态学和行为学检测。相比之下，小鼠外周感觉神经元中KCNQ 2的基因缺失显著减弱了紫杉醇诱导的外周感觉纤维变性和慢性疼痛的发展。这些发现可能会导致更好地了解PIPN的原因，并为开发新类别的KCNQ激活剂用于其治疗提供动力。
Cancer patients undergoing paclitaxel infusion usually experience peripheral nerve degeneration and serious neuropathic pain termed paclitaxel-induced peripheral neuropathy (PIPN). However, alterations in the dose or treatment schedule for paclitaxel do not eliminate PIPN, and no therapies are available for PIPN, despite numerous studies to uncover the mechanisms underlying the development/maintenance of this condition. Therefore, we aimed to uncover a novel mechanism underlying the pathogenesis of PIPN. Clinical studies suggest that acute over excitation of primary sensory neurons is linked to the pathogenesis of PIPN. We found that paclitaxel-induced acute hyperexcitability of primary sensory neurons results from the paclitaxel-induced inhibition of KCNQ potassium channels (mainly KCNQ2), found abundantly in sensory neurons and axons. We found that repeated application of XE-991, a specific KCNQ channel blocker, induced PIPN-like alterations in rats, including mechanical hypersensitivity and degeneration of peripheral nerves, as detected by both morphological and behavioral assays. In contrast, genetic deletion of KCNQ2 from peripheral sensory neurons in mice significantly attenuated the development of paclitaxel-induced peripheral sensory fiber degeneration and chronic pain. These findings may lead to a better understanding of the causes of PIPN and provide an impetus for developing new classes of KCNQ activators for its therapeutic treatment.
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