Inhibition of HSP90 Preserves Blood-Brain Barrier Integrity after Cortical Spreading Depression.
Inhibition of HSP90 Preserves Blood-Brain Barrier Integrity after Cortical Spreading Depression.
复制标题
抑制HSP90可保护皮层扩散性抑制后血脑屏障的完整性
DOI：
10.3390/pharmaceutics14081665
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发表时间：
2022-08-10
期刊：
影响因子：
5.4
通讯作者：
Largent-Milnes, Tally M.
中科院分区：
文献类型：
--
作者：
Palomino, Seph M.;Levine, Aidan A.;Wahl, Jared;Liktor-Busa, Erika;Streicher, John M.;Largent-Milnes, Tally M.
关键词：
皮质扩散性抑制（CSD）是包括偏头痛在内的头痛疾病的病理生理机制。CSD期间血脑屏障（BBB）通透性增加。最近的论文表明，热休克蛋白（HSP）有助于血脑屏障的完整性。在这项研究中，热休克蛋白90在CSD相关的血脑屏障泄漏在内皮细胞的可能作用进行了研究，使用体外模型，血内皮屏障（BEB），和一个完整的血脑屏障的体内模型。我们使用跨啮齿动物脑内皮细胞单层（bEnd.3）的跨内皮电阻（TEER）、蔗糖摄取测定和使用雌性Sprague道利大鼠的原位脑灌注来测量屏障完整性。在体外实验中通过应用60 mM KCl 5 min或在体内通过硬脑膜插管向皮质注射KCl（1 M，0.5 µ L）诱导CSD。17-AAG可选择性阻断HSP90。我们的数据表明，用17-AAG（1 µ M）预孵育可防止KCl脉冲对bEnd.3细胞单层造成的TEER值降低。KCl脉冲诱导的14 C-蔗糖在同一内皮细胞单层的摄取升高，与HSP 90抑制剂预孵育后显着降低。通过雌性大鼠原位脑灌注测定，预先暴露于17-AAG显著减轻了皮质KCl注射诱导的CSD后的短暂BBB渗漏。我们的结果表明，用选择性试剂17-AAG抑制HSP 90减少了CSD相关的BEB/BBB细胞旁渗漏。总的来说，这一新的观察结果支持HSP90抑制减轻KCl诱导的BBB通透性，并建议开发新的治疗方法，靶向HSP90在头痛疾病。
Cortical spreading depression (CSD) is a pathophysiological mechanism underlying headache disorders, including migraine. Blood–brain barrier (BBB) permeability is increased during CSD. Recent papers have suggested that heat shock proteins (HSP) contribute to the integrity of the blood–brain barrier. In this study, the possible role of HSP90 in CSD-associated blood–brain barrier leak at the endothelial cell was investigated using an in vitro model, for the blood–endothelial barrier (BEB), and an in vivo model with an intact BBB. We measured barrier integrity using trans endothelial electric resistance (TEER) across a monolayer of rodent brain endothelial cells (bEnd.3), a sucrose uptake assay, and in situ brain perfusion using female Sprague Dawley rats. CSD was induced by application of 60 mM KCl for 5 min in in vitro experiments or cortical injection of KCl (1 M, 0.5 µL) through a dural cannula in vivo. HSP90 was selectively blocked by 17-AAG. Our data showed that preincubation with 17-AAG (1 µM) prevented the reduction of TEER values caused by the KCl pulse on the monolayer of bEnd.3 cells. The elevated uptake of 14C-sucrose across the same endothelial monolayer induced by the KCl pulse was significantly reduced after preincubation with HSP90 inhibitor. Pre-exposure to 17-AAG significantly mitigated the transient BBB leak after CSD induced by cortical KCl injection as determined by in situ brain perfusion in female rats. Our results demonstrated that inhibition of HSP90 with the selective agent 17-AAG reduced CSD-associated BEB/BBB paracellular leak. Overall, this novel observation supports HSP90 inhibition mitigates KCl-induced BBB permeability and suggests the development of new therapeutic approaches targeting HSP90 in headache disorders.
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影响因子：
6.3
作者：
Andrew, R. David;Hsieh, Yi-Ting;Brisson, C. Devin
通讯作者：
Brisson, C. Devin
DOI：
10.1093/cercor/bhv054
发表时间：
2015-11
期刊：
Cerebral cortex (New York, N.Y. : 1991)
影响因子：
--
作者：
Enger R;Tang W;Vindedal GF;Jensen V;Johannes Helm P;Sprengel R;Looger LL;Nagelhus EA
通讯作者：
Nagelhus EA
DOI：
10.1152/ajpheart.01177.2006
发表时间：
2007-06-01
影响因子：
4.8
作者：
Colgan, Olga C.;Ferguson, Gail;Cummins, Philip M.
通讯作者：
Cummins, Philip M.
影响因子：
7
作者：
Kruse, Rikke;Krantz, James;Langlais, Paul R.
通讯作者：
Langlais, Paul R.
影响因子：
6.1
作者：
Gao Hong-mei;Li Le;Zhang Zhong-ling
通讯作者：
Zhang Zhong-ling