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https://www.readbyqxmd.com/read/27907096/global-deletion-of-tspo-does-not-affect-the-viability-and-gene-expression-profile
#1
Huaishan Wang, Kangle Zhai, Yingchao Xue, Jia Yang, Qi Yang, Yi Fu, Yu Hu, Fang Liu, Weiqing Wang, Lianxian Cui, Hui Chen, Jianmin Zhang, Wei He
Translocator Protein (18kDa, TSPO) is a mitochondrial outer membrane transmembrane protein. Its expression is elevated during inflammation and injury. However, the function of TSPO in vivo is still controversial. Here, we constructed a TSPO global knockout (KO) mouse with a Cre-LoxP system that abolished TSPO protein expression in all tissues and showed normal phenotypes in the physiological condition. The birth rates of TSPO heterozygote (Het) x Het or KO x KO breeding were consistent with Mendel's Law, suggesting a normal viability of TSPO KO mice at birth...
2016: PloS One
https://www.readbyqxmd.com/read/27903933/translocator-positron-emission-tomography-and-magnetic-resonance-spectroscopic-imaging-of-brain-glial-cell-activation-in-multiple-sclerosis
#2
Gourab Datta, Ines R Violante, Gregory Scott, Karl Zimmerman, Andre Santos-Ribeiro, Eugenii A Rabiner, Roger N Gunn, Omar Malik, Olga Ciccarelli, Richard Nicholas, Paul M Matthews
BACKGROUND: Multiple sclerosis (MS) is characterised by a diffuse inflammatory response mediated by microglia and astrocytes. Brain translocator protein (TSPO) positron-emission tomography (PET) and [myo-inositol] magnetic resonance spectroscopy (MRS) were used together to assess this. OBJECTIVE: To explore the in vivo relationships between MRS and PET [(11)C]PBR28 in MS over a range of brain inflammatory burden. METHODS: A total of 23 patients were studied...
November 30, 2016: Multiple Sclerosis: Clinical and Laboratory Research
https://www.readbyqxmd.com/read/27893897/imaging-of-glial-cell-activation-and-white-matter-integrity-in-brains-of-active-and-recently-retired-national-football-league-players
#3
Jennifer M Coughlin, Yuchuan Wang, Il Minn, Nicholas Bienko, Emily B Ambinder, Xin Xu, Matthew E Peters, John W Dougherty, Melin Vranesic, Soo Min Koo, Hye-Hyun Ahn, Merton Lee, Chris Cottrell, Haris I Sair, Akira Sawa, Cynthia A Munro, Christopher J Nowinski, Robert F Dannals, Constantine G Lyketsos, Michael Kassiou, Gwenn Smith, Brian Caffo, Susumu Mori, Tomas R Guilarte, Martin G Pomper
Importance: Microglia, the resident immune cells of the central nervous system, play an important role in the brain's response to injury and neurodegenerative processes. It has been proposed that prolonged microglial activation occurs after single and repeated traumatic brain injury, possibly through sports-related concussive and subconcussive injuries. Limited in vivo brain imaging studies months to years after individuals experience a single moderate to severe traumatic brain injury suggest widespread persistent microglial activation, but there has been little study of persistent glial cell activity in brains of athletes with sports-related traumatic brain injury...
November 28, 2016: JAMA Neurology
https://www.readbyqxmd.com/read/27886206/the-antidepressant-like-activity-of-ac-5216-a-ligand-for-18kda-translocator-protein-tspo-in-an-animal-model-of-diabetes-mellitus
#4
Zhi-Kun Qiu, Jia-Li He, Xu Liu, Guan-Hua Zhang, Jia Zeng, Hong Nie, Yong-Gang Shen, Ji-Sheng Chen
Diabetes mellitus is a chronic disease that is associated with depression. Also, depression is common in adults with type 2 diabetes mellitus (T2DM). Translocator protein (18kDa) (TSPO) and allopregnanolone play an important role in the depression treatment. However, few studies have evaluated TSPO and allopregnanolone in the treatment of depression in T2DM. AC-5216, a ligand for TSPO, produces anxiolytic- and antidepressant-like effects in animal models. The present study aimed to explore antidepressant-like effects of AC-5216 on diabetic rats...
November 25, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27884611/microglial-positron-emission-tomography-pet-imaging-in-epilepsy-applications-opportunities-and-pitfalls
#5
Gregory Scott, Mohammad Mahmud, David R Owen, Michael R Johnson
Neuroinflammation is increasingly implicated in epileptogenesis and epilepsy. Microglia are an important mediator of central nervous system inflammation, and the development of positron emission tomography (PET) radioligands which bind the Translocator Protein (TSPO), an outer mitochondrial membrane protein expressed by microglia, has enabled in vivo measurement of neuroinflammation. Here, we outline the principles and potential pitfalls of TSPO PET imaging in relation to epilepsy, and opportunities for using TSPO imaging as a biomarker for future anti-inflammatory based therapeutics in epilepsy...
November 13, 2016: Seizure: the Journal of the British Epilepsy Association
https://www.readbyqxmd.com/read/27875800/evaluation-of-tspo-pet-imaging-a-marker-of-glial-activation-to-study-the-neuroimmune-footprints-of-morphine-exposure-and-withdrawal
#6
Sylvain Auvity, Sébastien Goutal, Benoît Thézé, Catarina Chaves, Benoît Hosten, Bertrand Kuhnast, Wadad Saba, Raphaël Boisgard, Irène Buvat, Salvatore Cisternino, Nicolas Tournier
INTRODUCTION: A growing area of research suggests that neuroimmunity may impact the pharmacology of opioids. Microglia is a key component of the brain immunity. Preclinical and clinical studies have demonstrated that microglial modulators may improve morphine-induced analgesia and prevent the development of tolerance and dependence. Positron emission tomography (PET) using translocator protein 18kDa (TSPO) radioligand is a clinically validated strategy for the non-invasive detection of microglial activation...
November 8, 2016: Drug and Alcohol Dependence
https://www.readbyqxmd.com/read/27865893/sex-and-genetic-differences-in-the-effects-of-acute-diesel-exhaust-exposure-on-inflammation-and-oxidative-stress-in-mouse-brain
#7
Toby B Cole, Jacki Coburn, Khoi Dao, Pam Roqué, Yu-Chi Chang, Vrinda Kalia, Tomas R Guilarte, Jennifer Dziedzic, Lucio G Costa
In addition to increased morbidity and mortality caused by respiratory and cardiovascular diseases, air pollution may also contribute to central nervous system (CNS) diseases. Traffic-related air pollution is a major contributor to global air pollution, and diesel exhaust (DE) is its most important component. DE contains more than 40 toxic air pollutants and is a major constituent of ambient particulate matter (PM), particularly of ultrafine-PM. Limited information suggests that exposure to DE may cause oxidative stress and neuroinflammation in the CNS...
November 16, 2016: Toxicology
https://www.readbyqxmd.com/read/27856631/11c-er176-a-radioligand-for-18-kda-translocator-protein-tspo-has-adequate-sensitivity-to-robustly-image-all-three-affinity-genotypes-in-human-brain
#8
Masamichi Ikawa, Talakad G Lohith, Stal Shrestha, Sanjay Telu, Sami S Zoghbi, Sabrina Castellano, Sabrina Taliani, Federico Da Settimo, Masahiro Fujita, Victor W Pike, Robert B Innis
: For positron emission tomography (PET) imaging of 18-kDa translocator protein (TSPO), a biomarker of neuroinflammation, most second-generation radioligands are sensitive to the single nucleotide polymorphism rs6971; however this is probably not the case for the prototypical agent (11)C-PK 11195, which has a relatively lower signal-to-noise ratio. We recently found that (11)C-ER176, a new analog of (11)C-(R)-PK 11195, showed little sensitivity to rs6971 when tested in vitro and had high specific binding in monkey brain...
November 17, 2016: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/27855359/discovery-of-benzimidazole-derivatives-as-modulators-of-mitochondrial-function-a-potential-treatment-for-alzheimer-s-disease
#9
TaeHun Kim, Ha Yun Yang, Beoung Gun Park, Seo Yun Jung, Jong-Hyun Park, Ki Duk Park, Sun-Joon Min, Jinsung Tae, Hyejin Yang, Suengmok Cho, Sung Jin Cho, Hyundong Song, Inhee Mook-Jung, Jiyoun Lee, Ae Nim Pae
In this study, we designed a library of compounds based on the structures of well-known ligands of the 18 kDa translocator protein (TSPO), one of the putative components of the mPTP. We performed diverse mitochondrial functional assays to assess their ability to restore cells from Aβ-induced toxicity in vitro and in vivo. Among tested compounds, compound 25 effectively improved cognitive function in animal models of AD. Given the excellent in vitro and in vivo activity and a favorable pharmacokinetic profile of compound 25, we believe that it can serve as a promising lead compound for a potential treatment option for AD...
November 9, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27853987/evaluation-of-tspo-pet-ligands-18-f-vuiis1009a-and-18-f-vuiis1009b-tracers-for-cancer-imaging
#10
Dewei Tang, Jun Li, Jason R Buck, Mohamed Noor Tantawy, Yan Xia, Joel M Harp, Michael L Nickels, Jens Meiler, H Charles Manning
PURPOSE: Positron emission tomography (PET) ligands targeting translocator protein (TSPO) are potential imaging diagnostics of cancer. In this study, we report two novel, high-affinity TSPO PET ligands that are 5,7 regioisomers, [(18)F]VUIIS1009A ([(18)F]3A) and [(18)F]VUIIS1009B ([(18)F]3B), and their initial in vitro and in vivo evaluation in healthy mice and glioma-bearing rats. PROCEDURES: VUIIS1009A/B was synthesized and confirmed by X-ray crystallography. Interactions between TSPO binding pocket and novel ligands were evaluated and compared with contemporary TSPO ligands using 2D (1)H-(15)N heteronuclear single quantum coherence (HSQC) spectroscopy...
November 16, 2016: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
https://www.readbyqxmd.com/read/27845056/antidepressant-like-effects-of-yl-ipa08-a-potent-ligand-for-the-translocator-protein-18%C3%A2-kda-in-chronically-stressed-rats
#11
Li-Ming Zhang, Yu-Lu Wang, Yan-Qin Liu, Rui Xue, You-Zhi Zhang, Ri-Fang Yang, Yun-Feng Li
The present study aimed to examine the molecular and cellular mechanisms underlying the antidepressant-like effect of YL-IPA08, a novel TSPO ligand designed and synthesized at our institute. We firstly used the chronic unpredictable stress (CUS) procedure of rats, a well validated stress-related animal model of depression, to further determine the antidepressant-like of YL-IPA08. And we found that YL-IPA08 caused significant suppression of inhibiting of locomotor activity, reducing the sucrose preference and increasing the latency to eat induced by CUS...
November 11, 2016: Neuropharmacology
https://www.readbyqxmd.com/read/27803668/lentiviral-mediated-overexpression-of-the-18-kda-translocator-protein-tspo-in-the-hippocampal-dentate-gyrus-ameliorates-lps-induced-cognitive-impairment-in-mice
#12
Wei Wang, Liming Zhang, Xiaoying Zhang, Rui Xue, Lei Li, Weixing Zhao, Qiang Fu, Weidong Mi, Yunfeng Li
The 18 kDa translocator protein (TSPO) is involved in the immune/inflammatory response. However, the exact role that TSPO plays in neuroinflammation-induced cognitive impairment is still elusive. The purpose of our present study was to investigate the effects of lentiviral-mediated hippocampal overexpression of the TSPO in a mouse model of LPS-induced cognitive impairment. We established a mouse cognitive impairment model using systematic daily administration of lipopolysaccharide (LPS) (0.5 mg/kg). Microinjection of the dentate gyrus of the mouse with lentiviral vectors, which contained a cDNA targeting TSPO (Lv-TSPO), resulted in a significant increase in TSPO expression and allopregnanolone production...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/27790060/systematic-analysis-of-translocator-protein-18-kda-tspo-ligands-on-toll-like-receptors-mediated-pro-inflammatory-responses-in-microglia-and-astrocytes
#13
Ji-Won Lee, Hyeri Nam, Seong-Woon Yu
Translocator protein 18 kDa (TSPO) is a mitochondrial protein highly expressed on reactive microglia and astrocytes, and is considered as a biomarker for neurodegeneration and brain damage, especially neuroinflammation. Toll-like receptors (TLRs) are closely related with inflammatory responses of microglia and astrocytes and these signaling pathways regulate neuroinflammation. Previous reports have identified the anti-inflammatory effects of TSPO ligands, however study of their effects in relation to the TLR signaling was limited...
October 2016: Experimental Neurobiology
https://www.readbyqxmd.com/read/27784630/minimally-invasive-biomarkers-of-general-anesthetic-induced-developmental-neurotoxicity
#14
X Zhang, F Liu, W Slikker, C Wang, M G Paule
The association of general anesthesia with developmental neurotoxicity, while nearly impossible to study in pediatric populations, is clearly demonstrable in a variety of animal models from rodents to nonhuman primates. Nearly all general anesthetics tested have been shown to cause abnormal brain cell death in animals when administered during periods of rapid brain growth. The ability to repeatedly assess in the same subjects adverse effects induced by general anesthetics provides significant power to address the time course of important events associated with exposures...
October 23, 2016: Neurotoxicology and Teratology
https://www.readbyqxmd.com/read/27733171/persistent-neuroinflammation-and-cognitive-impairment-in-a-rat-model-of-acute-diisopropylfluorophosphate-intoxication
#15
Brenna M Flannery, Donald A Bruun, Douglas J Rowland, Christopher N Banks, Adam T Austin, David L Kukis, Yonggang Li, Byron D Ford, Daniel J Tancredi, Jill L Silverman, Simon R Cherry, Pamela J Lein
BACKGROUND: Acute intoxication with organophosphorus (OP) cholinesterase inhibitors can trigger convulsions that progress to life-threatening status epilepticus. Survivors face long-term morbidity including mild-to-severe decline in memory. It is posited that neuroinflammation plays a key role in the pathogenesis of OP-induced neuropsychiatric deficits. Rigorous testing of this hypothesis requires preclinical models that recapitulate relevant phenotypic outcomes. Here, we describe a rat model of acute intoxication with the OP diisopropylfluorophosphate (DFP) that exhibits persistent neuroinflammation and cognitive impairment...
October 12, 2016: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/27699720/preclinical-in-vivo-and-in-vitro-comparison-of-the-translocator-protein-pet-ligands-18-f-pbr102-and-18-f-pbr111
#16
S Eberl, A Katsifis, M A Peyronneau, L Wen, D Henderson, C Loc'h, I Greguric, J Verschuer, T Pham, P Lam, F Mattner, A Mohamed, M J Fulham
PURPOSE: To determine the metabolic profiles of the translocator protein ligands PBR102 and PBR111 in rat and human microsomes and compare their in vivo binding and metabolite uptake in the brain of non-human primates (Papio hamadryas) using PET-CT. METHODS: In vitro metabolic profiles of PBR102 and PBR111 in rat and human liver microsomes were assessed by liquid chromatography-tandem mass spectrometry. [(18)F]PBR102 and [(18)F]PBR111 were prepared by nucleophilic substitution of their corresponding p-toluenesulfonyl precursors with [(18)F]fluoride...
October 4, 2016: European Journal of Nuclear Medicine and Molecular Imaging
https://www.readbyqxmd.com/read/27698434/in-vivo-imaging-of-brain-microglial-activity-in-antipsychotic-free-and-medicated-schizophrenia-a-11-c-r-pk11195-positron-emission-tomography-study
#17
S E Holmes, R Hinz, R J Drake, C J Gregory, S Conen, J C Matthews, J M Anton-Rodriguez, A Gerhard, P S Talbot
Positron emission tomography (PET) imaging of the 18 kDa translocator protein (TSPO) has been used to investigate whether microglial activation, an indication of neuroinflammation, is evident in the brain of adults with schizophrenia. Interpretation of these studies is confounded by potential modulatory effects of antipsychotic medication on microglial activity. In the first such study in antipsychotic-free schizophrenia, we have used [(11)C](R)-PK11195 PET to compare TSPO availability in a predominantly antipsychotic-naive group of moderate-to-severely symptomatic unmedicated patients (n=8), similarly symptomatic medicated patients with schizophrenia taking risperidone or paliperidone by regular intramuscular injection (n=8), and healthy comparison subjects (n=16)...
December 2016: Molecular Psychiatry
https://www.readbyqxmd.com/read/27688189/synthesis-and-in%C3%A2-vitro-characterization-of-novel-fluorinated-derivatives-of-the-translocator-protein-18%C3%A2-kda-ligand-cfo-dpa-714
#18
Fanny Cacheux, Vincent Médran-Navarrete, Frédéric Dollé, Frank Marguet, Frédéric Puech, Annelaure Damont
The translocator protein 18 kDa (TSPO) is today a validated target for a number of therapeutic applications, but also a well-recognized diagnostic/imaging biomarker for the evaluation of inflammatory related-disease state and progression, prompting the development of specific and dedicated TSPO ligands worldwide. For this purpose, pyrazolo[1,5-a]pyrimidine acetamides constitute a unique class of high affinity and selectivity TSPO ligands; it includes DPA-714, a fluorine-containing derivative that has also been labelled with the positron-emitter fluorine-18, and is nowadays widely used as a Positron Emission Tomography imaging probe...
September 9, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27686563/neuroinflammatory-component-of-gray-matter-pathology-in-multiple-sclerosis
#19
Elena Herranz, Costanza Giannì, Céline Louapre, Constantina A Treaba, Sindhuja T Govindarajan, Russell Ouellette, Marco L Loggia, Jacob A Sloane, Nancy Madigan, David Izquierdo-Garcia, Noreen Ward, Gabriel Mangeat, Tobias Granberg, Eric C Klawiter, Ciprian Catana, Jacob M Hooker, Norman Taylor, Carolina Ionete, Revere P Kinkel, Caterina Mainero
OBJECTIVE: In multiple sclerosis (MS), using simultaneous magnetic resonance-positron emission tomography (MR-PET) imaging with (11) C-PBR28, we quantified expression of the 18kDa translocator protein (TSPO), a marker of activated microglia/macrophages, in cortex, cortical lesions, deep gray matter (GM), white matter (WM) lesions, and normal-appearing WM (NAWM) to investigate the in vivo pathological and clinical relevance of neuroinflammation. METHODS: Fifteen secondary-progressive MS (SPMS) patients, 12 relapsing-remitting MS (RRMS) patients, and 14 matched healthy controls underwent (11) C-PBR28 MR-PET...
November 2016: Annals of Neurology
https://www.readbyqxmd.com/read/27678494/test-retest-analysis-of-a-non-invasive-method-of-quantifying-11-c-pbr28-binding-in-alzheimer-s-disease
#20
Akshay Nair, Mattia Veronese, Xiaohui Xu, Charles Curtis, Federico Turkheimer, Robert Howard, Suzanne Reeves
PURPOSE: In order to maximise the utility of [(11)C]-PBR28 for use in longitudinal studies and clinical trials in Alzheimer's disease (AD), there is a need to develop non-invasive metrics of tracer binding that do not require arterial cannulation. Recent work has suggested that standardised uptake value (SUV)-based methods may be sensitive to changes in translocator protein (TSPO) levels associated with neurodegeneration. However, the test-retest reliability of these approaches in AD over a time period relevant for clinical trials is unknown...
December 2016: EJNMMI Research
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