Imaging Microglial/Macrophage Activation in Spinal Cords of Experimental Autoimmune Encephalomyelitis Rats by Positron Emission Tomography Using the Mitochondrial 18 kDa Translocator Protein Radioligand [18F]DPA-714
Imaging Microglial/Macrophage Activation in Spinal Cords of Experimental Autoimmune Encephalomyelitis Rats by Positron Emission Tomography Using the Mitochondrial 18 kDa Translocator Protein Radioligand [18F]DPA-714
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DOI：
10.1523/jneurosci.2900-11.2012
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发表时间：
2012-04-25
影响因子：
5.3
通讯作者：
Boisgard, Raphael
中科院分区：
文献类型：
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作者：
Abourbeh, Galith;Theze, Benoit;Boisgard, Raphael
多发性硬化症(MS)是一种中枢神经系统炎症性脱髓鞘疾病。活化的小胶质细胞/巨噬细胞在MS及其相应的动物模型实验性自身免疫性脑脊髓炎(EAE)的免疫发病机制中起着关键作用。小胶质细胞的激活始于疾病的早期阶段，并与18 kDa线粒体转运蛋白(TSPO)的表达升高有关。因此，使用TSPO特异性放射性配基对小胶质细胞激活的正电子发射断层扫描(PET)成像对于监测疾病相关的神经炎症过程可能是有价值的。使用一段髓鞘碱性蛋白在大鼠中诱导EAE，产生反映广泛脊髓炎症的急性临床疾病。Western印迹和免疫组织化学结果显示，EAE大鼠脊髓组织中TSPO的表达增强。用TSPO放射性配体[F-18]DPA-714[N，N-二乙基-2-(2-(4-(2-氟乙氧基)苯基)-5，7-二甲基吡唑并[1，5a]嘧啶-3-基)乙酰胺]在正常大鼠和EAE大鼠体内进行了生物分布研究。在注射后1小时，EAE大鼠脊髓中的[F-18]DPA-714水平几乎是对照组的五倍。竞争研究证实了[F-18]DPA-714与脊髓TSPO的特异性结合，过量使用未标记的(R，S)-PK11195[(R，S)-N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)异喹啉-3-甲基酰胺)]或DPA-714。MicroPET研究证实，EAE大鼠与对照组大鼠脊髓中的这种放射性摄取差异是可以检测和量化的。使用[F-18]DPA-714，PET可以显示EAE诱导的大鼠脊髓中的神经炎症，为监测中枢神经系统尤其是脊髓中的神经炎性病变提供了一种灵敏的技术。除了目前的MRI方案外，这种方法还可以为MS的检测、监测和研究提供神经炎症的分子图像。
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. Activated microglia/macrophages play a key role in the immunopathogenesis of MS and its corresponding animal models, experimental autoimmune encephalomyelitis (EAE). Microglia activation begins at early stages of the disease and is associated with elevated expression of the 18 kDa mitochondrial translocator protein (TSPO). Thus, positron emission tomography (PET) imaging of microglial activation using TSPO-specific radioligands could be valuable for monitoring disease-associated neuroinflammatory processes. EAE was induced in rats using a fragment of myelin basic protein, yielding acute clinical disease that reflects extensive spinal cord inflammation. Enhanced TSPO expression in spinal cords of EAE rats versus those of controls was confirmed by Western blot and immunohistochemistry. Biodistribution studies in control and EAE rats were performed using the TSPO radioligand [F-18] DPA-714 [N,N-diethyl-2-(2-(4-(2-fluoroethoxy) phenyl)-5,7-dimethylpyrazolo[1,5a] pyrimidin-3-yl) acetamide]. At 1 h after injection, almost fivefold higher levels of [F-18] DPA-714 were measured in spinal cords of EAE rats versus controls. The specific binding of [F-18] DPA-714 to TSPO in spinal cords was confirmed in competition studies, using unlabeled (R,S)-PK11195 [(R,S)-N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl) isoquinoline-3-carboxamide)] or DPA-714 in excess. MicroPET studies affirm that this differential radioactivity uptake in spinal cords of EAE versus control rats could be detected and quantified. Using [F-18] DPA-714, neuroinflammation in spinal cords of EAE-induced rats could be visualized by PET, offering a sensitive technique for monitoring neuroinflammatory lesions in the CNS and particularly in the spinal cord. In addition to current MRI protocols, this approach could provide molecular images of neuroinflammation for detection, monitoring, and research in MS.