Associate editor: C.N. Pope
Translocator protein 18 kDa (TSPO): Molecular sensor of brain injury and repair

https://doi.org/10.1016/j.pharmthera.2007.12.004Get rights and content

Abstract

For over 15 years, the peripheral benzodiazepine receptor (PBR), recently named translocator protein 18 kDa (TSPO) has been studied as a biomarker of reactive gliosis and inflammation associated with a variety of neuropathological conditions. Early studies documented that in the brain parenchyma, TSPO is exclusively localized in glial cells. Under normal physiological conditions, TSPO levels are low in the brain neuropil but they markedly increase at sites of brain injury and inflammation making it uniquely suited for assessing active gliosis. This research has generated significant efforts from multiple research groups throughout the world to apply TSPO as a marker of “active” brain pathology using in vivo imaging modalities such as Positron Emission Tomography (PET) in experimental animals and humans. Further, in the last few years, there has been an increased interest in understanding the molecular and cellular function(s) of TSPO in glial cells. The latest evidence suggests that TSPO may not only serve as a biomarker of active brain disease but also the use of TSPO-specific ligands may have therapeutic implications in brain injury and repair. This review presents an overview of the history and function of TSPO focusing on studies related to its use as a sensor of active brain disease in experimental animals and in human studies.

Section snippets

Reactive gliosis as a biomarker of brain injury

Reactive gliosis comprises the activation of microglia and astrocytes and is a hallmark response of the CNS to injury (O'Callaghan, 1991, Norton et al., 1992, O'Callaghan, 1993, Raivich et al., 1999, Streit et al., 1999, Streit, 2000, McGraw et al., 2001, Norenberg, 2004, Sriram and O'Callaghan, 2004, Streit, 2004, Ladeby et al., 2005, O'Callaghan and Sriram, 2005, Streit et al., 2005). Reactive gliosis has a graded morphological response that is directly associated with the degree of damage in

The peripheral benzodiazepine receptor/translocator protein 18 kDA—what is it?

Benzodiazepines are one of the most commonly prescribed drugs that have anxiolytic, anticonvulsant, muscle-relaxant, and hypnotic properties. Some of these therapeutic effects are mediated via specific benzodiazepine receptors located in the CNS. The central benzodiazepine receptor (CBR) is coupled to the γ-aminobutyric acid (GABA)A receptor and modulates GABA-regulated opening of Cl channels and inhibition of neuronal activity (Tallman et al., 1978, Tallman et al., 1980). In addition to CBR,

TSPO: a molecular sensor of active brain disease

Under normal physiological conditions TSPO levels in the CNS are very low and limited to glial cells (astrocytes and microglia). A dramatic increase in TSPO levels occurs in glial cells in response to brain injury or inflammation (Guilarte et al., 1995, Kuhlmann and Guilarte, 1997, Kuhlmann and Guilarte, 1999, Kuhlmann and Guilarte, 2000, Guilarte et al., 2003, Chen et al., 2004, Chen and Guilarte, 2006). Because of the availability of high affinity and selective ligands such as PK-11195, which

Temporal pattern of glial cells responses during brain injury and repair

The pattern of glial activation to neuropathological events appears to be a programmed response of the CNS to injury. Microglia respond and become activated within a short amount of time following perturbation of their environment by injury or inflammation (Davalos et al., 2005, Nimmerjahn et al., 2005). The microglia response peaks sometimes after the injury, depending upon the nature of the injury, and it decays with a temporal expression dependent upon the degree and chronicity of the

Concluding remarks

In vivo imaging of TSPO as a biomarker of reactive gliosis has gained a great deal of attention in the last decade. This is based on the fact that imaging and quantitation of TSPO levels provides an excellent approach for the detection of active brain disease, to study the progression of neurodegeneration, and to monitor the effects of therapeutic strategies. Current efforts to improve the in vivo characteristics of TSPO specific radioligands, the development of improved mathematical models for

Acknowledgment

This work was supported by NIEHS grant number ES07062 to T.R.G. The work with the cuprizone model of demyelination was performed in partial fulfillment of doctoral degree requirements for M-K.C.

References (179)

  • CarmelI. et al.

    Peripheral-type benzodiazepine receptors in the regulation of proliferation of MCF-7 human breast carcinoma cell line

    Biochem Pharmacol

    (1999)
  • CasellasP. et al.

    Peripheral benzodiazepine receptors and mitochondrial function

    Neurochem Int

    (2002)
  • CascioC. et al.

    Pathways of dehydroepiandrosterone formation in rat brain glia

    J Steroid Biochem Mol Biol

    (2000)
  • ChakiS. et al.

    Binding characteristics of [3H]-DAA1106, a novel and selective ligand for peripheral benzodiazepine receptors

    Eur J Pharmacol

    (1999)
  • CorsiL. et al.

    Nuclear location-dependent role of peripheral benzodiazepine receptor (PBR) in hepatic tumoral cell lines proliferation

    Life Sci

    (2005)
  • Demerle-PallardyC. et al.

    Peripheral type benzodiazepine binding sites following transient forebrain ischemia in the rat: Effect of neuroprotective drugs

    Brain Res

    (1991)
  • FargesR. et al.

    Molecular basis for the different binding properties of benzodiazepines to human and bovine peripheral-type benzodiazepine receptors

    FEBS Lett

    (1993)
  • FalchiA.M. et al.

    Intracellular cholesterol changes induced by translocator protein (18 kDa)TSPO/PBR ligands

    Neuropharmacology

    (2007)
  • GehlertD.R. et al.

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

    Neurochem Int

    (1997)
  • GerhardA. et al.

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

    Neuroimage

    (2005)
  • GerhardA. et al.

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

    Neurobiol Dis

    (2006)
  • GuilarteT.R. et al.

    Methamphetamine-induced deficits of brain monoaminergic neuronal markers: Distal axotomy or neuronal plasticity

    Neuroscience

    (2003)
  • HirschT. et al.

    PK11195, a ligand of the mitochondrial benzodiazepine receptor, facilitates the induction of apoptosis and reverses Bcl-2-mediated cytoprotection

    Exp Cell Res

    (1998)
  • JamesM.L. et al.

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

    Bioorg Med Chem

    (2005)
  • Kelly-HershkovitzE. et al.

    Effects of peripheral-type benzodiazepine receptor antisense knockout on MA-10 Leydig cell proliferation and steroidogenesis

    J Biol Chem

    (1998)
  • KnudsenJ.

    Acyl-CoA-binding and transport, an alternative function for diazepam binding inhibitor (DBI), which is identical with acyl-CoA-binding protein

    Neuropharmacology

    (1991)
  • KreutzbergG.W.

    Microglia: A sensor for pathological events in the CNS

    Trends Neurosci

    (1996)
  • KuhlmannA.C. et al.

    The peripheral benzodiazepine receptor is a sensitive indicator of domoic acid neurotoxicity

    Brain Res

    (1997)
  • LacapereJ.J. et al.

    Peripheral-type benzodiazepine receptor: Structure and function of a cholesterol-binding protein in steroid and bile acid biosynthesis

    Steroids

    (2003)
  • LacapereJ.J. et al.

    Structural and functional study of reconstituted peripheral benzodiazepine receptor

    Biochem Biophys Res Commun

    (2001)
  • LacorP. et al.

    Regulation of the expression of peripheral benzodiazepine receptors and their endogenous ligands during rat sciatic nerve degeneration and regeneration: A role for PBR in neurosteroidogenesis

    Brain Res

    (1999)
  • LadebyR. et al.

    Microglial cell population dynamics in the injured adult central nervous system

    Brain Res Brain Res Rev

    (2005)
  • LamaczM. et al.

    The endogenous benzodiazepine receptor ligand ODN increases cytosolic calcium in cultured rat astrocytes

    Brain Res Mol Brain Res

    (1996)
  • LammertsmaA.A. et al.

    Simplified reference tissue model for PET receptor studies

    Neuroimage

    (1996)
  • Le FurG. 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)
  • Le FurG. 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)
  • Le FurG. et al.

    Differentiation between two ligands for peripheral benzodiazepine binding sites, [3H]-RO5-4864 and [3H]-PK 11195, by thermodynamic studies

    Life Sci

    (1983)
  • LenfantM. et al.

    In vivo immunomodulating activity of PK-11195, a structurally unrelated ligand for “peripheral” benzodiazepine binding sites - I. Potentiation in mice of the humoral response to sheep red blood cells

    Int J Immunopharmacol

    (1986)
  • LockhartA. et al.

    The peripheral benzodiazepine receptor ligand PK11195 binds with high affinity to the acute phase reactant alpha1-acid glycoprotein: Implications for the use of the ligand as a CNS inflammatory marker

    Nucl Med Biol

    (2003)
  • McCannM.J. et al.

    Differential activation of microglia and astrocytes following trimethyltin-induced neurodegeneration

    Neuroscience

    (1996)
  • AlhoH. et al.

    Expression of mitochondrial benzodiazepine receptor and its putative endogenous ligand diazepam binding inhibitor in cultured primary astrocytes and C-6 cells: Relation to cell growth

    Cell Growth Differ

    (1994)
  • AltarC.A. et al.

    Systemic injection of kainic acid: Gliosis in olfactory and limbic brain regions quantified with [3H]-PK 11195 binding autoradiography

    Exp Neurol

    (1990)
  • Antkiewicz-MichalukL. et al.

    Molecular characterization and mitochondrial density of a recognition site for peripheral-type benzodiazepine ligands

    Mol Pharmacol

    (1988)
  • AzarashviliT. et al.

    High-affinity peripheral benzodiazepine receptor ligand, PK11195, regulates protein phosphorylation in rat brain mitochondria under control of Ca(2+)

    J Neurochem

    (2005)
  • BanatiR.B. 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)
  • BanatiR.B. et al.

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

    Neurology

    (1999)
  • BanatiR.B. 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)
  • BenavidesJ. et al.

    “Peripheral type” benzodiazepine binding sites in rat adrenals: Binding studies with [3H]-PK11195 and autoradiographic localization

    Arch Int Pharmacodyn Ther

    (1983)
  • BenavidesJ. et al.

    Labelling of “peripheral-type” benzodiazepine binding sites in the rat brain by using [3H]-PK11195, an isoquinoline carboxamide derivative: Kinetic studies and autoradiographic localization

    J Neurochem

    (1983)
  • Bernassau, J. M., Reversat, J. L., Ferrara, P., Caput, D., Lefur, G. (1993). A 3D model of the peripheral...
  • Cited by (0)

    1

    Current address: Department of Radiology, Yale New Haven Hospital, Room 826, 2nd Floor, East Pavillion, 20 York Street, New Haven, Connecticut, 06510.

    View full text