Elsevier

Progress in Neurobiology

Volume 80, Issue 6, December 2006, Pages 308-322
Progress in Neurobiology

The peripheral benzodiazepine receptor (Translocator protein 18 kDa) in microglia: From pathology to imaging

https://doi.org/10.1016/j.pneurobio.2006.10.002Get rights and content

Abstract

Microglia constitute the primary resident immune surveillance cell in the brain and are thought to play a significant role in the pathogenesis of several neurodegenerative disorders, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and HIV-associated dementia. Measuring microglial activation in vivo in patients suffering from these diseases may help chart progression of neuroinflammation as well as assess efficacy of therapies designed to modulate neuroinflammation. Recent studies suggest that activated microglia in the CNS may be detected in vivo using positron emission tomography (PET) utilizing pharmacological ligands of the mitochondrial peripheral benzodiazepine receptor (PBR (recently renamed as Translocator protein (18 kDa)). Beginning with the molecular characterization of PBR and regulation in activated microglia, we examine the rationale behind using PBR ligands to image microglia with PET. Current evidence suggests these findings might be applied to the development of clinical assessments of microglial activation in neurological disorders.

Section snippets

Microglia: origin and function

Microglia constitute up to 10% of the total cell population of the brain. As resident macrophages (histiocytes), microglia phagocytose cellular debris, present foreign antigens and presumably serve many other vital functions in the brain (Minghetti and Levi, 1998). Del Rio Hortega first recognized the pathological importance of microglia in the central nervous system (CNS), and he also coined their name (Del Rio Hortega, 1932). Microglia are derived from cells of the monocyte lineage. During

The peripheral benzodiazepine receptor: structure and function

Evidence indicating that diazepam bound with high affinity in the rat kidney led to the postulation and later characterization of the peripheral benzodiazepine receptor (PBR) (Braestrup et al., 1977), named to differentiate it from the previously described diazepam binding sites in the CNS (central benzodiazepine receptor). Within the CNS, two pharmacologically distinct benzodiazepine receptors exist: the central and the peripheral benzodiazepine receptors. The central benzodiazepine receptor

Summary

The low levels of mitochondrial PBR present in the normal CNS increase dramatically with injury and neurodegeneration, and predominantly in microglia, as suggested by several studies using animal models and human postmortem tissues. The mechanisms of PBR regulation and its functions in microglia are not known. In this review, we discuss the evidence supporting preferential increases in PBR in microglia. We also discuss hypothesized mechanisms of PBR regulation at the cellular level as well as

References (143)

  • N. De Stefano et al.

    Magnetic resonance spectroscopy as a measure of brain damage in multiple sclerosis

    J. Neurol. Sci.

    (2005)
  • H. Everett et al.

    Viruses and apoptosis: meddling with mitochondria

    Virology

    (2001)
  • D.R. Gehlert et al.

    Increased expression of peripheral benzodiazepine receptors in the facial nucleus following motor neuron axotomy

    Neurochem. Int.

    (1997)
  • J. Gehrmann et al.

    Microglia: intrinsic immuneffector cell of the brain

    Brain Res. Brain Res. Rev.

    (1995)
  • A. Gerhard et al.

    In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson's disease

    Neurobiol. Dis.

    (2006)
  • A. Gerhard et al.

    Evolution of microglial activation in patients after ischemic stroke: a [11C](R)-PK11195 PET study

    Neuroimage

    (2005)
  • B. Gulyas et al.

    [11C]vinpocetine: a prospective peripheral benzodiazepine receptor ligand for primate PET studies

    J. Neurol. Sci.

    (2005)
  • Y. Itzhak et al.

    Ontogeny of peripheral-type benzodiazepine receptors in cultured astrocytes and brain from rat

    Brain Res. Dev. Brain Res.

    (1995)
  • M.L. James et al.

    Synthesis and in vivo evaluation of a novel peripheral benzodiazepine receptor PET radioligand

    Bioorg. Med. Chem.

    (2005)
  • G.W. Kreutzberg

    Microglia: a sensor for pathological events in the CNS

    Trends Neurosci.

    (1996)
  • A.A. Lammertsma et al.

    Simplified reference tissue model for PET receptor studies

    Neuroimage

    (1996)
  • G. Le Fur et al.

    Peripheral benzodiazepine binding sites: effect of PK 11195, 1-(2-chlorophenyl)-N-methyl-(1-methylpropyl)-3 isoquinolinecarboxamide. II. In vivo studies

    Life Sci.

    (1983)
  • G. Le Fur et al.

    Peripheral benzodiazepine binding sites: effect of PK 11195, 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide. I. In vitro studies

    Life Sci.

    (1983)
  • L. Minghetti et al.

    Microglia as effector cells in brain damage and repair: focus on prostanoids and nitric oxide

    Prog. Neurobiol.

    (1998)
  • R.B. Banati

    Visualising microglial activation in vivo

    Glia

    (2002)
  • R.B. Banati et al.

    Mitochondria in activated microglia in vitro

    J. Neurocytol.

    (2004)
  • R.B. Banati et al.

    [11C](R)-PK11195 positron emission tomography imaging of activated microglia in vivo in Rasmussen's encephalitis

    Neurology

    (1999)
  • R.B. Banati et al.

    PK (‘peripheral benzodiazepine’)—binding sites in the CNS indicate early and discrete brain lesions: microautoradiographic detection of [3H]PK11195 binding to activated microglia

    J. Neurocytol.

    (1997)
  • R.B. Banati et al.

    The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity

    Brain

    (2000)
  • F. Bard et al.

    Epitope and isotype specificities of antibodies to beta -amyloid peptide for protection against Alzheimer's disease-like neuropathology

    Proc. Natl. Acad. Sci. U.S.A.

    (2003)
  • J. Bauer et al.

    Phagocytic activity of macrophages and microglial cells during the course of acute and chronic relapsing experimental autoimmune encephalomyelitis

    J. Neurosci. Res.

    (1994)
  • J. Benavides et al.

    Imaging of human brain lesions with an omega 3 site radioligand

    Ann. Neurol.

    (1988)
  • J. Benavides et al.

    “Peripheral type” benzodiazepine binding sites in rat adrenals: binding studies with [3H]PK 11195 and autoradiographic localization

    Arch. Int. Pharmacodyn. Ther.

    (1983)
  • J. Benavides et al.

    Labelling of “peripheral-type” benzodiazepine binding sites in the rat brain by using [3H]PK 11195, an isoquinoline carboxamide derivative: kinetic studies and autoradiographic localization

    J. Neurochem.

    (1983)
  • A. Biegon et al.

    Region-selective effects of neuroinflammation and antioxidant treatment on peripheral benzodiazepine receptors and NMDA receptors in the rat brain

    J. Neurochem.

    (2002)
  • C. Braestrup et al.

    High densities of benzodiazepine receptors in human cortical areas

    Nature

    (1977)
  • A. Cagnin et al.

    In vivo visualization of activated glia by [11C] (R)-PK11195-PET following herpes encephalitis reveals projected neuronal damage beyond the primary focal lesion

    Brain

    (2001)
  • A. Cagnin et al.

    In vivo detection of microglial activation in frontotemporal dementia

    Ann. Neurol.

    (2004)
  • A. Cagnin et al.

    In vivo imaging of cerebral “peripheral benzodiazepine binding sites” in patients with hepatic encephalopathy

    Gut

    (2006)
  • A. Chan et al.

    Phagocytosis of apoptotic inflammatory cells by microglia and its therapeutic implications: termination of CNS autoimmune inflammation and modulation by interferon-beta

    Glia

    (2003)
  • C.C. Chao et al.

    Activated microglia mediate neuronal cell injury via a nitric oxide mechanism

    J. Immunol.

    (1992)
  • C.C. Chao et al.

    Modulation of human microglial cell superoxide production by cytokines

    J. Leukoc. Biol.

    (1995)
  • C.C. Chao et al.

    Tumor necrosis factor-alpha production by human fetal microglial cells: regulation by other cytokines

    Dev. Neurosci.

    (1995)
  • P. Charbonneau et al.

    Peripheral-type benzodiazepine receptors in the living heart characterized by positron emission tomography

    Circulation

    (1986)
  • M.K. Chen et al.

    Peripheral benzodiazepine receptor imaging in CNS demyelination: functional implications of anatomical and cellular localization

    Brain

    (2004)
  • M.K. Chen et al.

    Imaging the peripheral benzodiazepine receptor response in Cns demyelination and remyelination

    Toxicol. Sci.

    (2006)
  • H.B. Choi et al.

    Inhibition of lipopolysaccharide-induced cyclooxygenase-2, tumor necrosis factor-alpha and [Ca2+]i responses in human microglia by the peripheral benzodiazepine receptor ligand PK11195

    J. Neurochem.

    (2002)
  • F. Cicchetti et al.

    Neuroinflammation of the nigrostriatal pathway during progressive 6-OHDA dopamine degeneration in rats monitored by immunohistochemistry and PET imaging

    Eur. J. Neurosci.

    (2002)
  • M.C. Cleij et al.

    Base-promoted dechlorination of (R)-[C-11]PK-11195

  • C.A. Colton et al.

    Protease production by cultured microglia: substrate gel analysis and immobilized matrix degradation

    J. Neurosci. Res.

    (1993)
  • Cited by (323)

    • Exercise protects synaptic density in a rat model of Parkinson's disease

      2021, Experimental Neurology
      Citation Excerpt :

      The lack of an effect of exercise on striatal dopamine levels is consistent with our findings of no treadmill exercise-induced preservation or restoration of the level of TH immunopositive nigral loss, nor reversal of the increased [3H]Raclopride binding which occurred in response to reduced synaptic striatal dopamine content, in the ipsilateral 6-OHDA injected brain. At post-mortem, PD subjects show microglial activation in the substantia nigra, striatum, and frontal association cortex (Marinova-Mutafchieva et al., 2009; Venneti et al., 2006; McGeer et al., 1988). Activated microglia express TSPO which can be detected in vivo using [11C]PK11195 or [11C]PBR28 PET.

    View all citing articles on Scopus
    View full text