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https://www.readbyqxmd.com/read/28609670/differential-effects-of-the-18-kda-translocator-protein-tspo-ligand-etifoxine-on-steroidogenesis-in-rat-brain-plasma-and-steroidogenic-glands-pharmacodynamic-studies
#1
Philippe Liere, Antoine Pianos, Jean-Paul Oudinet, Michael Schumacher, Yvette Akwa
Etifoxine is indicated in humans for treating anxiety. In rodents, besides its anxiolytic-like properties, it has recently shown neuroprotective and neuroregenerative activities. It acts by enhancing GABAA receptor function and by stimulating acute steroid biosynthesis via the activation of the 18-kDa translocator protein. However, the regulatory action of etifoxine on steroid production is not well characterized. In this work, we performed dose-response, acute and chronic time-course experiments on the effects of intraperitoneal injections of etifoxine on steroid levels in adult male rat brain and plasma analyzed by gas chromatography-mass spectrometry...
June 3, 2017: Psychoneuroendocrinology
https://www.readbyqxmd.com/read/28604733/imaging-microglial-activation-in-individuals-at-clinical-high-risk-for-psychosis-an-in-vivo-pet-study-with-18-f-feppa
#2
Sina Hafizi, Tania Da Silva, Cory Gerritsen, Michael Kiang, R Michael Bagby, Ivana Prce, Alan A Wilson, Sylvain Houle, Pablo M Rusjan, Romina Mizrahi
Several lines of evidence implicate microglial activation and abnormal immune response in the etiology of psychosis. Previous positron emission tomography (PET) neuroimaging studies of the translocator protein 18 kDa, TSPO, were limited by low affinity of the first-generation radioligand, low resolution scanners, and small sample sizes. Moreover, there is a dearth of literature on microglial activation in individuals at clinical high risk (CHR) for psychosis. We used a novel second-generation TSPO radioligand, [(18)F]FEPPA, to examine whether microglial activation is elevated in the dorsolateral prefrontal cortex (DLPFC) and hippocampus of antipsychotic-naïve CHR...
June 12, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28580888/kinetic-modelling-of-11-c-pbr28-for-18%C3%A2-kda-translocator-protein-pet-data-a-validation-study-of-vascular-modelling-in-the-brain-using-xbd173-and-tissue-analysis
#3
Mattia Veronese, Tiago Reis Marques, Peter S Bloomfield, Gaia Rizzo, Nisha Singh, Deborah Jones, Erjon Agushi, Dominic Mosses, Alessandra Bertoldo, Oliver Howes, Federico Roncaroli, Federico E Turkheimer
The 18 kDa translocator protein (TSPO) is a marker of microglia activation in the central nervous system and represents the main target of radiotracers for the in vivo quantification of neuroinflammation with positron emission tomography (PET). TSPO PET is methodologically challenging given the heterogeneous distribution of TSPO in blood and brain. Our previous studies with the TSPO tracers [(11)C]PBR28 and [(11)C]PK11195 demonstrated that a model accounting for TSPO binding to the endothelium improves the quantification of PET data...
January 1, 2017: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/28572290/the-variability-of-translocator-protein-signal-in-brain-and-blood-of-genotyped-healthy-humans-using-in-vivo-123-i-clinde-spect-imaging-a-test-retest-study
#4
Ling Feng, Per Jensen, Gerda Thomsen, Agnete Dyssegaard, Claus Svarer, Lars V Knudsen, Kirsten Møller, Carsten Thomsen, Jens D Mikkelsen, Denis Guilloteau, Gitte M Knudsen, Lars H Pinborg
(123)I-CLINDE is a radiotracer developed for SPECT and targets the 18-kDa translocator protein (TSPO). TSPO is upregulated in glial cells and used as a measure of neuroinflammation in a variety of central nervous system diseases. The aim of this study was to examine the test-retest variability of (123)I-CLINDE binding in healthy subjects. Methods: SPECT scans were acquired over 90 min in 16 healthy controls (9 women, 8 mixed-affinity binders [MABs] and 8 high-affinity binders [HABs] twice with an interval of 35 ± 15 d)...
June 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/28559417/the-ftd-like-syndrome-causing-trem2-t66m-mutation-impairs-microglia-function-brain-perfusion-and-glucose-metabolism
#5
Gernot Kleinberger, Matthias Brendel, Eva Mracsko, Benedikt Wefers, Linda Groeneweg, Xianyuan Xiang, Carola Focke, Maximilian Deußing, Marc Suárez-Calvet, Fargol Mazaheri, Samira Parhizkar, Nadine Pettkus, Wolfgang Wurst, Regina Feederle, Peter Bartenstein, Thomas Mueggler, Thomas Arzberger, Irene Knuesel, Axel Rominger, Christian Haass
Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk for several neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia (FTD). Homozygous TREM2 missense mutations, such as p.T66M, lead to the FTD-like syndrome, but how they cause pathology is unknown. Using CRISPR/Cas9 genome editing, we generated a knock-in mouse model for the disease-associated Trem2 p.T66M mutation. Consistent with a loss-of-function mutation, we observe an intracellular accumulation of immature mutant Trem2 and reduced generation of soluble Trem2 similar to patients with the homozygous p...
May 30, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28545084/feasibility-study-of-tspo-quantification-with-18f-feppa-using-population-based-input-function
#6
Rostom Mabrouk, Antonio P Strafella, Dunja Knezevic, Christine Ghadery, Romina Mizrahi, Avideh Gharehgazlou, Yuko Koshimori, Sylvain Houle, Pablo Rusjan
PURPOSE: The input function (IF) is a core element in the quantification of Translocator protein 18 kDa with positron emission tomography (PET), as no suitable reference region with negligible binding has been identified. Arterial blood sampling is indeed needed to create the IF (ASIF). In the present manuscript we study individualization of a population based input function (PBIF) with a single arterial manual sample to estimate total distribution volume (VT) for [18F]FEPPA and to replicate previously published clinical studies in which the ASIF was used...
2017: PloS One
https://www.readbyqxmd.com/read/28540077/role-of-molecular-imaging-with-positron-emission-tomographic-in-aortic-aneurysms
#7
REVIEW
Parmanand Singh, Zaid Almarzooq, Brian Salata, Richard B Devereux
Aortic aneurysms (AA) are often asymptomatic before the occurrence of acute, potentially fatal complications including dissection and/or rupture. Beyond aortic size, the ability to assess aortic wall characteristics and processes contributing to aneurysm development may allow improved selection of patients who may benefit from prophylactic surgical intervention. Current risk stratification for aneurysms relies upon routine noninvasive imaging of aortic size without assessing the underlying pathophysiologic processes, including features such as inflammation, which may be associated with aneurysm development and progression...
April 2017: Journal of Thoracic Disease
https://www.readbyqxmd.com/read/28533150/molecular-imaging-of-neuroinflammation-in-alzheimer-s-disease-and-mild-cognitive-impairment
#8
REVIEW
Dunja Knezevic, Romina Mizrahi
Neuroinflammatory changes have been demonstrated to be an important feature of Alzheimer's disease (AD); however, the exact role of neuroinflammation and its progression during disease is still not well understood. One of the main drivers of the neuroinflammatory process are microglial cells. Positron Emission Tomography allows for the quantification of microglial activation by labelling the Translocator Protein 18kDa (TSPO), which becomes overexpressed upon activation of microglial cells. Several radioligands have been designed to target TSPO and have been studied in-vivo in AD populations...
May 19, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
https://www.readbyqxmd.com/read/28530834/a-facile-radiolabeling-of-18-f-fdpa-via-spirocyclic-iodonium-ylides-preliminary-pet-imaging-studies-in-preclinical-models-of-neuroinflammation
#9
Lu Wang, Ran Cheng, Masayuki Fujinaga, Jian Yang, Yiding Zhang, Akiko Hatori, Katsushi Kumata, Jing Yang, Neil Vasdev, Yunfei Du, Chongzhao Ran, Ming-Rong Zhang, Steven H Liang
A suitable TSPO PET ligand may visualize and quantify neuroinflammation in living brain. Herein we report a (18)F-ligand, [(18)F]2 ([(18)F]FDPA) is radiolabeled in high yield and high specific activity based on our spirocyclic iodonium ylide (SCIDY) strategy. [(18)F]2 demonstrated saturable specific binding to TSPO, substantially-elevated brain uptake and slow washout of bound PET signal in the preclinical models of brain neuroinflammation (cerebral ischemia and Alzheimer's disease).
May 22, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28530125/pro-inflammatory-activation-of-primary-microglia-and-macrophages-increases-18%C3%A2-kda-translocator-protein-expression-in-rodents-but-not-humans
#10
David R Owen, Nehal Narayan, Lisa Wells, Luke Healy, Erica Smyth, Eugenii A Rabiner, Dylan Galloway, John B Williams, Joshua Lehr, Harpreet Mandhair, Laura An Peferoen, Peter C Taylor, Sandra Amor, Jack P Antel, Paul M Matthews, Craig S Moore
The 18kDa Translocator Protein (TSPO) is the most commonly used tissue-specific marker of inflammation in positron emission tomography (PET) studies. It is expressed in myeloid cells such as microglia and macrophages, and in rodent myeloid cells expression increases with cellular activation. We assessed the effect of myeloid cell activation on TSPO gene expression in both primary human and rodent microglia and macrophages in vitro, and also measured TSPO radioligand binding with (3)H-PBR28 in primary human macrophages...
January 1, 2017: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/28529627/-18-f-ge-180-pet-detects-reduced-microglia-activation-after-lm11a-31-therapy-in-a-mouse-model-of-alzheimer-s-disease
#11
Michelle L James, Nadia P Belichenko, Adam J Shuhendler, Aileen Hoehne, Lauren E Andrews, Christina Condon, Thuy-Vi V Nguyen, Vladimer Reiser, Paul Jones, William Trigg, Jianghong Rao, Sanjiv S Gambhir, Frank M Longo
Microglial activation is a key pathological feature of Alzheimer's disease (AD). PET imaging of translocator protein 18 kDa (TSPO) is a strategy to detect microglial activation in vivo. Here we assessed flutriciclamide ([(18)F]GE-180), a new second-generation TSPO-PET radiotracer, for its ability to monitor response to LM11A-31, a novel AD therapeutic in clinical trials. AD mice displaying pathology were treated orally with LM11A-31 for 3 months. Subsequent [(18)F]GE-180-PET imaging revealed significantly lower signal in cortex and hippocampus of LM11A-31-treated AD mice compared to those treated with vehicle, corresponding with decreased levels of TSPO immunostaining and microglial Iba1 immunostaining...
2017: Theranostics
https://www.readbyqxmd.com/read/28526927/sodium-thiosulphate-attenuates-brain-inflammation-induced-by-systemic-lipopolysaccharide-administration-in-c57bl-6j-mice
#12
Gonzalo Acero, Miryam Nava Catorce, Ricardo González-Mendoza, Marco Antonio Meraz-Rodríguez, Luis Fernando Hernández-Zimbron, Roberto González-Salinas, Goar Gevorkian
It has been demonstrated that peripheral infections accompanied by neuroinflammation may modify brain development or affect normal brain aging and represent major risk factors for the development of neurological disorders. A wide range of synthetic and natural compounds with anti-inflammatory properties have been evaluated in animal models of neuroinflammation and neurodegeneration as an adjuvant therapeutic strategy. In the present study we have demonstrated for the first time that sodium thiosulphate (STS), a known antidote approved for treatment of certain medical conditions, is capable of reducing brain inflammation caused by systemic LPS administration...
May 19, 2017: Inflammopharmacology
https://www.readbyqxmd.com/read/28516240/in-vivo-pet-imaging-of-neuroinflammation-in-alzheimer-s-disease
#13
REVIEW
Julien Lagarde, Marie Sarazin, Michel Bottlaender
Increasing evidence suggests that neuroinflammation contributes to the pathophysiology of many neurodegenerative diseases, especially Alzheimer's disease (AD). Molecular imaging by PET may be a useful tool to assess neuroinflammation in vivo, thus helping to decipher the complex role of inflammatory processes in the pathophysiology of neurodegenerative diseases and providing a potential means of monitoring the effect of new therapeutic approaches. For this objective, the main target of PET studies is the 18 kDa translocator protein (TSPO), as it is overexpressed by activated microglia...
May 17, 2017: Journal of Neural Transmission
https://www.readbyqxmd.com/read/28495374/metyrapone-prevents-brain-damage-induced-by-status-epilepticus-in-the-rat-lithium-pilocarpine-model
#14
Luis García-García, Ahmed A Shiha, Rubén Fernández de la Rosa, Mercedes Delgado, Ágata Silván, Pablo Bascuñana, Jens P Bankstahl, Francisca Gomez, Miguel A Pozo
The status epilepticus (SE) induced by lithium-pilocarpine is a well characterized rodent model of the human temporal lobe epilepsy (TLE) which is accompanied by severe brain damage. Stress and glucocorticoids markedly contribute to exacerbate neuronal damage induced by seizures but the underlying mechanisms are poorly understood. Herein we sought to investigate whether a single administration of metyrapone (150 mg/kg, i.p.), an 11β-hydroxylase inhibitor, enzyme involved in the peripheral and central synthesis of corticosteroids, had neuroprotective properties in this model...
May 8, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28475928/development-and-characterization-of-mitochondrial-membrane-affinity-chromatography-columns-derived-from-skeletal-muscle-and-platelets-for-the-study-of-mitochondrial-transmembrane-proteins
#15
Nagendra Surendra Singh, Kaia-Liisa Habicht, Ruin Moaddel, Ruth Shimmo
Mitochondrial membrane fragments from human platelets and monkey skeletal muscles were successfully immobilized onto immobilized artificial membrane chromatographic support for the first time, resulting in mitochondrial membrane affinity chromatography (MMAC) columns. These columns were validated by characterization of translocator protein (TSPO), where multiple concentrations of dipyridamole were run and the binding affinities (Kd) determined. Further, the relative ranking data of TSPO ligands was consistent with previously reported rankings for both, the platelet (MMAC-Platelet) and the skeletal muscle (MMAC-Muscle) column (dipyridamole>PK11195>protoporphyrin IX>rotenone)...
June 15, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/28467680/residence-time-rt-a-new-parameter-to-predict-neurosteroidogenic-efficacy-of-translocator-protein-tspo-ligands-n-n-dialkyl-2-arylindol-3-ylglyoxylamides-a-case-study
#16
Sabrina Taliani, Barbara Costa, Eleonora Da Pozzo, Elisabetta Barresi, Marco Robello, Chiara Cavallini, Sandro Cosconati, Federico Da Settimo, Ettore Novellino, Claudia Martini
Targeting neuroactive steroid biosynthetic pathway by specific 18 kDa Translocator Protein (TSPO) ligands may represent a therapeutic approach in a variety of neurodegenerative and neuropsychiatric diseases. However, the lack of correlation between the binding affinity and the in vitro steroidogenic efficacy has limited the identification of lead compounds by a traditional affinity-based drug discovery strategy. Our recent researches indicate that the key factor for robust steroidogenic TSPO ligand efficacy is not the binding affinity per se, but rather the time the compound spends into the target, namely its Residence Time (RT)...
May 3, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28462087/identification-of-brain-regions-predicting-epileptogenesis-by-serial-18-f-ge-180-positron-emission-tomography-imaging-of-neuroinflammation-in-a-rat-model-of-temporal-lobe-epilepsy
#17
Vera Russmann, Matthias Brendel, Erik Mille, Angela Helm-Vicidomini, Roswitha Beck, Lisa Günther, Simon Lindner, Axel Rominger, Michael Keck, Josephine D Salvamoser, Nathalie L Albert, Peter Bartenstein, Heidrun Potschka
Excessive activation of inflammatory signaling pathways seems to be a hallmark of epileptogenesis. Positron emission tomography (PET) allows in vivo detection of brain inflammation with spatial information and opportunities for longitudinal follow-up scanning protocols. Here, we assessed whether molecular imaging of the 18 kDa translocator protein (TSPO) can serve as a biomarker for the development of epilepsy. Therefore, brain uptake of [(18)F]GE-180, a highly selective radioligand of TSPO, was investigated in a longitudinal PET study in a chronic rat model of temporal lobe epilepsy...
2017: NeuroImage: Clinical
https://www.readbyqxmd.com/read/28456011/neurosteroid-biosynthesis-downregulation-and-changes-in-gabaa-receptor-subunit-composition-a-biomarker-axis-in-stress-induced-cognitive-and-emotional-impairment
#18
REVIEW
Andrea Locci, Graziano Pinna
By rapidly modulating neuronal excitability, neurosteroids regulate physiological processes, such as responses to stress and development. Excessive stress affects their biosynthesis and causes an imbalance in cognition and emotions. The progesterone derivative, allopregnanolone (Allo) enhances extrasynaptic and postsynaptic inhibition by directly binding at GABAA receptors, and thus, positively and allosterically modulates the function of GABA. Allo levels are decreased in stress-induced psychiatric disorders, including depression and post-traumatic stress disorder (PTSD), and elevating Allo levels may be a valid therapeutic approach to counteract behavioural dysfunction...
April 29, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28455699/an-in-vivo-11-c-r-pk11195-pet-and-in-vitro-pathology-study-of-microglia-activation-in-creutzfeldt-jakob-disease
#19
Leonardo Iaccarino, Rosa Maria Moresco, Luca Presotto, Orso Bugiani, Sandro Iannaccone, Giorgio Giaccone, Fabrizio Tagliavini, Daniela Perani
Microgliosis is part of the immunobiology of Creutzfeldt-Jakob disease (CJD). This is the first report using (11)C-(R)-PK11195 PET imaging in vivo to measure 18 kDa translocator protein (TSPO) expression, indexing microglia activation, in symptomatic CJD patients, followed by a postmortem neuropathology comparison. One genetic CJD (gCJD) patient, two sporadic CJD (sCJD) patients, one variant CJD (vCJD) patient (mean ± SD age, 47.50 ± 15.95 years), and nine healthy controls (mean ± SD age, 44.00 ± 11...
April 28, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28442392/4-chlorodiazepam-is-neuroprotective-against-amyloid-beta-in-organotypic-hippocampal-cultures
#20
B D Arbo, J B Hoppe, K Rodrigues, L M Garcia-Segura, C G Salbego, M F Ribeiro
The translocator protein (TSPO) is an outer mitochondrial membrane protein involved in the transport of cholesterol into the mitochondria, which is the first step for the synthesis of steroid hormones, as well as in the regulation of mitochondrial permeability transition pore opening and apoptosis. Studies have shown that the activation of TSPO may promote neuroprotective actions in experimental models of neurodegeneration and brain injury. In a previous study, our group showed that 4'-chlorodiazepam (4'-CD), a TSPO ligand, was neuroprotective against amyloid-beta (Aβ) in SHSY-5Y neuroblastoma cells...
April 23, 2017: Journal of Steroid Biochemistry and Molecular Biology
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