Yamashita Yuta, Irie Keiichi, Kochi Akane, Kimura Nami, Hayashi Toshinobu, Matsuo Koichi, Myose Takayuki, Sano Kazunori, Nakano Takafumi, Takase Yumi, Nakamura Yoshihiko, Satho Tomomitsu, Mishima Kenji, Mishima Kenichi
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma 8-19-1, Jonan-ku, Fukuoka, 814-0180, Japan.
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma 8-19-1, Jonan-ku, Fukuoka, 814-0180, Japan.
Neurosci Lett. 2017 Jul 13;653:337-340. doi: 10.1016/j.neulet.2017.05.069. Epub 2017 Jun 3.
Paclitaxel induces peripheral neuropathy, which is dose-limiting and results in loss of quality of life. Therefore, the prevention and treatment of paclitaxel-induced peripheral neuropathy are major concerns in clinical cancer therapy. However, the detailed mechanisms have not been fully elucidated. It has recently been reported that allelic variability in the Charcot-Marie-Tooth disease (CMT) genes, mitofusin 2 (MFN2), Rho guanine nucleotide exchange factor 10 (ARHGEF10), and periaxin (PRX), affected paclitaxel-induced peripheral neuropathy in clinical cases. Therefore, we hypothesized that paclitaxel may induce peripheral neuropathy due to changes in Mfn2, Arhgef10, and Prx mRNA expression. Paclitaxel (6mg/kg) was administered intraperitoneally, on two consecutive days per week for 4 weeks in rats. Paclitaxel-induced peripheral neuropathy was measured by the von Frey test and acetone test, mechanical allodynia, and cold hyperalgesia, respectively, on days 0, 3, 10, 17, and 24. Mfn2, Arhgef10, and Prx mRNA expression in the spinal cord were analyzed by qRT-PCR on days 3 and 24. Paclitaxel induced mechanical allodynia from days 17-24, but did not induce cold hyperalgesia. In addition, paclitaxel reduced Mfn2 mRNA expression, but not Arhgef10 or Prx mRNA expression, on days 3 and 24. In addition, Mfn2 mRNA level was decreased before the appearance of mechanical allodynia. The results of the present study suggest that a reduction in Mfn2 mRNA expression contributes to paclitaxel-induced mechanical allodynia.
紫杉醇会引发周围神经病变，这是剂量限制性的，并导致生活质量下降。因此，紫杉醇诱导的周围神经病变的防治是临床癌症治疗中的主要关注点。然而，其详细机制尚未完全阐明。最近有报道称，夏科-马里-图斯病（CMT）基因中的等位基因变异，即线粒体融合蛋白2（MFN2）、Rho鸟嘌呤核苷酸交换因子10（ARHGEF10）和外周蛋白（PRX），在临床病例中影响了紫杉醇诱导的周围神经病变。因此，我们推测紫杉醇可能由于Mfn2、Arhgef10和Prx mRNA表达的变化而诱发周围神经病变。在大鼠中，每周连续两天腹腔注射紫杉醇（6mg/kg），共4周。分别在第0、3、10、17和24天通过von Frey试验和丙酮试验、机械性异常性疼痛和冷痛觉过敏来测量紫杉醇诱导的周围神经病变。在第3天和第24天通过qRT-PCR分析脊髓中Mfn2、Arhgef10和Prx mRNA的表达。紫杉醇在第17 - 24天诱发了机械性异常性疼痛，但未诱发冷痛觉过敏。此外，在第3天和第24天，紫杉醇降低了Mfn2 mRNA的表达，但未降低Arhgef10或Prx mRNA的表达。此外，在机械性异常性疼痛出现之前，Mfn2 mRNA水平就已下降。本研究结果表明，Mfn2 mRNA表达的降低促成了紫杉醇诱导的机械性异常性疼痛。
