Up-regulation of matrix metalloproteinase-3 in the dorsal root ganglion of rats with paclitaxel-induced neuropathy
Up-regulation of matrix metalloproteinase-3 in the dorsal root ganglion of rats with paclitaxel-induced neuropathy
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DOI：
10.1111/j.1349-7006.2008.00877.x
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发表时间：
2008-08-01
期刊：
影响因子：
5.7
通讯作者：
Yamada, Katsushi
中科院分区：
文献类型：
--
作者：
Nishida, Kentaro;Kuchiiwa, Satoshi;Yamada, Katsushi
紫杉醇诱导的疼痛性周围神经病变是一个主要的剂量限制因素。最近，据报道，巨噬细胞积累在背根神经节的紫杉醇治疗的大鼠，和他们的激活，建议有助于神经病变的产生和发展。然而，巨噬细胞活化的机制仍然是未知的。在本研究中，为了探索参与紫杉醇治疗大鼠背根神经节中巨噬细胞激活机制的候选基因，我们建立了紫杉醇诱导的神经病理性疼痛大鼠模型，并进行了基因芯片分析，以分析背根神经节中基因表达的变化。在表达水平改变的基因中，我们关注基质金属蛋白酶-3（MMP-3，基质溶解素-1）和巨噬细胞标志物CD 163。逆转录-聚合酶链反应显示，紫杉醇处理后，背根神经节中MMP-3和CD 163的表达水平显著上调。作为免疫组化研究的结果，大的神经节神经元，但既不雪旺细胞也不巨噬细胞，主要表达MMP-3。这种MMP-3上调发生在背根神经节中巨噬细胞积聚之前。此外，重组MMP-3在体外可激活RAW 264巨噬细胞。综上所述，MMP-3的上调和随后在背根神经节中引起的巨噬细胞活化可能是触发一系列反应发展紫杉醇诱导的周围神经病理性疼痛的重要事件。（Cancer Sci 2008; 99：1618-1625）
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 reverse transcription-polymerase chain reaction, 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, 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. (Cancer Sci 2008; 99: 1618-1625)