Activation of Adenosine Monophosphate- activated Protein Kinase Suppresses Neuroinflammation and Ameliorates Bone Cancer Pain
Activation of Adenosine Monophosphate- activated Protein Kinase Suppresses Neuroinflammation and Ameliorates Bone Cancer Pain
复制标题
激活单磷酸腺苷激活的蛋白激酶可抑制神经炎症并减轻骨癌疼痛
DOI：
10.1097/aln.0000000000000856
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发表时间：
2015-11-01
期刊：
影响因子：
8.8
通讯作者：
Liu, Wentao
中科院分区：
文献类型：
--
作者：
Song, Huayuan;Han, Yuan;Liu, Wentao
背景资料：腺苷一磷酸激活激酶（AMPK）的激活与炎症性伤害感受的抑制和吗啡镇痛耐受的减弱有关。在这项研究中，作者调查了AMPK激活通过白藜芦醇治疗对骨癌pain.Methods的影响：通过测量大鼠（n = 8）的机械压痕反应的足退缩的发生率来评估伤害性感受。使用定量聚合酶链反应测量细胞因子表达（n = 8）。Western blot（n = 4）和免疫组化（n = 5）检测细胞信号转导。结果：AMPK激活剂白藜芦醇和5-氨基-1-D-呋喃核糖基咪唑-4-甲酰胺（5-amino-1--d-ribofuranosyl-imidazole-4-carboxamide，5-amino-1-d-ribofuranosyl-imidazole-4-carboxamide，5-amino-1-d-ribofuranosyl-imidazole-4-carboxamide）能显著减轻骨肿瘤细胞移植大鼠的疼痛（TCI;机械撤回阈值，白藜芦醇对载体：10.1 ± 0.56对4.1 ± 0.37; 5-氨基-1-β-d-呋喃核糖基-咪唑-4-甲酰胺对载体：8.2 +/- 0.17对比4.1 +/- 0.37，平均值+/- SEM）;这些作用被AMPK抑制剂化合物C逆转（化合物C对比白藜芦醇：6.2 +/- 1.35对比10.1 +/- 0.56，平均值+/- SEM）。白藜芦醇对TCI诱发的星形胶质细胞和小胶质细胞活化具有AMPK依赖性抑制作用。白藜芦醇的抗伤害作用部分介导的有丝分裂原活化蛋白激酶的磷酸化减少，并在AMPK依赖的方式减少促炎细胞因子的产生。此外，白藜芦醇有效地抑制神经元中炎症因子介导的蛋白激酶B/哺乳动物雷帕霉素靶信号传导。急性疼痛引起的促炎细胞因子在脊髓中显着衰减resveratrol.Conclusions：AMPK激活脊髓胶质细胞白藜芦醇可能有效用在治疗TCI诱导的神经炎症，我们的研究结果进一步牵连AMPK作为一个新的目标，为衰减骨癌疼痛。
Background: Activation of adenosine monophosphate-activated kinase (AMPK) has been associated with the inhibition of inflammatory nociception and the attenuation of morphine antinociceptive tolerance. In this study, the authors investigated the impact of AMPK activation through resveratrol treatment on bone cancer pain.Methods: The nociception was assessed by measuring the incidence of foot withdrawal in response to mechanical indentation in rats (n = 8). Cytokine expression was measured using quantitative polymerase chain reaction (n = 8). Cell signalings were assayed by western blot (n = 4) and immunohistochemistry (n = 5). The microglial cell line BV-2, primary astrocytes, and neuron-like SH-SY5Y cells were cultured to investigate the in vitro effects.Results: Resveratrol and 5-amino-1--d-ribofuranosyl-imidazole-4-carboxamide, the AMPK activators, significantly attenuated bone cancer pain in rats with tumor cell implantation (TCI; threshold of mechanical withdrawal, resveratrol vs. vehicle: 10.1 0.56 vs. 4.1 +/- 0.37; 5-amino-1--d-ribofuranosyl-imidazole-4-carboxamide vs. vehicle: 8.2 +/- 0.17 vs. 4.1 +/- 0.37, mean +/- SEM); these effects were reversed by the AMPK inhibitor compound C (compound C vs. resveratrol: 6.2 +/- 1.35 vs. 10.1 +/- 0.56, mean +/- SEM). Resveratrol has an AMPK-dependent inhibitory effect on TCI-evoked astrocyte and microglial activation. The antinociceptive effects of resveratrol were partially mediated by the reduced phosphorylation of mitogen-activated protein kinases and decreased production of proinflammatory cytokines in an AMPK-dependent manner. Furthermore, resveratrol potently inhibited inflammatory factors-mediated protein kinase B/mammalian target of rapamycin signaling in neurons. Acute pain evoked by proinflammatory cytokines in the spinal cord was significantly attenuated by resveratrol.Conclusions: AMPK activation in the spinal glia by resveratrol may have utility in the treatment of TCI-induced neuroinflammation, and our results further implicate AMPK as a novel target for the attenuation of bone cancer pain.