| 1 | Curr. Mol. Med. 2012 May 12: 426-42 |
|---|---|
| PMID | 22348611 |
| Title | Translocator protein (TSPO) and neurosteroids: implications in psychiatric disorders. |
| Abstract | The translocator protein (TSPO) is a five transmembrane domain protein localised primarily in the outer mitochondrial membrane of steroid-synthesizing tissues, including the brain. The TSPO mediates the rate-limiting step of steroidogenesis, consisting of the translocation of the substrate cholesterol from the outer to the inner mitochondrial membrane. In the recent years TSPO function has received attention in several psychiatric disorders since these diseases have been associated with unbalanced steroid levels. Accordingly, an alteration in the levels of TSPO has been found in various psychiatric disorders, including social phobia, post-traumatic stress disorder, adult separation anxiety and schizophrenia. The discovery that TSPO drug ligands are able to stimulate neurosteroid production in the brain, independently of peripheral endocrine sources, and restore neurosteroid-mediated neurotransmission, has made the TSPO an attractive drug target for treating a number of psychiatric disorders. In anxiety TSPO drug ligands have shown in vivo efficacy in pharmacologically induced anxiety models in both animals and humans. The focus of this review is to illustrate the currently available literature regarding the role of TSPO in psychiatric disorders. |
| SCZ Keywords | schizophrenia |
| 2 | J. Cereb. Blood Flow Metab. 2013 Jan 33: 53-8 |
| PMID | 22968319 |
| Title | A genetic polymorphism for translocator protein 18 kDa affects both in vitro and in vivo radioligand binding in human brain to this putative biomarker of neuroinflammation. |
| Abstract | Second-generation radioligands for translocator protein (TSPO), an inflammation marker, are confounded by the codominant rs6971 polymorphism that affects binding affinity. The resulting three groups are homozygous for high-affinity state (HH), homozygous for low-affinity state (LL), or heterozygous (HL). We tested if in vitro binding to leukocytes distinguished TSPO genotypes and if genotype could affect clinical studies using the TSPO radioligand [(11)C]PBR28. In vitro binding to leukocytes and [(11)C]PBR28 brain imaging were performed in 27 human subjects with known TSPO genotype. Specific [(3)H]PBR28 binding was measured in prefrontal cortex of 45 schizophrenia patients and 47 controls. Leukocyte binding to PBR28 predicted genotype in all subjects. Brain uptake was ?40% higher in HH than HL subjects. Specific [(3)H]PBR28 binding in LL controls was negligible, while HH controls had ?80% higher binding than HL controls. After excluding LL subjects, specific binding was 16% greater in schizophrenia patients than controls. This difference was insignificant by itself (P=0.085), but was significant after correcting for TSPO genotype (P=0.011). Our results show that TSPO genotype influences PBR28 binding in vitro and in vivo. Correcting for this genotype increased statistical power in our postmortem study and is recommended for in vivo positron emission tomography studies. |
| SCZ Keywords | schizophrenia |
| 3 | Prog. Neurobiol. 2014 Feb 113: 79-87 |
| PMID | 24215796 |
| Title | The role of allopregnanolone in depression and anxiety. |
| Abstract | Neuroactive steroids such as allopregnanolone do not only act as transcriptional factors in the regulation of gene expression after intracellular back-oxidation into the 5-? pregnane steroids but may also alter neuronal excitability through interactions with specific neurotransmitter receptors. In particular, certain 3?-reduced metabolites of progesterone such as 3?,5?-tetrahydroprogesterone (allopregnanolone) and 3?,5?-tetrahydroprogesterone (pregnanolone) are potent positive allosteric modulators of the GABA(A) receptor complex. During the last years, the downregulation of neurosteroid biosynthesis has been intensively discussed to be a possible contributor to the development of anxiety and depressive disorder. Reduced levels of allopregnanolone in the peripheral blood or cerebrospinal fluid were found to be associated with major depression, anxiety disorders, premenstrual dysphoric disorder, negative symptoms in schizophrenia, or impulsive aggression. The importance of allopregnanolone for the regulation of emotion and its therapeutical use in depression and anxiety may not only involve GABAergic mechanisms, but probably also includes enhancement of neurogenesis, myelination, neuroprotection, and regulatory effects on HPA axis function. Certain pharmacokinetic obstacles limit the therapeutic use of natural neurosteroids (low bioavailability, oxidation to the ketone). Until now synthetic neuroactive steroids could not be established in the treatment of anxiety disorders or depression. However, the translocator protein (18 kDa) (TSPO) which is important for neurosteroidogenesis has been identified as a potential novel target. TSPO ligands such as XBD 173 increase neurosteroidogenesis and have anxiolytic effects with a favorable side effect profile. |
| SCZ Keywords | schizophrenia |
| 4 | Pharmacogenomics 2015 Jan 16: 5-22 |
| PMID | 25560467 |
| Title | Investigation of TSPO variants in schizophrenia and antipsychotic treatment outcomes. |
| Abstract | TSPO is a neuroinflammatory biomarker and emerging therapeutic target in psychiatric disorders. We evaluated whether TSPO polymorphisms contribute to interindividual variability in schizophrenia, antipsychotic efficacy and antipsychotic-induced weight gain. We analyzed TSPO polymorphisms in 670 schizophrenia cases and 775 healthy controls. Gene-gene interactions between TSPO and other mitochondrial membrane protein-encoding genes (VDAC1 and ANT1) were explored. Positive findings were evaluated in two independent samples (Munich, n = 300; RUPP, n = 119). TSPO rs6971 was independently associated with antipsychotic-induced weight gain in the discovery (puncor = 0.04) and RUPP samples (p = 3.00 × 10(-3)), and interacted with ANT1 rs10024068 in the discovery (p = 1.15 × 10(-3)) and RUPP samples (p = 2.76 × 10(-4)). Our findings highlight TSPO as a candidate for future investigations of antipsychotic-induced weight gain, and support the involvement of mitochondrial membrane components in this serious treatment side effect. |
| SCZ Keywords | schizophrenia |
| 5 | Biochem. Soc. Trans. 2015 Aug 43: 586-92 |
| PMID | 26551697 |
| Title | The methodology of TSPO imaging with positron emission tomography. |
| Abstract | The 18-kDA translocator protein (TSPO) is consistently elevated in activated microglia of the central nervous system (CNS) in response to a variety of insults as well as neurodegenerative and psychiatric conditions. It is therefore a target of interest for molecular strategies aimed at imaging neuroinflammation in vivo. For more than 20 years, positron emission tomography (PET) has allowed the imaging of TSPO density in brain using [(11)C]-(R)-PK11195, a radiolabelled-specific antagonist of the TSPO that has demonstrated microglial activation in a large number pathological cohorts. The significant clinical interest in brain immunity as a primary or comorbid factor in illness has sparked great interest in the TSPO as a biomarker and a surprising number of second generation TSPO radiotracers have been developed aimed at improving the quality of TSPO imaging through novel radioligands with higher affinity. However, such major investment has not yet resulted in the expected improvement in image quality. We here review the main methodological aspects of TSPO PET imaging with particular attention to TSPO genetics, cellular heterogeneity of TSPO in brain tissue and TSPO distribution in blood and plasma that need to be considered in the quantification of PET data to avoid spurious results as well as ineffective development and use of these radiotracers. |
| SCZ Keywords | schizophrenia |
| 6 | Schizophr Bull 2015 Jan 41: 85-93 |
| PMID | 25385788 |
| Title | Imaging neuroinflammation in gray and white matter in schizophrenia: an in-vivo PET study with [18F]-FEPPA. |
| Abstract | Neuroinflammation and abnormal immune responses have been implicated in schizophrenia (SCZ). Past studies using positron emission tomography (PET) that examined neuroinflammation in patients with SCZ in vivo using the translocator protein 18kDa (TSPO) target were limited by the insensitivity of the first-generation imaging agent [(11)C]-PK11195, scanners used, and the small sample sizes studied. Present study uses a novel second-generation TSPO PET radioligand N-acetyl-N-(2-[(18)F]fluoroethoxybenzyl)-2-phenoxy-5-pyridinamine ([(18)F]-FEPPA) to evaluate whether there is increased neuroinflammation in patients with SCZ. A cross-sectional study was performed using [(18)F]-FEPPA and a high-resolution research tomograph (HRRT). Eighteen patients with SCZ with ongoing psychotic symptoms and 27 healthy volunteers (HV) were recruited from a tertiary psychiatric clinical setting and the community, respectively. All participants underwent [(18)F]-FEPPA PET and magnetic resonance imaging, and PET data were analyzed to obtain [(18)F]-FEPPA total volume of distribution (VT) using a 2-tissue compartment model with an arterial plasma input function, as previously validated. All subjects were classified as high-, medium- or low-affinity [(18)F]-FEPPA binders on the basis of rs6971 polymorphism, and genotype information was incorporated into the analyses of imaging outcomes. No significant differences in neuroinflammation indexed as [(18)F]-FEPPA VT were observed between groups in either gray (F(1,39) = 0.179, P = .674) or white matter regions (F(1,38) = 0.597, P = .445). The lack of significant difference in neuroinflammation in treated patients with SCZ in the midst of a psychotic episode and HV suggests that neuroinflammatory processes may take place early in disease progression or are affected by antipsychotic treatment. |
| SCZ Keywords | schizophrenia |
| 7 | Transl Psychiatry 2016 -1 6: e777 |
| PMID | 27070405 |
| Title | In vivo markers of inflammatory response in recent-onset schizophrenia: a combined study using [(11)C]DPA-713 PET and analysis of CSF and plasma. |
| Abstract | Several lines of evidence suggest aberrant immune response in schizophrenia, including elevated levels of cytokines. These cytokines are thought to be produced by activated microglia, the innate immune cells of the central nervous system. However, increase in translocator protein 18?kDa (TSPO), a marker of activated glia, has not been found in patients with chronic schizophrenia using second-generation radiotracers and positron emission tomography (PET)-based neuroimaging. In this study we focused on patients with recent onset of schizophrenia (within 5 years of diagnosis). Quantified levels of TSPO in the cortical and subcortical brain regions using the PET-based radiotracer [(11)C]DPA-713 were compared between the patients and healthy controls. Markers of inflammation, including interleukin 6 (IL-6), were assessed in the plasma and cerebrospinal fluid (CSF) in these participants. We observed no significant change in the binding of [(11)C]DPA-713 to TSPO in 12 patients with recent onset of schizophrenia compared with 14 controls. Nevertheless, the patients with recent onset of schizophrenia showed a significant increase in IL-6 in both plasma (P<0.001) and CSF (P=0.02). The CSF levels of IL-6 were significantly correlated with the levels of IL-6 in plasma within the total study population (P<0.001) and in patients with recent onset of schizophrenia alone (P=0.03). Our results suggest that increased levels of IL-6 may occur in the absence of changed TSPO PET signal in the brains of medicated patients with recent onset of schizophrenia. Future development of PET-based radiotracers targeting alternative markers of glial activation and immune response may be needed to capture the inflammatory signature present in the brains of patients with early-stage disease. |
| SCZ Keywords | schizophrenia |