Acute cold hypersensitivity characteristically induced by oxaliplatin is caused by the enhanced responsiveness of TRPA1 in mice.
Acute cold hypersensitivity characteristically induced by oxaliplatin is caused by the enhanced responsiveness of TRPA1 in mice.
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DOI：
10.1186/1744-8069-8-55
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发表时间：
2012-07-28
期刊：
影响因子：
3.3
通讯作者：
Kaneko S
中科院分区：
文献类型：
--
作者：
Zhao M;Isami K;Nakamura S;Shirakawa H;Nakagawa T;Kaneko S
奥沙利铂是一种以铂为基础的化疗药物，可引起不寻常的急性周围神经病变。奥沙利铂诱导的急性周围神经病变在几乎所有患者中均在输注后迅速出现，并由寒冷触发或加重，但其机制尚不清楚。在这项研究中，热敏瞬时受体电位通道（TRPA 1，TRPM 8和TRPV 1）在奥沙利铂诱导的小鼠急性超敏反应的参与进行了研究。奥沙利铂（1-10 mg/kg）单次腹腔内给药在2小时内以剂量依赖性方式诱导冷超敏反应，但不诱导机械超敏反应。输注奥沙利铂代谢产物草酸盐（1.7 mg/kg）也诱导急性冷超敏反应，而另一种基于铂的化疗剂顺铂（5 mg/kg）或不含铂的化疗剂紫杉醇（6 mg/kg）未能诱导机械或冷超敏反应。奥沙利铂诱导的急性冷超敏反应被TRPA 1拮抗剂HC-030031（100 mg/kg）和TRPA 1缺乏消除。在用奥沙利铂（1-10 mg/kg）处理2 h的小鼠中，足底注射烯丙基异硫氰酸酯（AITC; TRPA 1激动剂）引起的伤害性行为以剂量依赖性方式显著增强，而辣椒素（TRPV 1激动剂）引起的伤害性行为不受影响。奥沙利铂预处理也增强了MENELINE（TRPM 8/TRPA 1激动剂）诱发的伤害性行为，TRPA 1缺乏则抑制了这种行为。同样，草酸盐增强，但顺铂和紫杉醇都不影响AITC诱发的伤害性行为。用奥沙利铂（30-300 μM）预处理培养的小鼠背根神经节（DRG）神经元1、2或4 h，以浓度依赖性方式显著增加AITC敏感神经元的数量，而薄荷醇或辣椒素敏感神经元的数量没有变化。总之，这些结果表明，奥沙利铂或其代谢产物草酸盐的短暂治疗足以增强DRG神经元表达的TRPA 1的反应性，但不足以增强TRPM 8和TRPV 1的反应性，这可能导致奥沙利铂诱导的特征性急性周围神经病变。
Oxaliplatin, a platinum-based chemotherapeutic agent, causes an unusual acute peripheral neuropathy. Oxaliplatin-induced acute peripheral neuropathy appears in almost all patients rapidly after infusion, and is triggered or exacerbated by cold, while its mechanisms are poorly understood. In this study, the involvement of thermosensitive transient receptor potential channels (TRPA1, TRPM8 and TRPV1) in oxaliplatin-induced acute hypersensitivity was investigated in mice. A single intraperitoneal administration of oxaliplatin (1–10 mg/kg) induced cold but not mechanical hypersensitivity within 2 h in a dose-dependent manner. Infusion of the oxaliplatin metabolite, oxalate (1.7 mg/kg), also induced acute cold hypersensitivity, while another platinum-based chemotherapeutic agent, cisplatin (5 mg/kg), or the non-platinum-containing chemotherapeutic agent, paclitaxel (6 mg/kg) failed to induce mechanical or cold hypersensitivity. The oxaliplatin-induced acute cold hypersensitivity was abolished by the TRPA1 antagonist HC-030031 (100 mg/kg) and by TRPA1 deficiency. The nocifensive behaviors evoked by intraplantar injections of allyl-isothiocyanate (AITC; TRPA1 agonist) were significantly enhanced in mice treated for 2 h with oxaliplatin (1–10 mg/kg) in a dose-dependent manner, while capsaicin (TRPV1 agonist)-evoked nocifensive behaviors were not affected. Menthol (TRPM8/TRPA1 agonist)-evoked nocifensive-like behaviors were also enhanced by oxaliplatin pretreatment, which were inhibited by TRPA1 deficiency. Similarly, oxalate enhanced, but neither cisplatin nor paclitaxel affected AITC-evoked nocifensive behaviors. Pretreatment of cultured mouse dorsal root ganglia (DRG) neurons with oxaliplatin (30–300 μM) for 1, 2, or 4 h significantly increased the number of AITC-sensitive neurons in a concentration-dependent manner whereas there was no change in the number of menthol- or capsaicin-sensitive neurons. Taken together, these results suggest that a brief treatment with oxaliplatin or its metabolite oxalate is sufficient to enhance the responsiveness of TRPA1 but not that of TRPM8 and TRPV1 expressed by DRG neurons, which may contribute to the characteristic acute peripheral neuropathy induced by oxaliplatin.
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