Simvastatin Attenuates Formalin-Induced Nociceptive Behaviors by Inhibiting Microglial RhoA and p38 MAPK Activation
Simvastatin Attenuates Formalin-Induced Nociceptive Behaviors by Inhibiting Microglial RhoA and p38 MAPK Activation
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辛伐他汀通过抑制小胶质细胞 RhoA 和 p38 MAPK 激活来减轻福尔马林诱导的伤害行为
DOI：
10.1016/j.jpain.2013.05.011
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发表时间：
2013-11-01
期刊：
影响因子：
4
通讯作者：
Fu, Kai-Yuan
中科院分区：
文献类型：
--
作者：
Chen, Xin-Yi;Li, Kai;Fu, Kai-Yuan
最近的几项研究表明，他汀类药物除了在体内和体外具有降脂特性外，还具有抗炎作用。最近，他汀类药物被证明可以减轻神经性疼痛模型中与创伤相关的疼痛。本研究的目的是探讨亲脂性他汀类药物辛伐他汀对福尔马林致痛大鼠的镇痛作用机制。鞘内注射辛伐他汀可显著减弱福尔马林注射引起的第二时相急性伤害性反应，每日注射辛伐他汀7 d可抑制福尔马林注射引起的长时程机械性痛觉过敏。脊髓小胶质细胞活化（检测lba-1和CD 11 B免疫组化和蛋白质印迹），磷酸化p38丝裂原活化蛋白激酶（检测免疫组化和蛋白质印迹）显着抑制辛伐他汀治疗福尔马林注射后第7天。此外，外周福尔马林注射诱导脊髓中小胶质细胞RhoA活化的显著增加（使用Western印迹通过膜RhoA易位率检测）。辛伐他汀可逆转小胶质细胞脊髓RhoA的激活。这些研究结果表明，辛伐他汀衰减福尔马林诱导的伤害性行为，至少部分，通过抑制小胶质细胞RhoA和p38丝裂原活化蛋白激酶activation.Perspective：我们的新发现表明，辛伐他汀衰减福尔马林诱导的伤害性反应，通过抑制小胶质细胞RhoA和p38丝裂原活化蛋白激酶活化。RhoA-p38信号通路的失活可能是治疗小胶质细胞介导的中枢神经系统炎症和慢性疼痛的药理学靶点。(C)2013年美国疼痛协会American Pain Society
Several recent studies have revealed that statins exert anti-inflammatory effects in addition to their lipid-lowering property in vivo and in vitro. Recently, statins were shown to alleviate pain associated trauma in a neuropathic pain model. The aim of the present study was to investigate the underlying mechanisms of analgesia caused by the lipophilic statin simvastatin in an animal model of formalin-induced pain in the rat. Intrathecal pretreatment with simvastatin significantly attenuated the second phase of the acute nociceptive response to formalin injection, and daily administration of simvastatin for 7 days inhibited the long-term mechanical hyperalgesia caused by formalin injection. Spinal microglial activation (detected by lba-1 and CD11 b immunohistochemistry and Western blot), and phosphorylated-p38 mitogen-activated protein kinase (detected by immunohistochemistry and Western blot) were significantly inhibited by simvastatin treatment at day 7 after formalin injection. In addition, peripheral formalin injection induced a significant increase in microglial RhoA activation (detected by membrane RhoA translocation ratio using Western blot) in the spinal cord. The spinal RhoA activation in microglia was reversed by simvastatin treatment. These findings suggest that simvastatin attenuates formalin-induced nociceptive behaviors, at least in part, by inhibiting microglial RhoA and p38 mitogen-activated protein kinase activation.Perspective: Our novel findings indicated that simvastatin attenuated formalin-induced nociceptive responses by inhibiting micro glial RhoA and p38 mitogen-activated protein kinase activation. Inactivation of RhoA-p38 signaling pathway may be a pharmacologic target for treating microglia-directed central nervous system inflammation and chronic pain conditions. (C) 2013 by the American Pain Society