Decorin prevents the development of juvenile communicating hydrocephalus
Decorin prevents the development of juvenile communicating hydrocephalus
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DOI：
10.1093/brain/awt203
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发表时间：
2013-09-01
期刊：
影响因子：
14.5
通讯作者：
Logan, Ann
中科院分区：
文献类型：
--
作者：
Botfield, Hannah;Gonzalez, Ana Maria;Logan, Ann
在出血后和其他形式的交通性脑积水中，脑脊液流动和引流被蛛网膜下纤维化阻塞，其中强效纤维化细胞因子转化生长因子-β在病因学上被牵连。在这里，假设转化生长因子β拮抗剂核心蛋白聚糖具有减少纤维化和脑室扩大的治疗潜力，使用幼年交通性脑积水的大鼠模型进行了测试。在3周龄大鼠中通过单次基底池注射高岭土诱导脑积水，随后立即连续脑室内输注3或14天的人重组核心蛋白聚糖或磷酸盐缓冲盐水（载体）。在第14天通过磁共振成像测量心室扩张。在第14天评价纤维化、转化生长因子-β/Smad 2/3活化和脑积水病理学，并在第3天和第14天通过免疫组织化学和基础组织学评价炎症反应。脑室大小的分析证实了注射高岭土的大鼠中脑积水的发展，但也揭示了连续的核心蛋白聚糖输注防止了脑室扩大，使得脑室大小保持与完整对照大鼠中的脑室大小相似。核心蛋白聚糖阻止高岭土注射后整个脑室系统中转化生长因子-β 1和磷酸化Smad 2/3水平的增加，并抑制蛛网膜下腔中细胞外基质分子、层粘连蛋白和纤连蛋白的沉积。此外，核心蛋白聚糖保护免受脑积水脑损伤推断的神经胶质和炎症反应的衰减。因此，我们得出结论，核心蛋白聚糖通过阻断转化生长因子-β诱导的蛛网膜下腔纤维化来防止幼年大鼠脑积水的发展，并防止脑积水性脑损伤。结果表明，核心蛋白聚糖是一个潜在的临床治疗青少年出血后交通性脑积水的治疗。
In post-haemorrhagic and other forms of communicating hydrocephalus, cerebrospinal fluid flow and drainage is obstructed by subarachnoid fibrosis in which the potent fibrogenic cytokine transforming growth factor-beta has been aetiologically implicated. Here, the hypothesis that the transforming growth factor-beta antagonist decorin has therapeutic potential for reducing fibrosis and ventriculomegaly was tested using a rat model of juvenile communicating hydrocephalus. Hydrocephalus was induced by a single basal cistern injection of kaolin in 3-week-old rats, immediately followed by 3 or 14 days of continuous intraventricular infusion of either human recombinant decorin or phosphate-buffered saline (vehicle). Ventricular expansion was measured by magnetic resonance imaging at Day 14. Fibrosis, transforming growth factor-beta/Smad2/3 activation and hydrocephalic brain pathology were evaluated at Day 14 and the inflammatory response at Days 3 and 14 by immunohistochemistry and basic histology. Analysis of ventricular size demonstrated the development of hydrocephalus in kaolin-injected rats but also revealed that continuous decorin infusion prevented ventricular enlargement, such that ventricle size remained similar to that in intact control rats. Decorin prevented the increase in transforming growth factor-beta 1 and phosphorylated Smad2/3 levels throughout the ventricular system after kaolin injection and also inhibited the deposition of the extracellular matrix molecules, laminin and fibronectin in the subarachnoid space. In addition, decorin protected against hydrocephalic brain damage inferred from attenuation of glial and inflammatory reactions. Thus, we conclude that decorin prevented the development of hydrocephalus in juvenile rats by blocking transforming growth factor-beta-induced subarachnoid fibrosis and protected against hydrocephalic brain damage. The results suggest that decorin is a potential clinical therapeutic for the treatment of juvenile post-haemorrhagic communicating hydrocephalus.