School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, Louisiana, USA.
Biofactors. 2022 Jul;48(4):926-933. doi: 10.1002/biof.1833. Epub 2022 Mar 10.
Dysfunction of the blood-brain barrier (BBB) endothelium increases infiltration of lymphocytes and innate immune cells in the brain, leading to the development of neurological disorders. Heat shock protein 90 (Hsp90) inhibitors are anti-inflammatory agents and P53 inducers, which reduce the production of reactive oxygen species (ROS) in a diverse variety of human tissues. In this study, we investigate the effects of those compounds in LPS-induced brain endothelial inflammation, by utilizing human cerebral microvascular endothelial cells (hCMEC/D3). Our results suggest that Hsp90 inhibitors suppress inflammation by inhibiting the LPS-induced signal transducer and activator of transcription 3 (STAT3); and P38 activation. Moreover, those compounds reduce the P53 suppressors murine double minute 2 (MDM2) and murine double minute 4 (MDM4). Immunoglobulin heavy chain binding protein/glucose-regulated protein 78 (BiP/Grp78)-a key element of endothelial barrier integrity-was also increased by Hsp90 inhibition. Hence, we conclude that application of Hsp90 inhibitors in diseases related to BBB dysfunction may deliver a novel therapeutic possibility in the affected population.
血脑屏障（BBB）内皮功能障碍会增加淋巴细胞和固有免疫细胞向大脑的浸润，导致神经紊乱的发生。热休克蛋白 90（Hsp90）抑制剂是一种抗炎剂和 P53 诱导剂，可减少多种人体组织中活性氧（ROS）的产生。在这项研究中，我们利用人脑血管内皮细胞（hCMEC/D3）研究了这些化合物在 LPS 诱导的脑内皮炎症中的作用。结果表明，Hsp90 抑制剂通过抑制 LPS 诱导的信号转导和转录激活因子 3（STAT3）和 P38 的激活来抑制炎症。此外，这些化合物还降低了 P53 抑制剂鼠双微体 2（MDM2）和鼠双微体 4（MDM4）。免疫球蛋白重链结合蛋白/葡萄糖调节蛋白 78（BiP/Grp78）——内皮屏障完整性的关键因素——也被 Hsp90 抑制所增加。因此，我们得出结论，在与 BBB 功能障碍相关的疾病中应用 Hsp90 抑制剂可能为受影响人群提供一种新的治疗可能性。
