Laboratory of Pathoneurochemistry, Department of Neurochemistry, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 A. Pawińskiego str., 02-106 Warsaw, Poland.
Electron Microscopy Research Unit, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 A. Pawińskiego str., 02-106 Warsaw, Poland.
Cells. 2024 Oct 2;13(19):1641. doi: 10.3390/cells13191641.
Kinins are vasoactive peptides that are involved in various cellular mechanisms, including the inflammatory response. Kinins, released in vessel walls, exacerbate inflammation by modulating the production and release of pro-inflammatory factors via two types of G protein-related receptors-B1 and B2 receptors. B1 R is overexpressed during the inflammation that accompanies numerous neurological disorders, including multiple sclerosis (MS), in which loss of BBB integrity is an early pathomechanism of the disease. In this work, we apply pharmacological inhibition of the kinin B1 receptor with DALBK to investigate its effect on blood-brain barrier (BBB) permeability during the course of EAE, an animal model of MS. Functional, ultrastructural and molecular analyses were performed. The expression of selected BBB-associated proteins such as occludin and claudin-5 was assessed, as well as the astrocytic marker GFAP. We show that administration of a specific antagonist attenuates neurological symptoms in EAE rats and recovers the downregulation of TJ proteins and BBB leakage observed during the course of the disease, as well as significantly reducing the disease-specific activation of astroglia. The results show that B1 R-mediated signaling is involved in inducing molecular changes at the level of cerebral microvessels, leading to increased permeability of the BBB following neuroinflammation in EAE.
激肽是参与多种细胞机制的血管活性肽，包括炎症反应。激肽在血管壁中释放，通过两种类型的 G 蛋白相关受体-B1 和 B2 受体来调节促炎因子的产生和释放，从而加剧炎症。在伴随许多神经疾病（包括多发性硬化症）的炎症中，B1R 过度表达，在这些疾病中，血脑屏障（BBB）的完整性丧失是疾病的早期发病机制。在这项工作中，我们应用激肽 B1 受体的药理学抑制剂 DALBK 来研究其在实验性自身免疫性脑脊髓炎（EAE）过程中对血脑屏障（BBB）通透性的影响，EAE 是多发性硬化症的动物模型。进行了功能、超微结构和分子分析。评估了选定的 BBB 相关蛋白的表达，如紧密连接蛋白（occludin）和闭合蛋白-5（claudin-5），以及星形胶质细胞标志物 GFAP。我们表明，特定拮抗剂的给药可减轻 EAE 大鼠的神经症状，并恢复在疾病过程中观察到的 TJ 蛋白下调和 BBB 渗漏，同时显著减少疾病特异性星形胶质细胞的激活。结果表明，B1R 介导的信号转导参与诱导脑微血管水平的分子变化，导致 EAE 中的神经炎症后 BBB 通透性增加。
