Analysis for functional mechanism of peripheral neuropathy induced by anti-cancer drug Paclitaxel

抗癌药物紫杉醇致周围神经病变的作用机制分析

• 批准号: 18590145
• 负责人: YAMADA Katsushi
• 金额: $ 2.42万
• 依托单位: Kagoshima University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590145/
• 关键词: neuropathy; anti-neoplastic agent; adverse effect; 痛み; 薬学; 薬理学

Paclitaxel-induced painful peripheral neuropathy is a major dose-limiting factor. Recently, it has been reported that macrophages accumulated in the dorsal root ganglion of paclitaxel-treated rats, and their activation is suggested to contribute to generation and development of the neuropathy. However, the mechanism for macrophage activation is still unknown. In this study, to explore candidate genes involved in the mechanism for macrophage activation in the dorsal root ganglion of paclitaxel-treated rats, we developed model rats for paclitaxel-induced neuropathic pain and performed a microarray assay to analyze the changes of gene expressions in the dorsal root ganglion. Among the genes with changed expression levels, we focused on matrix metalloproteinase-3 (MMP-3, stromelysin-1) and CD163, a macrophage marker. By RT-PCR, the expression levels of MMP-3 and CD163 were markedly up-regulated in paclitaxel-treated dorsal root ganglion. As a result of immunohistochemical study, large ganglion neurons, but neither Schwann cells nor macrophages, predominantly expressed MMP-3. This MMP-3 up-regulation occurred prior to macrophage accumulation in the dorsal root ganglion. In addition, recombinant MMP-3 led to the activation of RAW264 macrophages in vitro. Taken together, we suggested that the up-regulation of MMP-3 and following macrophage activation caused in the dorsal root ganglion might be a significant event to trigger a series of reactions developing paclitaxel-induced peripheral neuropathic pain.

紫杉醇引起的疼痛性周围神经病是主要的剂量限制因素。最近，据报道，巨噬细胞在紫杉醇治疗的大鼠的背根神经节中积聚，并且它们的激活被认为有助于神经病变的产生和发展。然而，巨噬细胞激活的机制仍不清楚。在本研究中，为了探索紫杉醇治疗大鼠背根神经节巨噬细胞激活机制中涉及的候选基因，我们建立了紫杉醇诱导的神经病理性疼痛模型大鼠，并进行了微阵列分析，分析了背根神经节中基因表达的变化。在表达水平发生变化的基因中，我们重点关注基质金属蛋白酶-3（MMP-3、stromelysin-1）和巨噬细胞标记物 CD163。 RT-PCR结果显示，紫杉醇处理后的背根神经节中MMP-3和CD163的表达水平显着上调。免疫组织化学研究的结果是，大神经节神经元主要表达 MMP-3，但雪旺细胞和巨噬细胞均不表达。 MMP-3 的上调发生在巨噬细胞在背根神经节中积累之前。此外，重组MMP-3导致RAW264巨噬细胞在体外被激活。综上所述，我们认为背根神经节中 MMP-3 的上调和随后引起的巨噬细胞激活可能是引发紫杉醇诱导的周围神经病理性疼痛的一系列反应的重要事件。

项目成果

Effect of methotrexate treatment on expression levels of multidrug resis tance protein 2,breast cancer resistance protein and organic anion tran sporters Oatl,Oat2 and Oat3 in rats

甲氨蝶呤治疗对大鼠多药耐药蛋白2、乳腺癌耐药蛋白及有机阴离子转运蛋白Oat1、Oat2、Oat3表达水平的影响

• 发表时间: 2006
• 期刊: Cancer Sci. 97
• 作者: Yamada K;Takeda Y;他7名
• 通讯作者: 他7名

Up-regulation of matrix metalloproteinase-3 in the dorsal root ganglion of rats with paclitaxel-induced neuropathy

• DOI: 10.1111/j.1349-7006.2008.00877.x
• 发表时间: 2008-08-01
• 期刊: CANCER SCIENCE
• 影响因子: 5.7
• 作者: Nishida, Kentaro;Kuchiiwa, Satoshi;Yamada, Katsushi
• 通讯作者: Yamada, Katsushi

The small heat shock protein alphaB-crystallin inhibits differentiation-induced caspase 3 activation and myogenic differentiation

小热休克蛋白 αB-晶状体蛋白抑制分化诱导的 caspase 3 激活和肌原性分化

• 发表时间: 2006
• 期刊: BiolPharm Bull 29
• 作者: Ikeda R;Yoshida K;Ushiyama M;Yamaguchi T;Iwashita K;Futagawa T;Shibayama Y;Oiso S;Takeda Y;Kariyazono H;Furukawa T;Nakamura K;Akiyama S;Inoue I;Yamada K.
• 通讯作者: Yamada K.

A retrospective study of the relationship between methotrexate clearance and hyperuricemia following high-dose methotrexate therapy.

大剂量甲氨蝶呤治疗后甲氨蝶呤清除率与高尿酸血症关系的回顾性研究。

• 发表时间: 2006
• 期刊: Journal of Applied Therapeutic Research 6
• 作者: Shibayama;Y.;Takeda;Y.;Yamada;K.et al.
• 通讯作者: K.et al.

Characterization of the PAC 1 variants expressed in the mouse heart

小鼠心脏中表达的 PAC 1 变体的表征

• 发表时间: 2006
• 期刊: Ann N. Y. Acad. Sci. 1070
• 作者: 上竹勇三郎;下澤達雄;Ushiyama M;Iwata S;宮田 篤郎;M. Ushiyama;S. Iwata;Ushiyama. Mina;Iwata Shinichi;Narimatsu S;Fujikawa K;Ushiyama M;Iwata S;Shimizu T;宮田 篤郎;S. Narimatsu;K. Fujikawa;M. Ushiyama
• 通讯作者: M. Ushiyama