Quantitative analysis of Gd in the protein content of the brain following single injection of gadolinium-based contrast agents (GBCAs) by size exclusion chromatography
Quantitative analysis of Gd in the protein content of the brain following single injection of gadolinium-based contrast agents (GBCAs) by size exclusion chromatography
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DOI：
10.1259/bjr.20190062
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发表时间：
2019-01-01
影响因子：
2.6
通讯作者：
Tsushima, Yoshito
中科院分区：
文献类型：
--
作者：
Kartamihardja, Achmad Adhipatria Perayabangsa;Hanaoka, Hirofumi;Tsushima, Yoshito
目的：研究一次大剂量注射钆基造影剂（GBCA）后转运蛋白在脑内钆（Gd）分布和滞留中的作用。方法和材料：将30只ddY小鼠随机分为三个治疗组，分别静脉注射钆双胺或钆双胺。（线性GBCA）、Gadobutrol（大环GBCA）或Gadoterate（大环GBCA），而对照组中的5只小鼠接受250 μ L盐水。分别于注射后5 min和10 d取脑脊液（CSF）、脉络丛（CP）、脑膜和相关血管（MAV），解剖脑组织，获取嗅球、大脑皮质、海马、小脑和脑干。通过尺寸排阻高效液相色谱（SEC）系统提取和分离蛋白质，并通过电感耦合等离子体质谱（ICP-MS）定量Gd浓度。结果：注射后5 m，钆双胺组具有最高的Gd浓度，而钆特酸盐在脑的所有部分中具有最低的Gd浓度（p <0.05）。注射后5分钟，钆双胺组的脑脊液（CSF）中Gd浓度最高（578.4 +/- 135.3 nmol），而钆布醇组的MAV中Gd浓度最高（379.7 +/- 75.4 nmol）。在第10天，尽管所有GBCA的Gd显著降低（p < 0.01），但在整个脑中检测到钆双胺的几种大小不同的分子中保留的Gd。在嗅球中检测到的钆布醇Gd（8.7 +/- 4.5 nmol）显著高于大脑其他部位。虽然大多数钆从钆布醇中发现的分子大小类似于钆布醇，它也被发现在几个蛋白质分子的分子大小大于造影剂。结论：GBCAs可以通过完整的脑屏障，其化学结构可能影响Gd的脑渗透能力。钆双胺和钆布醇在脑组织中保留的Gd可能与一些有机分子结合，包括蛋白质。知识进展：完整的GBCA能够在给药后立即穿透一系列脑屏障，无论螯合物的类型如何。Gd可能与大分子结合，这可能导致Gd在脑中滞留。
Objective: To investigate the role of transporter proteins in gadolinium (Gd) distribution and retention in the brain after one high-dose injection of Gd-based contrast agent (GBCA).Methods and materials: 30 ddY mice were randomly divided into three treatment groups to be intravenously injected with either Gadodiamide (linear GBCA), Gadobutrol (macrocyclic GBCA), or Gadoterate (macrocyclic GBCA) at a dose of 5 mmol/kg, while five mice in the control group received 250 mu L saline. Five minutes (5min) and ten days (10d) post-injection, the cerebrospinal fluid (CSF), choroid plexus (CP), and meninges and associated vasculature (MAV) were collected, The brain was then dissected to obtain the olfactory bulb, cerebral cortex, hippocampus, cerebellum, and brainstem. Proteins were extracted and separated by a size-exclusion high-performance liquid chromatography (SEC) system, and Gd concentrations were quantified by inductively coupled plasma mass spectrometry (ICP-MS).Results: 5 m post-injection, the Gadodiamide group had the highest Gd concentration, while Gadoterate had the lowest Gd concentration in all parts of the brain (p < .05). Gd concentration was highest in the cerebrospinal fluid (CSF) of the Gadodiamide group (578.4 +/- 135.3 nmol), while Gd concentration was highest in MAV in the Gadobutrol group (379.7 +/- 75.4 nmol) at 5 min post-injection. At 10d, in spite of the significant decrease of Gd from all GBCAs ( p < 0.01), retained Gd from Gadodiamide was detected all over the brain in several molecules that varied in size. Gd from Gadobutrol detected in the olfactory bulb (8.7 +/- 4.5 nmol) was significantly higher than in other parts of the brain. Although most Gd from Gadobutrol was found in molecules similar in size to Gadobutrol, it was also found in several protein molecules of molecular size larger than the contrast agents. Only a small amount of Gd from Gadoterate was found in the brain.Conclusion: GBCAs may be able to pass through intact brain barriers, and the chemical structures of GBCAs may affect the penetration capability of Gd into the brain. Retained Gd in the brain tissue from Gadodiamide and Gadobutrol may be bound to some organic molecules, including proteins.Advances in knowledge: Intact GBCA are able to penetrate a series of brain barrier immediately after administration regardless the type of the chelate. Gd may be bound with macromolecules that may cause Gd retention in the brain.