Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy Department of Molecular Cell Biology, Katholieke Universiteit, Leuven, Belgium Department of Pharmacology, Chiesi Farmaceutici, Parma, Italy Department of Pharmaceutical Chemistry, University of Ferrara, Ferrara, Italy Chemistry Department, University of Ferrara, Ferrara, Italy.
Pain. 2011 Jul;152(7):1621-1631. doi: 10.1016/j.pain.2011.02.051. Epub 2011 Apr 9.
Platinum-based anticancer drugs cause neurotoxicity. In particular, oxaliplatin produces early-developing, painful, and cold-exacerbated paresthesias. However, the mechanism underlying these bothersome and dose-limiting adverse effects is unknown. We hypothesized that the transient receptor potential ankyrin 1 (TRPA1), a cation channel activated by oxidative stress and cold temperature, contributes to mechanical and cold hypersensitivity caused by oxaliplatin and cisplatin. Oxaliplatin and cisplatin evoked glutathione-sensitive relaxation, mediated by TRPA1 stimulation and the release of calcitonin gene-related peptide from sensory nerve terminals in isolated guinea pig pulmonary arteries. No calcium response was observed in cultured mouse dorsal root ganglion neurons or in naïve Chinese hamster ovary (CHO) cells exposed to oxaliplatin or cisplatin. However, oxaliplatin, and with lower potency, cisplatin, evoked a glutathione-sensitive calcium response in CHO cells expressing mouse TRPA1. One single administration of oxaliplatin produced mechanical and cold hyperalgesia in rats, an effect selectively abated by the TRPA1 antagonist HC-030031. Oxaliplatin administration caused mechanical and cold allodynia in mice. Both responses were absent in TRPA1-deficient mice. Administration of cisplatin evoked mechanical allodynia, an effect that was reduced in TRPA1-deficient mice. TRPA1 is therefore required for oxaliplatin-evoked mechanical and cold hypersensitivity, and contributes to cisplatin-evoked mechanical allodynia. Channel activation is most likely caused by glutathione-sensitive molecules, including reactive oxygen species and their byproducts, which are generated after tissue exposure to platinum-based drugs from cells surrounding nociceptive nerve terminals.
铂类抗癌药物会引起神经毒性。特别是奥沙利铂会引起早期出现的、疼痛的、遇冷加重的感觉异常。然而，这些令人烦恼的、剂量限制的不良反应的机制尚不清楚。我们假设瞬时受体电位锚蛋白 1（TRPA1），一种由氧化应激和冷温度激活的阳离子通道，有助于奥沙利铂和顺铂引起的机械性和冷敏性。奥沙利铂和顺铂引起谷胱甘肽敏感的松弛，这是由 TRPA1 刺激和感觉神经末梢中降钙素基因相关肽的释放介导的，在分离的豚鼠肺动脉中。在暴露于奥沙利铂或顺铂的培养的小鼠背根神经节神经元或未成熟的中国仓鼠卵巢（CHO）细胞中未观察到钙反应。然而，奥沙利铂和低效力的顺铂在表达小鼠 TRPA1 的 CHO 细胞中引起谷胱甘肽敏感的钙反应。单次给予奥沙利铂会在大鼠中引起机械性和冷超敏反应，这种作用被 TRPA1 拮抗剂 HC-030031 选择性减弱。奥沙利铂给药会引起小鼠的机械性和冷痛觉过敏。TRPA1 缺陷型小鼠中这两种反应均不存在。顺铂给药会引起机械性痛觉过敏，这种作用在 TRPA1 缺陷型小鼠中减少。因此，TRPA1 是奥沙利铂引起的机械性和冷敏性所必需的，并且有助于顺铂引起的机械性痛觉过敏。通道激活最可能是由谷胱甘肽敏感的分子引起的，包括活性氧及其副产物，这些物质是在细胞暴露于铂类药物后由伤害性神经末梢周围的细胞产生的。
