Zhao Hengguang, Luo Fuling, Li Hongzhong, Zhang Li, Yi Yongfen, Wan Jingyuan
Department of Dermatology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Pharmacy, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
PLoS One. 2014 Apr 10;9(4):e94586. doi: 10.1371/journal.pone.0094586. eCollection 2014.
Tetrandrine (TET) is a bisbenzylisoquinoline alkaloid that is isolated from the Stephania Tetrandra. It is known to possess anti-inflammatory and immunomodulatory effects. We have shown that TET can effectively suppress the production of bacterial lipopolysaccharide (LPS)-induced inflammatory mediators, including cyclooxygenases (COXs), in macrophages. However, whether TET has an antinociceptive effect on LPS-induced hyperalgesia is unknown. In the present study, we investigated the potential antinociceptive effects of TET and the mechanisms by which it elicits its effects on LPS-induced hyperalgesia. LPS effectively evoked hyperalgesia and induced the production of PGE2 in the sera, brain tissues, and cultured astroglia. TET pretreatment attenuated all of these effects. LPS also activated inhibitor of κB (IκB) kinase β (IKKβ) and its downstream components in the IκB/nuclear factor (NF)-κB signaling pathway, including COX-2; the increase in expression levels of these components was significantly abolished by TET. Furthermore, in primary astroglia, knockdown of IKKβ, but not IKKα, reversed the effects of TET on the LPS-induced increase in IκB phosphorylation, P65 phosphorylation, and COX-2. Our results suggest that TET can effectively exert antinociceptive effects on LPS-induced hyperalgesia in mice by inhibiting IKKβ phosphorylation, which leads to the reduction in the production of important pain mediators, such as PGE2 and COX-2, via the IKKβ/IκB/NF-κB pathway.
粉防己碱（TET）是一种从防己科植物粉防己中分离得到的双苄基异喹啉生物碱。已知其具有抗炎和免疫调节作用。我们已经表明，TET可以有效抑制巨噬细胞中细菌脂多糖（LPS）诱导的炎症介质的产生，包括环氧化酶（COXs）。然而，TET对LPS诱导的痛觉过敏是否具有镇痛作用尚不清楚。在本研究中，我们研究了TET的潜在镇痛作用及其对LPS诱导的痛觉过敏产生作用的机制。LPS有效诱发痛觉过敏，并在血清、脑组织和培养的星形胶质细胞中诱导PGE2的产生。TET预处理减弱了所有这些作用。LPS还激活了IκB激酶β（IKKβ）及其在IκB/核因子（NF）-κB信号通路中的下游成分，包括COX-2；TET显著消除了这些成分表达水平的增加。此外，在原代星形胶质细胞中，敲低IKKβ而非IKKα可逆转TET对LPS诱导的IκB磷酸化、P65磷酸化和COX-2增加的作用。我们的结果表明，TET可以通过抑制IKKβ磷酸化，有效发挥对小鼠LPS诱导的痛觉过敏的镇痛作用，这通过IKKβ/IκB/NF-κB途径导致重要疼痛介质如PGE2和COX-2的产生减少。
