The analgesic effects of triptolide in the bone cancer pain rats via inhibiting the upregulation of HDACs in spinal glial cells.
The analgesic effects of triptolide in the bone cancer pain rats via inhibiting the upregulation of HDACs in spinal glial cells.
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雷公藤甲素通过抑制脊髓胶质细胞HDACs上调对骨癌疼痛大鼠的镇痛作用
DOI：
10.1186/s12974-017-0988-1
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发表时间：
2017-11-02
影响因子：
9.3
通讯作者：
Dong YL
中科院分区：
文献类型：
--
作者：
Hu XF;He XT;Zhou KX;Zhang C;Zhao WJ;Zhang T;Li JL;Deng JP;Dong YL
骨癌疼痛（BCP）严重影响生活质量，而目前的治疗仍然不令人满意。在这里，我们测试了雷公藤内酯醇（T10），一种对BCP具有相当大的抗肿瘤功效的物质的抗伤害作用，并研究了针对脊髓背角（SDH）的潜在机制。采用胫骨内接种步行者256乳腺癌细胞的方法建立大鼠BCP模型。鞘内注射T10，并通过测量缩爪阈值（PWT）来测试机械异常性疼痛。在机制研究中，通过Iba-1、GFAP、p-ERK、p-p38和p-JNK的免疫荧光染色或Western印迹分析来评估SDH中小胶质细胞、星形胶质细胞和丝裂原活化蛋白激酶（MAPK）通路的活化。检测组蛋白去乙酰化酶1和2的表达和细胞定位，探讨其分子机制。鞘内注射T10可抑制骨癌引起的机械性痛觉超敏反应，ED 50为5.874 μg/kg。停药后6天仍观察到该效应。骨癌导致脊髓小胶质细胞和神经元中HDAC 1表达显著增加，脊髓星形胶质细胞中HDAC 2表达显著增加，这伴随着MAPK通路的上调以及SDH中小胶质细胞和星形胶质细胞的激活。T10可逆转HDAC的增加，尤其是胶质细胞中HDAC的增加，并抑制胶质细胞的活化。提示HDAC的上调参与了脊髓胶质细胞的病理性激活和骨癌引起的慢性疼痛，而T10可能通过抑制SDH中胶质细胞HDAC的上调，进而阻断胶质细胞激活引起的神经炎症而减轻BCP。
Bone cancer pain (BCP) severely compromises the quality of life, while current treatments are still unsatisfactory. Here, we tested the antinociceptive effects of triptolide (T10), a substance with considerable anti-tumor efficacies on BCP, and investigated the underlying mechanisms targeting the spinal dorsal horn (SDH). Intratibial inoculation of Walker 256 mammary gland carcinoma cells was used to establish a BCP model in rats. T10 was intrathecally injected, and mechanical allodynia was tested by measuring the paw withdrawal thresholds (PWTs). In mechanism study, the activation of microglia, astrocytes, and the mitogen-activated protein kinase (MAPK) pathways in the SDH were evaluated by immunofluorescence staining or Western blot analysis of Iba-1, GFAP, p-ERK, p-p38, and p-JNK. The expression and cellular localization of histone deacetylases (HDACs) 1 and 2 were also detected to investigate molecular mechanism. Intrathecal injection of T10 inhibited the bone cancer-induced mechanical allodynia with an ED50 of 5.874 μg/kg. This effect was still observed 6 days after drug withdrawal. Bone cancer caused significantly increased expression of HDAC1 in spinal microglia and neurons, with HDAC2 markedly increased in spinal astrocytes, which were accompanied by the upregulation of MAPK pathways and the activation of microglia and astrocytes in the SDH. T10 reversed the increase of HDACs, especially those in glial cells, and inhibited the glial activation. Our results suggest that the upregulation of HDACs contributes to the pathological activation of spinal glial cells and the chronic pain caused by bone cancer, while T10 help to relieve BCP possibly via inhibiting the upregulation of HDACs in the glial cells in the SDH and then blocking the neuroinflammation induced by glial activation.
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影响因子：
2.7
作者：
Clark AK;Old EA;Malcangio M
通讯作者：
Malcangio M
影响因子：
11.4
作者：
通讯作者：
--
影响因子：
17.1
作者：
Chugh R;Sangwan V;Patil SP;Dudeja V;Dawra RK;Banerjee S;Schumacher RJ;Blazar BR;Georg GI;Vickers SM;Saluja AK
通讯作者：
Saluja AK
影响因子：
7.4
作者：
Cheng, Chau-Fu;Cheng, Jen-Kun;Tsaur, Meei-Ling
通讯作者：
Tsaur, Meei-Ling
雷公藤甲素可防止 APP/PS1 小鼠的记忆缺陷和淀粉样蛋白 β 聚集，同时抑制炎症和 MAPK 活性。
影响因子：
2.1
作者：
Cui, Yan-Qiu;Wang, Qi;Wang, Xiao-Min
通讯作者：
Wang, Xiao-Min