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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
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
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)...
October 4, 2016: Molecular Psychiatry
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
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) and 12 relapsing-remitting MS (RRMS) cases, and 14 matched healthy controls underwent (11) C-PBR28 MR-PET...
September 30, 2016: Annals of Neurology
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
Aurélie Doméné, Chelsea Cavanagh, Guylène Page, Sylvie Bodard, Christophe Klein, Cécile Delarasse, Sylvie Chalon, Slavica Krantic
Recent mouse studies of the presymptomatic stage of Alzheimer's disease (AD) have suggested that proinflammatory changes, such as glial activation and cytokine induction, may occur already at this early stage through unknown mechanisms. Because TNFα contributes to increased Aβ production from the Aβ precursor protein (APP), we assessed a putative correlation between APP/Aβ and TNFα during the presymptomatic stage as well as early astrocyte activation in the hippocampus of 3-month-old APPswe/PS1dE9 mice...
2016: International Journal of Alzheimer's Disease
Eryn L Werry, Victoria A King, Melissa L Barron, Samuel D Banister, Renee Sokias, Michael Kassiou
The 18kDa translocator protein (TSPO) is a target for novel glioblastoma therapies due to its upregulation in this cancer and relatively low levels of expression in the healthy cortex. The pyrazolo[1,5-a]pyrimidine acetamides, exemplified by DPA-713 and DPA-714, are a class of high affinity TSPO ligands with selectivity over the central benzodiazepine receptor. In this study we have explored the potential anti-glioblastoma activity of a library of DPA-713 and DPA-714 analogues, and investigated the effect of amending the alkyl ether chain on TSPO affinity and functional potential...
September 19, 2016: European Journal of Pharmaceutical Sciences
Michalis Tsamatsoulis, Chris J Kapelios, Lambros Katsaros, Stella Vakrou, Vasilis Sousonis, Stefania Sventzouri, Nicholas Michelinakis, Despoina N Perrea, Maria Anastasiou-Nana, Konstantinos Malliaras
BACKGROUND: The Translocator Protein (TSPO) of the mitochondrial membrane has been recognized as a potential therapeutic target for mitigation of myocardial ischemia-reperfusion injury. Administration of 4-chlorodiazepam (4-CLD), a TSPO ligand, has been shown to confer acute cardioprotective effects in small animals; however, long-term studies and studies in clinically-relevant large animal models are lacking. In the present study we investigated a potential cardioprotective effect of intracoronary administration of 4-CLD in small and large animal models of ischemia-reperfusion...
September 10, 2016: International Journal of Cardiology
I Marginedas-Freixa, C Hattab, G Bouyer, F Halle, A Chene, S D Lefevre, M Cambot, A Cueff, M Schmitt, B Gamain, J J Lacapere, S Egee, F Bihel, C Le Van Kim, M A Ostuni
After invading red blood cells (RBCs), Plasmodium falciparum (Pf) can export its own proteins to the host membrane and activate endogenous channels that are present in the membrane of RBCs. This transport pathway involves the Voltage Dependent Anion Channel (VDAC). Moreover, ligands of the VDAC partner TranSlocator PrOtein (TSPO) were demonstrated to inhibit the growth of the parasite. We studied the expression of TSPO and VDAC isoforms in late erythroid precursors, examined the presence of these proteins in membranes of non-infected and infected human RBCs, and evaluated the efficiency of TSPO ligands in inhibiting plasmodium growth, transporting the haem analogue Zn-protoporphyrin-IX (ZnPPIX) and enhancing the accumulation of reactive oxygen species (ROS)...
2016: Scientific Reports
Shlomi Lazar, Inbal Egoz, Rachel Brandeis, Shira Chapman, Eugenia Bloch-Shilderman, Ettie Grauer
Sarin is an irreversible organophosphate cholinesterase inhibitor and a highly toxic warfare agent. Following the overt, dose-dependent signs (e.g. tremor, hyper secretion, seizures, respiratory depression and eventually death), brain damage is often reported. The goal of the present study was to characterize the early histopathological and biochemical events leading to this damage. Rats were exposed to 1LD50 of sarin (80μg/kg, i.m.). Brains were removed at 1, 2, 6, 24 and 48h and processed for analysis. Results showed that TSPO (translocator protein) mRNA increased at 6h post exposure while TSPO receptor density increased only at 24h...
November 1, 2016: Toxicology and Applied Pharmacology
Olga V Chechneva, Wenbin Deng
No abstract text is available yet for this article.
July 2016: Neural Regeneration Research
Chad Brouwer, Kimberly J Jenko, Sami S Zoghbi, Cheryl L Morse, Robert B Innis, Victor W Pike
Modifications to an N-methyl-(quinolin-4-yl)oxypropanamide scaffold were explored to discover leads for developing new radioligands for PET imaging of brain TSPO (translocator protein), a biomarker of neuroinflammation. Whereas contraction of the quinolinyl portion of the scaffold or cyclization of the tertiary amido group abolished high TSPO affinity, insertion of an extra nitrogen atom into the 2-arylquinolinyl portion was effective in retaining sub-nanomolar affinity for rat TSPO, while also decreasing lipophilicity to within the moderate range deemed preferable for a PET radioligand...
August 25, 2016: European Journal of Medicinal Chemistry
Sina Hafizi, Huai-Hsuan Tseng, Naren Rao, Thiviya Selvanathan, Miran Kenk, Richard P Bazinet, Ivonne Suridjan, Alan A Wilson, Jeffrey H Meyer, Gary Remington, Sylvain Houle, Pablo M Rusjan, Romina Mizrahi
OBJECTIVE: Neuroinflammation and abnormal immune responses are increasingly implicated in the pathophysiology of schizophrenia. Previous positron emission tomography (PET) studies targeting the translocator protein 18 kDa (TSPO) have been limited by high nonspecific binding of the first-generation radioligand, low-resolution scanners, small sample sizes, and psychotic patients being on antipsychotics or not being in the first episode of their illness. The present study uses the novel second-generation TSPO PET radioligand [(18)F]FEPPA to evaluate whether microglial activation is elevated in the dorsolateral prefrontal cortex and hippocampus of untreated patients with first-episode psychosis...
September 9, 2016: American Journal of Psychiatry
Gurpreet Manku, Martine Culty
Translocator protein 18 kDa (TSPO) is a high affinity cholesterol- and drug-binding protein highly expressed in steroidogenic cells, such as Leydig cells, where it plays a role in cholesterol mitochondrial transport. We have previously shown that TSPO is expressed in postnatal day 3 rat gonocytes, precursors of spermatogonial stem cells. Gonocytes undergo regulated phases of proliferation and migration, followed by retinoic acid (RA)-induced differentiation. Understanding these processes is important since their disruption may lead to the formation of carcinoma in situ, a precursor of testicular germ cell tumors (TGCTs)...
2016: International Journal of Molecular Sciences
TaeHun Kim, Ae Nim Pae
INTRODUCTION: The translocator protein (TSPO) is an emerging target in diverse neurodegenerative diseases. Up-regulated TSPO in the central nervous system (CNS) appears to be involved in neuroinflammatory processes; therefore, the development of potent TSPO ligands is a promising method for alleviating or imaging patients with neurodegenerative diseases. AREAS COVERED: This review will provide an overview of recently developed TSPO ligands patented from 2010 to 2015...
September 8, 2016: Expert Opinion on Therapeutic Patents
Thalia F van der Doef, Lot D de Witte, Arjen L Sutterland, Ellen Jobse, Maqsood Yaqub, Ronald Boellaard, Lieuwe de Haan, Jonas Eriksson, Adriaan A Lammertsma, René S Kahn, Bart N M van Berckel
Evidence is accumulating that immune dysfunction is involved in the pathophysiology of schizophrenia. It has been hypothesized that microglia activation is present in patients with schizophrenia. Various in vivo and post-mortem studies have investigated this hypothesis, but as yet with inconclusive results. Microglia activation is associated with elevations in 18 kDa translocator protein (TSPO) levels, which can be measured with the positron emission tomography (PET) tracer (R)-[(11)C]PK11195. The purpose of the present study was to investigate microglia activation in psychosis in vivo at an early stage of the disease...
2016: NPJ Schizophrenia
T A Gudasheva, O A Deeva, M A Yarkova, S B Seredenin
The elevated plus maze test showed that GD-23 (N-carbobenzoxy-L-tryptophanyl-L-isoleucine amide), an original dipeptide ligand of TSPO, exerted anxiolytic effect when injected intraperitoneally at a dose of 0.5 mg/kg. This effect was completely blocked by the selective neurosteroid synthesis inhibitors, enzymes trilostane and finasteride. The same inhibitors do not prevent the anxiolytic effects of the benzodiazepine tranquillizer diazepam. The results of the study indicate the selective neurosteroidogenic mechanism of the anxiolytic action of GD-23...
July 2016: Doklady. Biochemistry and Biophysics
TaeHun Kim, Ae Nim Pae
INTRODUCTION: The 18-kDa translocator protein (TSPO) has been highlighted as a potential drug target in diverse neurodegenerative diseases because the up-regulation of TSPO in the CNS is related to neuroinflammation. Diverse TSPO ligands are currently in clinical trials or are under development at the preclinical stage for the treatment and/or diagnosis of neurodegenerative processes. These TSPO ligands may shed light on novel therapeutics for neurodegenerative diseases in the near future...
September 6, 2016: Expert Opinion on Therapeutic Patents
Laura Garay, Paula Gonzalez Giqueaux, Rachida Guennoun, Michael Schumacher, Maria Claudia Gonzalez Deniselle, Alejandro F De Nicola
Previous studies of experimental autoimmune encephalomyelitis (EAE) have shown that progesterone decreases inflammatory cell infiltration and proinflammatory factors, increases myelination and attenuates clinical grade of EAE mice. To elucidate potential mediators of these effects, we analyzed the mRNA expression of neurosteroidogenic enzymes in the spinal cord, in view of the protective role of steroids in EAE. We also analyzed mitochondrial morphology and dynamics (fusion and fission proteins), considering the role of mitochondria in neurosteroidogenesis...
September 2, 2016: Journal of Steroid Biochemistry and Molecular Biology
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