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Metabolic Brain Disease

, Volume 33, Issue 5, pp 1733–1742 | Cite as

Neuroinflammation in acute hepatic encephalopathy rats: imaging and therapeutic effectiveness evaluation using 11C-PK11195 and 18F-DPA-714 micro-positron emission tomography

  • Song Luo
  • Xiang Kong
  • Jin Rong Wu
  • Chun Yan Wang
  • Ying Tian
  • Gang Zheng
  • Yun Yan Su
  • Guang Ming Lu
  • Long Jiang Zhang
  • Gui Fen Yang
Original Article
  • 148 Downloads

Abstract

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.

Keywords

Hepatic encephalopathy Positron emission tomography Neuroinflammation Minocycline Dexamethasone 

Abbreviations

PET

Positron emission tomography

AHE

Acute hepatic encephalopathy

ALF

Acute liver failure

TSPO

Translocator protein

TAA

Thioacetamide

MINO

Minocycline

DEXA

Dexamethasone

NS

Normal saline

%ID/g

Percentage injected dose per gram

FOV

Field of view

ROIs

Regions of interest

ALT

Alanine transaminase

AST

Aspartate transaminase

IL

Interleukin

TNF-α

Tumor necrosis factor alpha

H&E

Hematoxylin-eosin

DAB

Diaminobenzidine

SD

Standard deviation

ANOVA

Analysis of variance

Notes

Acknowledgements

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.

Authors contributions

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.

Supplementary material

11011_2018_282_MOESM1_ESM.docx (25 kb)
ESM 1 (DOCX 24 kb)
11011_2018_282_Fig1_ESM.png (406 kb)
Supplementary figure S1

Histological findings of the liver gross specimen and H&E staining (original magnification ×100) of control group (A, B) and AHE group (C, D). The liver specimen of a control rat reveals smooth surface of the liver (A) with eumorphis in H&E staining image (B). AHE group rats show acute live injury with diffusion spotty foci in the gross specimen (C). The liver H&E staining image reveals inflammatory infiltration (arrows) with edema and partial necrosis (arrowhead) of liver cells (D). H&E = hematoxylin-eosin; AHE = acute hepatic encephalopathy. (JPG 285 kb) (JPG 285 kb)

11011_2018_282_Fig2_ESM.png (254 kb)
Supplementary figure S2

The representative micrographs showing CD11b immunohistochemistry microglia in basal ganglia of control group (A) and AHE group (B) (original magnification ×400). The microglial cells of control rats show ramified shapes (resting microglia) (A), while AHE rats show ameboid shapes (activated microglia) (B) in basal ganglia. AHE = acute hepatic encephalopathy. (JPG 161 kb)

11011_2018_282_MOESM2_ESM.docx (21 kb)
Supplementary Table S1 (DOCX 21 kb)
11011_2018_282_MOESM3_ESM.docx (22 kb)
Supplementary Table S2 (DOCX 21 kb)
11011_2018_282_MOESM4_ESM.docx (22 kb)
Supplementary Table S3 (DOCX 22 kb)
11011_2018_282_MOESM5_ESM.docx (22 kb)
Supplementary Table S4 (DOCX 22 kb)
11011_2018_282_MOESM6_ESM.docx (28 kb)
Supplementary Table S5 (DOCX 28 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Song Luo
    • 1
  • Xiang Kong
    • 1
  • Jin Rong Wu
    • 2
  • Chun Yan Wang
    • 1
  • Ying Tian
    • 1
  • Gang Zheng
    • 1
  • Yun Yan Su
    • 1
  • Guang Ming Lu
    • 1
  • Long Jiang Zhang
    • 1
  • Gui Fen Yang
    • 3
  1. 1.Department of Medical Imaging, Jinling HospitalMedical School of Nanjing UniversityNanjingChina
  2. 2.Department of Pathology, Jinling HospitalMedical School of Nanjing UniversityNanjingChina
  3. 3.Department of Nuclear MedicineJinling Hospital, Medical School of Nanjing UniversityNanjingChina

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