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.

中文翻译：

---

17-二甲基氨基乙基氨基-17-去甲氧基格尔德霉素减弱实验性中风的炎症反应。

热激蛋白90（HSP90）是一种普遍存在的分子伴侣，参与许多蛋白的正确构象。HSP90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]）与HSP90结合并使其失活，从而抑制了炎症过程中涉及的一些关键信号通路。由于大量证据表明炎症是大脑缺血性损伤进展的原因，因此我们研究了17-DMAG是否可以调节大脑中动脉闭塞（MCAO）小鼠的炎症反应。将雄性C57 / BL6小鼠用17-DMAG或溶媒预处理7 d，然后进行大脑中动脉的短暂闭塞和再灌注。MCAO后24小时评估小鼠的神经功能缺损评分。而且，以核因子κB（NF-κB）途径为研究对象，研究了17-DMAG的抗炎作用机理。17-DMAG显着减少了脑梗塞并改善了神经功能。17-DMAG抑制了小胶质细胞的活化，并抑制了抑制性（I）κB的磷酸化，进而降低了p65的核易位，从而最终下调了NF-κB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。最终下调了NF-κB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。最终下调了NF-κB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。