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

Abstract

Neuroinflammation has an important influence in pathogenesis of acute hepatic encephalopathy (AHE). C-PK11195 andF-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 F-DPA-714, we analyzed the effectiveness of therapeutic treatment for neuroinflammation in AHE. First, we performed a comparative study ofC-PK1195 and F-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)].F-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 C-PK11195 andF-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 C-PK11195 andF-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 F-DPA-714 PET.

[18F]PBR146 and [18F]DPA-714 in vivo Imaging of Neuroinflammation in Chronic Hepatic Encephalopathy Rats

“…All subjects were randomized into two groups: sham group (n = 8) or BDL group (n = 12). The sample size was determined by considering the mortality rate according to previous studies (Kong et al, 2016;Luo et al, 2018). Details regarding the BDL procedure are described in the Supplementary Materials.…”

“…Detailed procedures are described in the Supplementary Materials. (Fookes et al, 2008;Lavisse et al, 2015;Kong et al, 2016;Luo et al, 2018). Procedures for the synthesis of [ 18 F]DPA-714 and [ 18 F]PBR146 are provided in the Supplementary Materials.…”

“…Previously, [ 18 F]DPA-714 and [ 11 C]PK11195 imaging has been performed in acute and chronic HE rat models. Studies demonstrated that [ 18 F]DPA-714 may be a more suitable agent in HE experimental models (Kong et al, 2016;Luo et al, 2018). Another radiotracer [ 18 F]PBR146 (N,N-diethyl-2-(2-(4-(3-[ 18 F] fluoropropoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3 -yl)acetamide) was proposed in 2007 and was found to have high in vitro affinity and selectivity for PBR (Fookes et al, 2008).…”

The Direct Contribution of Astrocytes and Microglia to the Pathogenesis of Hepatic Encephalopathy

“…86 In the context of acute HE, 11 C-PK1195 and 18 F-DPA-714 have been used and found to detect neuroinflammation in thioacetamide-treated rats by binding to translocator protein. 87 Interestingly, translocator protein has been deleted from astrocytes, demonstrating an increase of mitochondria permeability transition and cell volume in response to ammonia, indicating that this protein is involved in more processes than just neuroinflammation. 88 That being said, not all evidence shows induction of a proinflammatory phenotype during HE as microglia polarization occurs in cirrhotic patients, with both pro-inflammatory M1 and anti-inflammatory M2 phenotypes being present.…”

Gliosis and Neurodegenerative Diseases: The Role of PET and MR Imaging

“…The first-generation radioligand [ 11 C](R)-PK11195 has been the most widely studied in clinical studies and different neurodegenerative diseases, including multiple sclerosis (Airas et al, 2018), Creutzfeldt-Jakob disease (Iaccarino et al, 2018), and also in psychiatric disorders such as schizophrenia (Di Biase et al, 2017). Although the findings of an increased uptake of this tracer in these pathologies, limitations including low signalto-noise ratio and high non-specific binding has addressed for the synthesis of second-and third-generation TSPO-specific radiopharmaceuticals, linked to [ 11 C] or [ 18 F] and including (Luo et al, 2018;Singhal et al, 2018;Best et al, 2019). Similarly, different studies have reported selective microglial uptake of these tracers in multiple sclerosis animal models and patients (Hagens et al, 2018;Herranz et al, 2019;Nack et al, 2019), amyotrophic lateral sclerosis (Zürcher et al, 2015;Datta et al, 2017), Alzheimer's disease (Alam et al, 2017;Keller et al, 2018;Focke et al, 2019), and Lyme disease on humans (Coughlin et al, 2018), and stroke experimental models (Miyajima et al, 2018), with more discordant results for psychiatric patients, suffering from schizophrenia (Di Biase et al, 2017;Hafizi et al, 2017;Ottoy et al, 2018;Selvaraj et al, 2018) and major depression (Li et al, 2018), probably due to the different stage of disease.…”