Selective suppression of the JNK-MMP2/9 signal pathway by tetramethylpyrazine attenuates neuropathic pain in rats.
Selective suppression of the JNK-MMP2/9 signal pathway by tetramethylpyrazine attenuates neuropathic pain in rats.
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四甲基吡嗪选择性抑制 JNK-MMP2/9 信号通路可减轻大鼠神经性疼痛
DOI：
10.1186/s12974-017-0947-x
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发表时间：
2017-08-31
影响因子：
9.3
通讯作者：
Liu WT
中科院分区：
文献类型：
--
作者：
Jiang L;Pan CL;Wang CY;Liu BQ;Han Y;Hu L;Liu L;Yang Y;Qu JW;Liu WT
活化的星形胶质细胞释放基质金属蛋白酶-2/9（MMP-2/9）以诱导中枢敏化并维持神经病理性疼痛。然而，在疼痛过程中星形胶质细胞上MMP-2/9的激活机制仍然知之甚少。同时，目前还缺乏有效的治疗方法来抑制MMP-2/9对星形胶质细胞的活化。在这项研究中，我们的目的是研究川芎嗪（TMP），一种天然化合物，具有镇痛作用，但机制不明，对MMP-2/9在神经病理性疼痛的影响。通过测量大鼠（n = 6）中响应于机械压痕的足缩回的发生率来评估伤害感受。使用蛋白质印迹（n = 6）和免疫组织化学（n = 5）测定细胞信号传导。培养星形胶质细胞系C8-D1 A以研究体外作用。川芎嗪显著减弱慢性缩窄性损伤（CCI）诱导的神经病理性疼痛的维持，抑制星形胶质细胞的活化，并降低MMP-2/9的表达。此外，我们的研究结果表明，TMP可以选择性地抑制JNK活性，但对ERK和p38没有显着的影响。我们的研究还表明，TMP的作用可能依赖于TAK 1的抑制。川芎嗪对脊髓星形胶质细胞活化的抑制可能在CCI诱导的神经炎症的治疗中具有实用性，并且我们的结果进一步暗示JNK-MMP-2/9是减轻神经病理性疼痛的新靶点。本文的在线版本（10.1186/s12974-017-0947-x）包含补充材料，可供授权用户使用。
Activated astrocytes release matrix metalloproteinase-2/9 (MMP-2/9) to induce central sensitization and maintain neuropathic pain. However, the mechanisms involved in the activation of MMP-2/9 on astrocytes during pain remain poorly understood. Meanwhile, there is a lack of effective treatment to inhibit the activation of MMP-2/9 on astrocytes. In this study, we aim to investigate the effect of tetramethylpyrazine (TMP), a natural compound with analgesic effects but unknown mechanisms, on MMP-2/9 in neuropathic pain. The nociception was assessed by measuring the incidence of foot withdrawal in response to mechanical indentation in rats (n = 6). Cell signaling was assayed using western blotting (n = 6) and immunohistochemistry (n = 5). The astrocyte cell line C8-D1A was cultured to investigate the in vitro effects. TMP significantly attenuated the maintenance of chronic constrictive injury (CCI)-induced neuropathic pain, inhibited the activation of astrocytes, and decreased the expression of MMP-2/9. Furthermore, our results indicated that TMP could selectively suppress JNK activity but had no notable effects on ERK and p38. Our study also revealed that the effect of TMP may be dependent on the inhibition of TAK1. Inhibition of astrocyte activation in the spinal cord by tetramethylpyrazine may have utility in the treatment of CCI-induced neuroinflammation, and our results further implicate JNK-MMP-2/9 as a novel target for the attenuation of neuropathic pain. The online version of this article (10.1186/s12974-017-0947-x) contains supplementary material, which is available to authorized users.
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