Nakagawa Takayuki, Kaneko Shuji
Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital.
Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University.
Biol Pharm Bull. 2017;40(7):947-953. doi: 10.1248/bpb.b17-00243.
Chemotherapy-induced peripheral neuropathy (CIPN), characterized by symptoms of paresthesia, dysesthesia, numbness, and pain, is a common adverse effect of several chemotherapeutic agents, including platinum-based agents, taxanes, and vinca alkaloids. However, no effective prevention or treatment strategies exist for CIPN because the mechanisms underpinning this neuropathy are poorly understood. Recent accumulating evidence suggests that some transient receptor potential (TRP) channels functioning as nociceptors in primary sensory neurons are responsible for CIPN. In this review, we focus on the specific roles of redox-sensitive TRP ankyrin 1 (TRPA1), which was first reported to be a cold nociceptor, in acute cold hypersensitivity induced by oxaliplatin, a platinum-based agent, because it induces a peculiar cold-triggered CIPN during or within hours after its infusion. Oxaliplatin-induced rapid-onset cold hypersensitivity is ameliorated by TRPA1 blockade or deficiency in mice. Consistent with this, oxaliplatin enhances the responsiveness of TRPA1 stimulation, but not of TRP melastatin 8 (TRPM8) and TRP vanilloid 1 (TRPV1), in mice and cultured mouse dorsal root ganglion neurons. These responses are mimicked by an oxaliplatin metabolite, oxalate. In human TRPA1 (hTRPA1)-expressing cells, oxaliplatin or oxalate causes TRPA1 sensitization to reactive oxygen species (ROS) by inhibiting prolyl hydroxylases (PHDs). Inhibition of PHD-mediated hydroxylation of a proline residue within the N-terminal ankyrin repeat of hTRPA1 endows TRPA1 with cold sensitivity by its sensing of cold-evoked ROS. This review discusses these findings and summarizes the evidence demonstrating that oxaliplatin-induced acute cold hypersensitivity is caused by TRPA1 sensitization to ROS via PHD inhibition, which enables TRPA1 to convert ROS signaling into cold sensitivity.
化疗引起的周围神经病变（CIPN），其特征为感觉异常、感觉迟钝、麻木和疼痛等症状，是包括铂类药物、紫杉烷类和长春花生物碱在内的多种化疗药物常见的副作用。然而，由于对这种神经病变的潜在机制了解甚少，目前尚无有效的CIPN预防或治疗策略。最近越来越多的证据表明，一些在初级感觉神经元中作为伤害感受器发挥作用的瞬时受体电位（TRP）通道与CIPN有关。在本综述中，我们重点关注氧化还原敏感的TRP锚蛋白1（TRPA1）的特定作用，TRPA1最初被报道为冷伤害感受器，在铂类药物奥沙利铂诱导的急性冷超敏反应中发挥作用，因为奥沙利铂在输注期间或输注后数小时内会引发一种特殊的冷触发CIPN。在小鼠中，TRPA1阻断或缺失可改善奥沙利铂诱导的快速发作性冷超敏反应。与此一致的是，在小鼠和培养的小鼠背根神经节神经元中，奥沙利铂增强了TRPA1刺激的反应性，但没有增强TRP褪黑素8（TRPM8）和TRP香草酸1（TRPV1）的反应性。这些反应可被奥沙利铂的代谢产物草酸盐模拟。在表达人TRPA1（hTRPA1）的细胞中，奥沙利铂或草酸盐通过抑制脯氨酰羟化酶（PHD）使TRPA1对活性氧（ROS）敏感。抑制PHD介导的hTRPA1 N端锚蛋白重复序列内脯氨酸残基的羟基化，通过其对冷诱发ROS的感知赋予TRPA1冷敏感性。本综述讨论了这些发现，并总结了证据，证明奥沙利铂诱导的急性冷超敏反应是由TRPA1通过PHD抑制对ROS敏感所致，这使得TRPA1能够将ROS信号转化为冷敏感性。
