Molecular pharmacological study on the roles of chemokines in neuropathic pain

趋化因子在神经病理性疼痛中作用的分子药理学研究

基本信息

批准号：
16590047
负责人：
MINAMI Masabumi
金额：
$ 1.92万
依托单位：
HOKKAIDO UNIVERSITY (2005)Kyoto University (2004)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590047/
关键词：
MCP-1 ATF3 Primary sensory neuron Microglia Allodynia Hyperalgesia

项目摘要

Monocyte chemoattractant protein-1(MCP-1,CCL2) is a well-defined CC chemokine implicated in the pathology of various types of brain injuries, such as ischemic and traumatic injuries. Previously, we demonstrated that MCP-1 production was upregulated in the dorsal root ganglia (DRG) of neuropathic pain model rats. In this study, we carried out the double immunofluorescent staining between MCP-1 and activating transcription factor-3(ATF3) to examine whether MCP-1 was produced in the injured or uninjured DRG neurons after the nerve ligation. In the small-sized neurons (cell body area <600 μm^2), MCP-1-immunoreactivity (ir) was observed not only in the injured neurons, but also in the uninjured ones. On the other hand, in the large-sized neurons (>1200μm^2), almost all of the MCP-1-ir neurons were ATF3-ir-positive. This result suggests that intercellular interaction between the injured and uninjured neurons is involved in the MCP-1 upregulation in the small-sized DRG neurons.Furthermore, we investigated the effects of adenosine 5'-O-(3-thiotriphosphate)(ATPγS) on MCP-1 production using the rat cortico-striatal slice culture. ATPγS induced MCP-1 mRNA expression and protein production in astrocytes. The involvement of MAP kinases in this induction was examined by using several kinds of MAP kinase inhibitors. PD98059 and U0126, MEK inhibitors, significantly suppressed ATPγS-induced MCP-1 mRNA expression and protein production. Inhibition of JNK by SP600125 resulted in a partial suppression of them. On the other hand, SB203580, a p38 MAP kinase inhibitor, significantly enhanced ATPγS-induced MCP-1 productfon. Further investigation revealed that SB203580 extended the duration of MCP-1 mRNA expression induced by ATPγS and thereby increased the net production of MCP-1. These results demonstrate the reciprocal regulation of ATPγS-induced MCP-1 production by ERK and p38 MAP kinases in astrocytes.

单核细胞趋化剂蛋白1（MCP-1，CCL2）是一种明确定义的CC趋化因子，植入了各种类型的脑损伤的病理中，例如缺血性和创伤性损伤。以前，我们证明了MCP-1的产生在神经性疼痛模型大鼠的背根神经节（DRG）中进行了更新。在这项研究中，我们在MCP-1和激活转录因子-3（ATF3）之间进行了双重免疫荧光染色，以检查神经连接后受伤或未受伤的DRG神经元中是否产生MCP-1。在小型神经元（细胞体积<600μm^2）中，MCP-1-免疫反应性（IR）不仅在受伤的神经元中，而且在未受伤的神经元中观察到。另一方面，在大型神经元（>1200μm^2）中，几乎所有的MCP-1-IR神经元都是ATF3-IR阳性。该结果表明，受伤的和未受伤的神经元之间的细胞间相互作用参与了小型DRG神经元的MCP-1上调。Furthermore，我们研究了使用Rat rat Cortiatal slice cruite MCP-1生产腺苷5'-O-（3- thiotriph磷酸盐）（ATPγS）对MCP-1生产的影响。 ATPγS诱导星形胶质细胞中的MCP-1 mRNA表达和蛋白质产生。通过使用几种MAP激酶抑制剂检查了MAP激酶参与该诱导的诱导。 PD98059和U0126，MEK抑制剂，显着抑制了ATPγS诱导的MCP-1 mRNA表达和蛋白质产生。 SP600125对JNK的抑制导致对它们的部分抑制。另一方面，p38 MAP激酶抑制剂SB203580显着增强了ATPγS诱导的MCP-1乘积。进一步的研究表明，SB203580延长了ATPγS诱导的MCP-1 mRNA表达的持续时间，从而增加了MCP-1的净产量。这些结果表明，ATPγS诱导的ERK和p38 MAP激酶在星形胶质细胞中的相互调节。