17-Dimethylaminoethylamino-17-demethoxygeldanamycin attenuates inflammatory responses in experimental stroke.
17-Dimethylaminoethylamino-17-demethoxygeldanamycin attenuates inflammatory responses in experimental stroke.
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DOI：
10.1248/bpb.b14-00208
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发表时间：
2014-11
影响因子：
2
通讯作者：
J. Qi;Xiao Han;Hai Liu;Ting Chen;Jin Zhang;Ping Yang;Shuhong Bo;Xiaotong Lu;Jian Zhang
中科院分区：
文献类型：
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作者：
J. Qi;Xiao Han;Hai Liu;Ting Chen;Jin Zhang;Ping Yang;Shuhong Bo;Xiaotong Lu;Jian Zhang
热休克蛋白90（HSP 90）是一种普遍存在的分子伴侣，参与许多蛋白质的正确构象。HSP 90抑制剂（17-二甲基氨基乙基氨基-17-去甲氧基格尔德霉素盐酸盐[17-DMAG]）结合并抑制HSP 90，抑制炎症过程中涉及的一些关键信号通路。由于相当多的证据表明，炎症占脑缺血性损伤的进展，我们调查是否17-DMAG可以调节大脑中动脉闭塞（MCAO）小鼠的炎症反应。雄性C57/BL 6小鼠在进行大脑中动脉短暂闭塞和再灌注之前用17-DMAG或载体预处理7 d。在MCAO后24小时评价小鼠的神经功能缺损评分。此外，还重点从核因子κ B（NF-κB）途径探讨了17-DMAG的抗炎作用机制。17-DMAG显著减少脑梗死和改善神经功能结局。17-DMAG可抑制小胶质细胞的活化，抑制性（I）κB的磷酸化及随后的p65核转位，最终下调NF-κ B调控基因的表达。这些结果表明，17-DMAG通过抗炎机制在缺血性中风治疗中具有有希望的治疗效果。
Heat shock protein 90 (HSP90) is a ubiquitous molecular chaperone involved in the proper conformation of many proteins. HSP90 inhibitors (17-dimethyl aminoethylamino-17-demethoxygeldanamycin hydrochloride [17-DMAG]) bind to and inactivate HSP90, suppressing some key signaling pathways involved in the inflammatory process. Since considerable evidence suggests that inflammation accounts for the progression of cerebral ischemic injury, we investigated whether 17-DMAG can modulate inflammatory responses in middle cerebral artery occluded (MCAO) mice. Male C57/BL6 mice were pretreated with 17-DMAG or vehicle for 7 d before being subjected to transient occlusion of middle cerebral artery and reperfusion. Mice were evaluated at 24 h after MCAO for neurological deficit scoring. Moreover, the mechanism of the anti-inflammatory effect of 17-DMAG was investigated with a focus on nuclear factor kappa B (NF-κB) pathway. 17-DMAG significantly reduced cerebral infarction and improved neurological outcome. 17-DMAG suppressed activation of microglia and decreased phosphorylation of inhibitory (I)κB and subsequent nuclear translocation of p65, which eventually downregulated expression of NF-κB-regulated genes. These results suggest that 17-DMAG has a promising therapeutic effect in ischemic stroke treatment through an anti-inflammatory mechanism.