Involvement of benzodiazepine receptors in neuroinflammatory and neurodegenerative diseases: evidence from activated microglial cells in vitro

Wilms, Henrik; Claasen, Jan-Hendrik; Röhl, Claudia; Sievers, Jobst; Deuschl, Günther; Lucius, Ralph

doi:10.1016/j.nbd.2003.07.002

Cited by 147 publications

(142 citation statements)

References 49 publications

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“…This finding is interesting because it differs from all imaging studies with [ 11 C](R)-PK11195 [11], microarray studies [5], studies in vitro [27,28], animal model [3,29,30] and post-mortem brains [22] that showed high expression of PBR in activated microglia in a variety of inflammatory, degenerative, infective and vascular CNS disorders. Our approach of combining the evaluation of PBR using [ 11 C](R)-PK11195 PET-scan and immunohistochemistry offered the advantage of studying the binding capacity of this molecule in vivo and, on tissues its distribution in the cell types constituting the two astrocytomas without the changes that may occur examining microglia in vitro, outside the complexity of interactions with other cell types [5].…”

Section: Discussionmentioning

confidence: 85%

The lack of expression of the peripheral benzodiazepine receptor characterises microglial response in anaplastic astrocytomas

et al. 2007

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The peripheral benzodiazepine receptor (PBR) is a 18 kDa molecule mainly involved in cholesterol transport through the mitochondrial membrane. In microglia, PBR is expressed from the earliest stages of activation and appears to exert a pro-inflammatory function. This molecule is commonly up-regulated in inflammatory, degenerative, infective and ischaemic lesions of the central nervous system but it has never been reported in glioma-infiltrating microglia. We examined two anaplastic astrocytomas showing minimal contrast-enhancement and therefore little damage of the blood brain barrier to minimise the presence of blood borne macrophages within tumour tissue. The two lesions were studied in vivo using positron emission tomography (PET) with the specific PBR ligand [ 11 C](R)-PK11195 and the corresponding tumour tissue was investigated with an anti-PBR antibody. Glioma-infiltrating microglia were characterised for molecules involved in antigen presentation and cytotoxic activity. As comparison, PBR was investigated in three brains with multiple sclerosis (MS) and three with Parkinson's disease (PD). The expression profile of four anaplastic astrocytomas was also exploited and results were compared to the profile of eleven samples of normal temporal lobe and nine cases of PD. PET studies showed that [ 11 C](R)-PK11195 binding was markedly lower in tumours than in the contralateral grey matter. Pathological investigation revealed that glioma-infiltrating microglia failed to express PBR and cytotoxic molecules although some cells still expressed antigen presenting molecules. PBR and cytotoxic molecules were highly represented in MS and PD. Evaluation of microarray datasets confirmed these differences. Our results demonstrated PBR suppression in glioma-infiltrating microglia and suggested that PBR may have a relevant role in modulating the anti-tumour inflammatory response in astrocytic tumours.

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Section: Discussionmentioning

confidence: 85%

The lack of expression of the peripheral benzodiazepine receptor characterises microglial response in anaplastic astrocytomas

et al. 2007

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“…Although the PBR is only modestly expressed in normal brain parenchyma, in vivo studies in humans have demonstrated an over-expression of the PBR within a number of pathological disease states including malignant brain tumours [24] and a number of neurodegenerative and neuroinflammatory diseases [25]. The exact cellular source of this increased PBR density in the brain had been controversial for many years until a number of in vitro and in vivo studies using PK 11195, a specific PBR ligand, were performed.…”

Section: Introductionmentioning

confidence: 99%

Development of Ligands for the Peripheral Benzodiazepine Receptor

James¹,

Selleri²,

Kassiou

2006

CMC

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Abstract:The peripheral benzodiazepine receptor (PBR) initially characterised as a high affinity binding site for diazepam, is densely distributed in most peripheral organs whilst only moderately expressed in the healthy brain. The predominant cell type expressing the PBR at regions of central nervous system (CNS) pathology are activated microglial cells. Under neuroinflammatory conditions there is an over-expression of PBR binding sites indicating that measurements of PBR density can act as a useful index of brain disease activity. The PBR is now considered a significant therapeutic and diagnostic target which has provided the impetus for PBR ligand development. There are several classes of PBR ligands available including benzodiazepines (Ro5 -4864), isoquinoline carboxamides (PK 11195), indoleacetamides (FGIN-1-27), phenoxyphenyl-acetamides (DAA1106) and pyrazolopyrimidines (DPA-713). Subsequent conformationally restrained isoquinoline and indoleacetamide analogues have been synthesised in an attempt to yield PBR ligands with superior affinity and brain kinetics. Even though the PBR has been linked to a number of biochemical processes, including cell proliferation, apoptosis, steroidogenesis, porphyrin transport and immunomodulation, its exact physiological role is yet to be deciphered. Selective PBR ligands with favourable in vivo binding properties and kinetics is required to gain a more complete understanding on the normal functioning of the PBR and the chemical pathways underlying several pathological conditions. Novel PBR ligands with unique binding properties and functional activity may also generate information on the localisation of the PBR and the possibility of PBR subtypes. This review highlights the main classes of PBR ligands to date. In addition the biological activity and therapeutic potential of certain PBR ligands is discussed.

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“…A number of reports show an increase in the number of TSPO binding sites in the central and peripheral nervous systems during inflammation as well as neuroprotective effects by TSPO ligands (Ferzaz et al, 2002;Wilms et al, 2003;Mattner et al, 2011;Girard et al, 2012;Daugherty et al, 2013;Mattner et al, 2013;Bae et al, 2014;Morato et al, 2014). Because the principal effector cells in neuroinflammatory and neuro-degenerative disorders are microglia, monocyte-derived macrophages, macrophages in the perivascular space, the choroid plexus and the meninges (Bogie et al, 2014), the use of the RAW cell line (derived from murine macrophages) was an appropriate choice for this study.…”

Section: Discussionmentioning

confidence: 99%

“…This broad spectrum of bioactivities makes it an attractive theurapeutic drug target and a number of TSPO ligands has been synthesised and evaluated for their functional effects on TSPO and development of potential therapeutic agents (Szewczyk and Wojtczak, 2002;Galiegue et al, 2003;Karlstetter et al, 2014;Selvaraj et al, 2015). In addition, the development of radiolabelled TSPO ligands as molecular markers for imaging (Katsifis et al, 2000;Fookes et al, 2008;Pulli and Chen, 2014;Katsifis et al, 2004) helped localizing and monitoring the TSPO upregulation on activated microglia and/or astrocytes which is one of the hallmarks of neuroinflammation and neurodegeneration (Wilms et al, 2003;Girard et al, 2008;Mattner et al, 2011;Daugherty et al, 2013;Mattner et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Double Application of Translocator Protein Ligands and RAW Cells Inflammatory Milieu

Staykova¹,

Mattner²,

Liñares³

et al. 2016

American Journal of Immunology

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Ligands targeting the translocator protein exhibit a variety of anti-inflammatory and neuroprotective properties. A double application of eight translocator protein ligands to activated murine macrophagelike cells changed to a different extent the levels of secreted reactive nitrogen intermediates, pro-and anti-inflammatory cytokines. To our knowledge this is the first report suggesting that multiple applications of different translocator protein ligands may have selective effects on the macrophage inflammatory milieu that do not appear to be related to just the ligand affinity.

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Involvement of benzodiazepine receptors in neuroinflammatory and neurodegenerative diseases: evidence from activated microglial cells in vitro

Cited by 147 publications

References 49 publications

The lack of expression of the peripheral benzodiazepine receptor characterises microglial response in anaplastic astrocytomas

The lack of expression of the peripheral benzodiazepine receptor characterises microglial response in anaplastic astrocytomas

Development of Ligands for the Peripheral Benzodiazepine Receptor

Double Application of Translocator Protein Ligands and RAW Cells Inflammatory Milieu

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