Neuroinflammation in acute hepatic encephalopathy rats: imaging and therapeutic effectiveness evaluation using 11C-PK11195 and 18F-DPA-714 micro-positron emission tomography
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Neuroinflammation has an important influence in pathogenesis of acute hepatic encephalopathy (AHE). 11C-PK11195 and 18F-DPA-714 targeted to translocator protein (TSPO) have potential application in positron emission tomography (PET) as a molecular probe of neuroinflammation. The aim of this study was to compare these two radiotracers and their effectiveness in detecting neuroinflammation for the imaging of AHE rat models. Furthermore, using the new radiotracer 18F-DPA-714, we analyzed the effectiveness of therapeutic treatment for neuroinflammation in AHE. First, we performed a comparative study of 11C-PK1195 and 18F-DPA-714 PET to image neuroinflammation in AHE rats induced by thioacetamide. Twenty-four rats were divided into either control group (n = 12) or AHE group (n = 12). Next, each group was subdivided depending on the radiotracer used during PET imaging (n = 6). Radiotracer uptake values encompassing the whole brain were compared. Lastly, we used the optimized tracer to monitor anti-neuroinflammation effects in AHE-induced rats. Forty-six rats were divided into four groups: [normal saline (NS) group (n = 13), minocycline (MINO) group (n = 11), dexamethasone (DEXA) group (n = 11), MINO+DEXA group (n = 11)]. 18F-DPA-714 PET was performed and the uptake values were calculated. The rotarod test, biochemical indices, and histopathological examinations were quantitatively measured and compared. AHE rats showed reduced motor ability, elevated ammonia levels, and higher liver function indices (all P < 0.05) with unchanged inflammatory factors (all P > 0.05), compared to control group. Both 11C-PK11195 and 18F-DPA-714 PET can detect neuroinflammation of AHE rats. Behavioral studies showed that MINO and/or DEXA improved the motor ability in AHE rats (P < 0.05); however, no differences were found for liver function or inflammatory markers among the four groups (all P > 0.05). The average uptake values of whole brain and multiple brain areas in the MINO+DEXA group were lower compared to all other groups (all P < 0.05), which was demonstrated by CD11b stains of microglia. Our results show that both 11C-PK11195 and 18F-DPA-714 PET can detect neuroinflammation in AHE-induced rat models. Additionally, the combined use of minocycline and dexamethasone can effectively inhibit neuroinflammation in AHE-induced rats, which can be sensitively monitored by 18F-DPA-714 PET.
KeywordsHepatic encephalopathy Positron emission tomography Neuroinflammation Minocycline Dexamethasone
Positron emission tomography
Acute hepatic encephalopathy
Acute liver failure
Percentage injected dose per gram
Field of view
Regions of interest
Tumor necrosis factor alpha
Analysis of variance
This work were supported by grants from National Natural Science Foundation of China (grants No. 81322020, 81230032, and 81171313 to L.J.Z. and 81401468 to G.F.Y. and 81471644 to G.Z.) and the program B for Outstanding PhD candidate of Nanjing University (No. 201801B055 to X.K.). The authors would like to thank Professor U. Joseph Schoepf, Medical University of South Carolina, USA for his contribution in polishing this manuscript. Besides, they would also like to thank Bo Hua Xu, Yan Wang, Cheng Long Yan, Peng Fang, Shan You Yu, and Chao Xu at the Jiangsu Institute of Nuclear Medicine for their core facility and excellent technical assistance.
LJZ, GML, and GFY conceived and designed the study. SL and XK carried out the majority of the animal model preparation, data acquisition, drafting and revision of the manuscript. JRW performed the histology analysis and immunoassays. CYW and YT contributed to data analysis and the interpretation of the data. GZ and YYS contributed to the interpretation of the data and revision of the manuscript. All authors read and approved the final version of the manuscript.
Compliance with ethical standards
Conflict of interest
All authors have no conflict of interest to declare.
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