Associate editor: C.N. PopeTranslocator protein 18 kDa (TSPO): Molecular sensor of brain injury and repair
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)
- et al.
Immunohistochemistry of diazepam binding inhibitor (DBI) in the central nervous system and peripheral organs: Its possible role as an endogenous regulator of different types of benzodiazepine receptors
Neuropharmacology
(1991) - et al.
The peripheral-type benzodiazepine receptor. Localization to the mitochondrial outer membrane
J Biol Chem
(1986) - et al.
Peripheral type benzodiazepine binding sites are a sensitive indirect index of neuronal damage
Brain Res
(1987) - et al.
The quantification of brain lesions with an omega 3 site ligand: A critical analysis of animal models of cerebral ischaemia and neurodegeneration
Brain Res
(1990) - et al.
Late evolutionary appearance of ‘peripheral-type’ binding sites for benzodiazepines
Brain Res
(1985) - et al.
Distribution and characterization of diazepam binding inhibitor (DBI) in peripheral tissues of rat
Regul Pept
(1990) - et al.
Role of the peripheral-type benzodiazepine receptor in adrenal and brain steroidogenesis
Int Rev Neurobiol
(2001) - et al.
Location-dependent role of the human glioma cell peripheral-type benzodiazepine receptor in proliferation and steroid biosynthesis
Cancer Lett
(2000) - et al.
In-vivo measurement of activated microglia in dementia
Lancet
(2001) - et al.
Distribution profile and properties of peripheral-type benzodiazepine receptors on human hemopoietic cells
Life Sci
(1993)
Peripheral-type benzodiazepine receptors in the regulation of proliferation of MCF-7 human breast carcinoma cell line
Biochem Pharmacol
Peripheral benzodiazepine receptors and mitochondrial function
Neurochem Int
Pathways of dehydroepiandrosterone formation in rat brain glia
J Steroid Biochem Mol Biol
Binding characteristics of [3H]-DAA1106, a novel and selective ligand for peripheral benzodiazepine receptors
Eur J Pharmacol
Nuclear location-dependent role of peripheral benzodiazepine receptor (PBR) in hepatic tumoral cell lines proliferation
Life Sci
Peripheral type benzodiazepine binding sites following transient forebrain ischemia in the rat: Effect of neuroprotective drugs
Brain Res
Molecular basis for the different binding properties of benzodiazepines to human and bovine peripheral-type benzodiazepine receptors
FEBS Lett
Intracellular cholesterol changes induced by translocator protein (18 kDa)TSPO/PBR ligands
Neuropharmacology
Increased expression of peripheral benzodiazepine receptors in the facial nucleus following motor neuron axotomy
Neurochem Int
Evolution of microglial activation in patients after ischemic stroke: A [11C]-(R)-PK11195 PET study
Neuroimage
In vivo imaging of microglial activation with [11C]-(R)-PK11195 PET in idiopathic Parkinson's disease
Neurobiol Dis
Methamphetamine-induced deficits of brain monoaminergic neuronal markers: Distal axotomy or neuronal plasticity
Neuroscience
PK11195, a ligand of the mitochondrial benzodiazepine receptor, facilitates the induction of apoptosis and reverses Bcl-2-mediated cytoprotection
Exp Cell Res
Synthesis and in vivo evaluation of a novel peripheral benzodiazepine receptor PET radioligand
Bioorg Med Chem
Effects of peripheral-type benzodiazepine receptor antisense knockout on MA-10 Leydig cell proliferation and steroidogenesis
J Biol Chem
Acyl-CoA-binding and transport, an alternative function for diazepam binding inhibitor (DBI), which is identical with acyl-CoA-binding protein
Neuropharmacology
Microglia: A sensor for pathological events in the CNS
Trends Neurosci
The peripheral benzodiazepine receptor is a sensitive indicator of domoic acid neurotoxicity
Brain Res
Peripheral-type benzodiazepine receptor: Structure and function of a cholesterol-binding protein in steroid and bile acid biosynthesis
Steroids
Structural and functional study of reconstituted peripheral benzodiazepine receptor
Biochem Biophys Res Commun
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
Microglial cell population dynamics in the injured adult central nervous system
Brain Res Brain Res Rev
The endogenous benzodiazepine receptor ligand ODN increases cytosolic calcium in cultured rat astrocytes
Brain Res Mol Brain Res
Simplified reference tissue model for PET receptor studies
Neuroimage
Peripheral benzodiazepine binding sites: Effect of PK 11195, 1-(2-chlorophenyl)-N-methyl-(1-methylpropyl)-3 isoquinolinecarboxamide. II. In vivo studies
Life Sci
Peripheral benzodiazepine binding sites: Effect of PK 11195, 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide. I. In vitro studies
Life Sci
Differentiation between two ligands for peripheral benzodiazepine binding sites, [3H]-RO5-4864 and [3H]-PK 11195, by thermodynamic studies
Life Sci
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
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
Differential activation of microglia and astrocytes following trimethyltin-induced neurodegeneration
Neuroscience
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
Systemic injection of kainic acid: Gliosis in olfactory and limbic brain regions quantified with [3H]-PK 11195 binding autoradiography
Exp Neurol
Molecular characterization and mitochondrial density of a recognition site for peripheral-type benzodiazepine ligands
Mol Pharmacol
High-affinity peripheral benzodiazepine receptor ligand, PK11195, regulates protein phosphorylation in rat brain mitochondria under control of Ca(2+)
J Neurochem
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
[11C](R)-PK11195 positron emission tomography imaging of activated microglia in vivo in Rasmussen's encephalitis
Neurology
The peripheral benzodiazepine binding site in the brain in multiple sclerosis: Quantitative in vivo imaging of microglia as a measure of disease activity
Brain
“Peripheral type” benzodiazepine binding sites in rat adrenals: Binding studies with [3H]-PK11195 and autoradiographic localization
Arch Int Pharmacodyn Ther
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
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