Department of Radiology, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan.
Department of Brain Function, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
Ann Nucl Med. 2021 Jan;35(1):8-16. doi: 10.1007/s12149-020-01530-2. Epub 2020 Sep 28.
The activation of microglia in various brain pathologies is accompanied by an increase in the expression of peripheral benzodiazepine receptor/18 kDa translocator protein (PBR/TSPO). However, whether activated microglia have a neuroprotective or neurotoxic effect on neurons in the brain is yet to be determined. In this study, we investigated the ability of the novel PBR/TSPO ligand FEPPA to detect activated microglia in an animal model of primary neurotoxic microglia activation.
[F] FEPPA positron emission tomography (PET) imaging was performed before and after intraperitoneal administration of lipopolysaccharide (LPS) (LPS group) or saline (control group) in a unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of Parkinson's disease. Images were compared between these groups. After imaging, the brains were collected, and the activated microglia at the disease sites were analyzed by the expression of inflammatory cytokines and immunohistochemistry staining. These results were then comparatively examined with those obtained by PET imaging.
In the unilateral 6-OHDA lesion rat model, the PBR/TSPO PET signal was significantly increased in the LPS group compared with the saline group. As the increased signal was observed 4 h after the injection, we considered it an acute response to brain injury. In the post-imaging pathological examination, activated microglia were found to be abundant at the site where strong signals were detected, and the expression of the inflammatory cytokines TNF-α and IL-1β was increased. Intraperitoneal LPS administration further increased the expression of inflammatory cytokines, and the PBR/TSPO PET signal increased concurrently. The increase in inflammatory cytokine expression correlated with enhanced signal intensity.
PET signal enhancement by PBR/TSPO at the site of brain injury correlated with the activation of microglia and production of inflammatory cytokines. Furthermore, because FEPPA enables the detection of neurotoxic microglia on PET images, we successfully constructed a novel PET detection system that can monitor neurodegenerative diseases.
在各种脑部病变中，小胶质细胞的激活伴随着外周苯二氮䓬受体/18 kDa 转位蛋白（PBR/TSPO）表达的增加。然而，激活的小胶质细胞对大脑中的神经元是否具有神经保护或神经毒性作用仍有待确定。在这项研究中，我们研究了新型 PBR/TSPO 配体 FEPPA 在原发性神经毒性小胶质细胞激活的动物模型中检测激活的小胶质细胞的能力。
在单侧 6-羟多巴胺（6-OHDA）帕金森病大鼠模型中，在腹腔内给予脂多糖（LPS）（LPS 组）或生理盐水（对照组）之前和之后进行[F]FEPPA 正电子发射断层扫描（PET）成像。比较这些组之间的图像。成像后，收集大脑，并通过炎症细胞因子的表达和免疫组织化学染色分析病变部位的激活小胶质细胞。然后将这些结果与 PET 成像获得的结果进行比较。
在单侧 6-OHDA 损伤大鼠模型中，与生理盐水组相比，LPS 组的 PBR/TSPO PET 信号显著增加。由于在注射后 4 小时观察到增加的信号，我们认为这是对脑损伤的急性反应。在成像后的病理检查中，在检测到强信号的部位发现了丰富的激活小胶质细胞，并且炎症细胞因子 TNF-α和 IL-1β的表达增加。腹腔内 LPS 给药进一步增加了炎症细胞因子的表达，同时 PBR/TSPO PET 信号增加。炎症细胞因子表达的增加与信号强度的增强相关。
脑损伤部位 PBR/TSPO 的 PET 信号增强与小胶质细胞的激活和炎症细胞因子的产生相关。此外，由于 FEPPA 能够在 PET 图像上检测到神经毒性小胶质细胞，我们成功构建了一种新型的 PET 检测系统，可以监测神经退行性疾病。
