水通道蛋白4介导铁过载对脑室内出血后脑积水的影响。

Aquaporin 4 Mediates the Effect of Iron Overload on Hydrocephalus After Intraventricular Hemorrhage.

作者信息

Li Ying, Nan Ding, Liu Ran, Li Jieyu, Zhang Zhuangzhuang, Deng Jianwen, Zhang Yang, Yan Ziguang, Hou Chao, Yao Ensheng, Sun Weiping, Wang Zhaoxia, Huang Yining

机构信息

Department of Neurology, Peking University First Hospital, 8 Xishiku Street, Xicheng District, Beijing, 100034, China.

Beijing Key Laboratory of Neurovascular Disease Discovery, Beijing, China.

出版信息

Neurocrit Care. 2024 Feb;40(1):225-236. doi: 10.1007/s12028-023-01746-w. Epub 2023 May 19.

DOI:10.1007/s12028-023-01746-w

PMID:37208490

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10861395/

Abstract

BACKGROUND

Iron overload plays an important role in hydrocephalus development following intraventricular hemorrhage (IVH). Aquaporin 4 (AQP4) participates in the balance of cerebrospinal fluid secretion and absorption. The current study investigated the role of AQP4 in the formation of hydrocephalus caused by iron overload after IVH.

METHODS

There were three parts to this study. First, Sprague-Dawley rats received an intraventricular injection of 100 µl autologous blood or saline control. Second, rats had IVH and were treated with deferoxamine (DFX), an iron chelator, or vehicle. Third, rats had IVH and were treated with 2-(nicotinamide)-1,3,4-thiadiazole (TGN-020), a specific AQP4 inhibitor, or vehicle. Rats underwent T2-weighted and T2* gradient-echo magnetic resonance imaging to assess lateral ventricular volume and intraventricular iron deposition at 7, 14, and 28 days after intraventricular injection and were then euthanized. Real-time quantitative polymerase chain reaction, western blot analysis, and immunofluorescence analyses were conducted on the rat brains to evaluate the expression of AQP4 at different time points. Hematoxylin and eosin-stained brain sections were obtained to assess the ventricular wall damage on day 28.

RESULTS

Intraventricular injection of autologous blood caused a significant ventricular dilatation, iron deposition, and ventricular wall damage. There was increased AQP4 mRNA and protein expression in the periventricular tissue in IVH rats through day 7 to day 28. The DFX treatment group had a lower lateral ventricular volume and less intraventricular iron deposition and ventricular wall damage than the vehicle-treated group after IVH. The expression of AQP4 protein in periventricular tissue was also inhibited by DFX on days 14 and 28 after IVH. The use of TGN-020 attenuated hydrocephalus development after IVH and inhibited the expression of AQP4 protein in the periventricular tissue between day 14 and day 28 without a significant effect on intraventricular iron deposition or ventricular wall damage.

CONCLUSIONS

AQP4 located in the periventricular area mediated the effect of iron overload on hydrocephalus after IVH.

摘要

背景

铁过载在脑室内出血（IVH）后脑积水的发展中起重要作用。水通道蛋白4（AQP4）参与脑脊液分泌与吸收的平衡。本研究探讨了AQP4在IVH后铁过载所致脑积水形成中的作用。

方法

本研究分为三个部分。首先，将100 μl自体血或生理盐水对照脑室内注射到Sprague-Dawley大鼠体内。其次，对IVH大鼠给予去铁胺（DFX，一种铁螯合剂）或赋形剂治疗。第三，对IVH大鼠给予2-（烟酰胺）-1,3,4-噻二唑（TGN-020，一种特异性AQP4抑制剂）或赋形剂治疗。在脑室内注射后第7、14和28天，对大鼠进行T2加权和T2*梯度回波磁共振成像，以评估侧脑室体积和脑室内铁沉积，然后实施安乐死。对大鼠脑进行实时定量聚合酶链反应、蛋白质印迹分析和免疫荧光分析，以评估不同时间点AQP4的表达。获取苏木精-伊红染色的脑切片，以评估第28天的脑室壁损伤情况。

结果

脑室内注射自体血导致明显的脑室扩张、铁沉积和脑室壁损伤。在IVH大鼠的脑室周围组织中，从第7天到第28天，AQP4 mRNA和蛋白表达均增加。与IVH后接受赋形剂治疗的组相比，DFX治疗组的侧脑室体积更小，脑室内铁沉积和脑室壁损伤更少。IVH后第14天和第28天，DFX还抑制了脑室周围组织中AQP4蛋白的表达。使用TGN-020可减轻IVH后的脑积水发展，并在第14天至第28天抑制脑室周围组织中AQP4蛋白的表达，而对脑室内铁沉积或脑室壁损伤无显著影响。