Distribution profile and properties of peripheral-type benzodiazepine receptors on human hemopoietic cells

doi:10.1016/0024-3205(93)90293-C

Life Sciences

Volume 52, Issue 1, 1993, Pages 107-118

https://doi.org/10.1016/0024-3205(93)90293-C Get rights and content

Abstract

The cellular localization of peripheral-type benzodiazepine receptors (PBRs) was characterized in several human blood cell subpopulations including erythrocytes, platelets, monocytes and polymorphonuclear neutrophils (PMN), B, NK, T8 and T4-cells. Pharmacological properties of the PBR were established by binding studies and PBR mRNA expression was measured by quantitative polymerase chain reaction based method. These data clearly indicate 1) the PBR is pharmacologically homogeneous in the various types of blood cells, 2) the rank order of PBR cell density is monocytes = PMN > lymphocytes ⪢ platelets > erythrocytes, 3) the PBR appears to be transcriptionally regulated since mRNA levels are roughly correlated with PBR density.

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2020, European Journal of Radiology
Citation Excerpt :
Given the nascent understanding of the role of MMPs to the disease process, PET tracers targeting MMPs could serve as a source of selective biomarkers when evaluating synthetic inhibitors of MMPs. Trans-locator protein (TSPO), originally known as peripheral benzodiazepine receptor (PBR), is expressed on the mitochondrial outer membrane of several cells, notably monocytes and neutrophils [43], and has been widely explored as a marker of neuroinflammation [44–49], several groups have synthesised PET ligands that target TSPO. The first substrate to be explored to assess pulmonary inflammation was (R)-[1(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide] labelled with Carbon-11 (herein, 11C(R)-PK11195).
Respiratory diseases are one of the leading causes of death worldwide, yet effective treatment options remain limited. Although inflammation is thought to be a key driver in the pathogenesis and progression of several lung diseases, the underlying molecular mechanisms of lung dysfunction remain poorly understood. Imaging techniques may help to further our understanding of the pathophysiology and facilitate the translation of novel therapies. Positron Emission Tomography (PET) is a functional imaging technique which has the potential to interrogate the underlying inflammatory response. We present a systematic review of the literature summarising the emerging PET radiotracers developed to quantify pulmonary inflammation.
We performed a systematic review using the following databases: Medline, Embase, Scopus, PubMed, Web of Science and Cochrane. We included articles between 1995 and 2019 for all studies using PET radiotracers to evaluate inflammatory response in the lung. From a total of 911 articles covering both animal and human studies, two reviewers selected papers based on the inclusion/exclusion criteria and extracted data from 68 articles selected.
53 out of 68 papers, including both human and animal studies, were eligible for synthesis. Heterogenous study populations and differences in study design, image acquisition and analysis made data pooling unfeasible; instead, we provide a narrative synthesis.
Currently, very few novel radiotracers targeting lung inflammation have crossed the translational gap from animal models to human studies. Nevertheless, our results highlight a handful of promising tracers which warrant further evaluation in humans. ¹⁸F-FDG has been investigated most extensively; although ¹⁸F-FDG is not a specific inflammatory tracer, human studies of several pulmonary diseases support its use as a biomarker for inflammation. Despite ongoing debate about the optimal analysis methodology for ¹⁸F-FDG lung images, standardisation of image acquisition and analysis should help to improve confidence in research outcomes. PET radiotracers can provide quantitative, targeted biomarkers which relate to the activity of molecular pathways and may expedite development of specific anti-inflammatory drugs.
TSPO and amyloid deposits in sub-regions of the hippocampus in the 3xTgAD mouse model of Alzheimer's disease
2019, Neurobiology of Disease
The involvement of the 18kDa translocator protein (TSPO), a marker of neuroinflammation, in Alzheimer's disease (AD) remains controversial. In the present report, we used [¹²⁵I]-CLINDE, a SPECT TSPO radiotracer never before used in AD, and we investigated the relationship between TSPO and amyloid plaque density (using [¹²⁵I]-DRM106) in a triple transgenic mouse model of AD (3xTgAD, APP_SWE, PS1_M146V and Tau_P301L). Our results show that TSPO increases appear before those of amyloid deposits. Moreover, the different parts of the hippocampus are differentially affected. Indeed, for both TSPO and amyloid, the subiculum is affected earlier and the ventral hippocampus later than the dorsal hippocampus. In the subiculum and the dorsal hippocampus of 3xTgAD mice, a positive correlation between TSPO and of amyloid deposit levels is observed. This data supports the hypothesis that TSPO could be used as a predictive marker of amyloid pathology. In addition, our immunohistochemical data shows a segregation of TSPO in the hippocampus and immunofluorescence imaging revealed a mainly microglial origin of the TSPO expression. Thus, imaging TSPO with CLINDE may be a good alternative to PET radiotracers.
Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation
2019, Brain, Behavior, and Immunity
Fibromyalgia (FM) is a poorly understood chronic condition characterized by widespread musculoskeletal pain, fatigue, and cognitive difficulties. While mounting evidence suggests a role for neuroinflammation, no study has directly provided evidence of brain glial activation in FM. In this study, we conducted a Positron Emission Tomography (PET) study using [¹¹C]PBR28, which binds to the translocator protein (TSPO), a protein upregulated in activated microglia and astrocytes. To enhance statistical power and generalizability, we combined datasets collected independently at two separate institutions (Massachusetts General Hospital [MGH] and Karolinska Institutet [KI]). In an attempt to disentangle the contributions of different glial cell types to FM, a smaller sample was scanned at KI with [¹¹C]-_L-deprenyl-D₂ PET, thought to primarily reflect astrocytic (but not microglial) signal.
Thirty-one FM patients and 27 healthy controls (HC) were examined using [¹¹C]PBR28 PET. 11 FM patients and 11 HC were scanned using [¹¹C]-_L-deprenyl-D₂ PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (V_T) were computed from the [¹¹C]PBR28 data. [¹¹C]-_L-deprenyl-D₂ was quantified using λ k₃. PET imaging metrics were compared across groups, and when differing across groups, against clinical variables.
Compared to HC, FM patients demonstrated widespread cortical elevations, and no decreases, in [¹¹C]PBR28 V_T and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [¹¹C]-_L-deprenyl-D₂ signal, including those demonstrating elevated [¹¹C]PBR28 signal in patients (p’s ≥ 0.53, uncorrected). The elevations in [¹¹C]PBR28 V_T and SUVR were correlated both spatially (i.e., were observed in overlapping regions) and, in several areas, also in terms of magnitude. In exploratory, uncorrected analyses, higher subjective ratings of fatigue in FM patients were associated with higher [¹¹C]PBR28 SUVR in the anterior and posterior middle cingulate cortices (p’s < 0.03). SUVR was not significantly associated with any other clinical variable.
Our work provides the first in vivo evidence supporting a role for glial activation in FM pathophysiology. Given that the elevations in [¹¹C]PBR28 signal were not also accompanied by increased [¹¹C]-_L-deprenyl-D₂ signal, our data suggests that microglia, but not astrocytes, may be driving the TSPO elevation in these regions. Although [¹¹C]-_L-deprenyl-D₂ signal was not found to be increased in FM patients, larger studies are needed to further assess the role of possible astrocytic contributions in FM. Overall, our data support glial modulation as a potential therapeutic strategy for FM.
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[¹¹C]PBR28 is a PET radioligand used to estimate densities of the 18 kDa translocator protein (TSPO) in vivo. Since there is no suitable reference region, arterial blood samples are required for full quantification. Here, we evaluate a methodology for full quantification of [¹¹C]PBR28 PET data that does not require either a reference region or blood samples.
Simultaneous estimation (SIME) uses time-activity curves from several brain regions to estimate binding potential (BP_ND), a theoretically more sensitive outcome measure than total distribution volume. SIME can be employed with either a measured arterial input function (AIF) or a template input function (tIF) that has similar shape as the AIF, but with arbitrary amplitude.
We evaluated the ability of SIME to detect group differences in TSPO densities using PET and arterial plasma data from 21 Alzheimer's disease (AD) patients and 15 controls that underwent [¹¹C]PBR28 imaging. Regional BP_ND obtained with tIFs were compared to those obtained using measured AIFs. Standard kinetic modeling was also employed for comparison. The sensitivity of each method to detect group differences in TSPO densities were assessed by comparing estimated effect sizes between AD patients and controls. For this purpose, BP_ND estimated for one region with high pathological burden (inferior temporal cortex), and for one region with low pathological burden (cerebellum) was used.
BP_ND estimates obtained with SIME and tIFs were close to identical to those obtained with AIF (3.0 ± 21% difference, r² = 0.78). In this dataset, the effect sizes between AD patients and controls for both SIME with AIF and SIME with tIF were similar (30.3%, p = 0.001 and 31.0%, p = 0.004, respectively) and were each greater than the effect size observed using the two-tissue compartment model (16.1%, p = 0.12). None of the tested methods showed difference in TSPO binding in cerebellum.
These results demonstrate that BP_ND can be estimated for [¹¹C]PBR28 using SIME, and may be useful in clinical studies. In addition, arterial sampling may not be necessary if tIFs can be reliably estimated.
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2022, BMJ Open

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Distribution profile and properties of peripheral-type benzodiazepine receptors on human hemopoietic cells

Abstract

Biochem. Pharmacol.

Life Sci.

Life Sci.

J. Biol. Chem.

J. Biol. Chem.

Int. J. Immunopharmac.

Neuropharmacology

Life Sci.

J. Immunol. Methods

Anal. Biochem.

Biochem. Pharmacol.

Eur. J. Pharmacol.

Biochem. Pharmacol.

Int. J. Immunopharmac.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

Blood

Nature

Life Sci.