Abstract

Inflammatory pathways involved in blood–brain barrier (BBB) vulnerability and hypoxic brain oedema in models of perinatal brain injury seem to provide putative therapeutic targets. To investigate impacts of C1-esterase inhibitor (C1-INH; 7.5–30 IU/kg, i.p.) on functional BBB properties in the hypoxic developing mouse brain (P7; 8% O₂ for 6 h), expression of pro-apoptotic genes (BNIP3, DUSP1), inflammatory markers (IL-1ß, TNF-alpha, IL-6, MMP), and tight junction proteins (ZO-1, occludin, claudin-1, -5), and S100b protein concentrations were analysed after a regeneration period of 24 h. Apoptotic cell death was quantified by CC3 immunohistochemistry and TUNEL staining. In addition to increased apoptosis in the parietal cortex, hippocampus, and subventricular zone, hypoxia significantly enhanced the brain-to-plasma albumin ratio, the cerebral S100b protein levels, BNIP3 and DUSP1 mRNA concentrations as well as mRNA expression of pro-inflammatory cytokines (IL-1ß, TNF-alpha). In response to C1-INH, albumin ratio and S100b concentrations were similar to those of controls. However, the mRNA expression of BNIP3 and DUSP1 and pro-inflammatory cytokines as well as the degree of apoptosis were significantly decreased compared to non-treated controls. In addition, occludin mRNA levels were elevated in response to C1-INH (p < 0.01). Here, we demonstrate for the first time that C1-INH significantly decreased hypoxia-induced BBB leakage and apoptosis in the developing mouse brain, indicating its significance as a promising target for neuroprotective therapy.

中文翻译：

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C1酯酶抑制剂可减少缺氧发育中小鼠大脑中的BBB泄漏和细胞凋亡。

摘要

围产期脑损伤模型中涉及血脑屏障（BBB）脆弱性和缺氧性脑水肿的炎症途径似乎提供了假定的治疗目标。研究C1酯酶抑制剂（C1-INH; 7.5–30 IU / kg，ip）对低氧发育中小鼠大脑中功能性BBB特性的影响（P7; 8％O ₂持续6小时），促凋亡基因（BNIP3，DUSP1），炎性标记（IL-1ß，TNF-α，IL-6，MMP）和紧密连接蛋白（ZO-1，occludin，claudin-1， -5），并且在24小时的再生期后分析了S100b蛋白的浓度。通过CC3免疫组织化学和TUNEL染色定量凋亡细胞死亡。缺氧除了会增加顶叶皮质，海马和脑室下区的细胞凋亡外，还显着提高了脑浆蛋白比，脑S100b蛋白水平，BNIP3和DUSP1 mRNA浓度以及促炎性细胞因子的mRNA表达（ IL-1ß，TNF-α）。响应C1-INH，白蛋白比率和S100b浓度与对照组相似。然而，与未治疗的对照组相比，BNIP3和DUSP1的mRNA表达和促炎细胞因子以及凋亡程度均明显降低。此外，对C1-INH的影响，occludin mRNA水平升高（p  <0.01）。在这里，我们首次证明了C1-INH显着降低了发育中的小鼠大脑缺氧诱导的BBB渗漏和细胞凋亡，表明其作为神经保护疗法的有希望的靶标的重要性。