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https://www.readbyqxmd.com/read/28442392/4-chlorodiazepam-is-neuroprotective-against-amyloid-beta-in-organotypic-hippocampal-cultures
#1
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 22, 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28438557/the-isozyme-selective-phosphodiesterase-4-inhibitor-abi-4-attenuates-the-effects-of-lipopolysaccharide-in-human-cells-and-rodent-models-of-peripheral-and-cns-inflammation
#2
Joseph R Hedde, Ashley N Hanks, Christopher J Schmidt, Zoë A Hughes
Inhibitors of phosphodiesterase-4 (PDE4) have been approved for the treatment of inflammatory disorders, but are associated with dose-limiting nausea and vomiting. These side effects are hypothesized to be mediated by inhibition of the PDE4D isozyme. Here we demonstrate the anti-inflammatory effects of the novel brain penetrant PDE4D-sparing PDE4 inhibitor, ABI-4. ABI-4 was a potent (EC50 ∼14 nM) inhibitor of lipopolysaccharide (LPS) induced TNF-α release from mouse microglia and human PBMCs. ABI-4 (0.32 mg/kg) blocked LPS-induced release of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in blood and brain of mice...
April 21, 2017: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/28435076/design-synthesis-biological-evaluation-and-molecular-modelling-of-2-2-aryloxyphenyl-1-4-dihydroisoquinolin-3-2h-ones-a-novel-class-of-tspo-ligands-modulating-amyloid-%C3%AE-induced-mptp-opening
#3
Ahmed Elkamhawy, Jung-Eun Park, Ahmed H E Hassan, Ae Nim Pae, Jiyoun Lee, Beoung-Geon Park, Sora Paik, Jimin Do, Jong-Hyun Park, Ki Duk Park, Bongjin Moon, Woo Kyu Park, Heeyeong Cho, Dae Young Jeong, Eun Joo Roh
Translocator protein (TSPO) is involved in modulating mitochondrial permeability transition pore (mPTP) opening/closure leading to either apoptotic cell death via opening of mPTP or cell protection mediated by mPTP blocking and hence intercepting mPTP induced apoptosis. Herein, 2-(2-aryloxyphenyl)-1,4-dihydroisoquinolin-3(2H)-one derivatives have been designed and synthesized as new modulators for amyloid-β-induced mPTP opening. Among all, compound 7c remarkably enhanced mPTP opening while compound 7e showed the highest mPTP blocking activity...
April 20, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28422499/development-of-a-18f-labeled-radiotracer-with-improved-brain-kinetics-for-positron-emission-tomography-imaging-of-translocator-protein-18-kda-in-ischemic-brain-and-glioma
#4
Masayuki Fujinaga, Rui Luo, Katsushi Kumata, Yiding Zhang, Akiko Hatori, Tomoteru Yamasaki, Lin Xie, Wakana Mori, Yusuke Kurihara, Masanao Ogawa, Nobuki Nengaki, Feng Wang, Ming-Rong Zhang
We designed four novel acetamidobenzoxazolone compounds 7a-d as candidates of positron emission tomography (PET) radiotracers for imaging translocator protein (18 kDa, TSPO) in ischemic brain and glioma. Among these compounds, 2-(5-(6-fluoropyridin-3-yl)-2-oxobenzo[d]oxazol-3(2H)-yl)-N-methyl-N-phenylacetamide (7d) exhibited high binding affinity (Ki = 13.4 nM) with TSPO and moderate lipophilicity (LogD: 1.92). [18F]7d was radiosynthesized by [18F]fluorination of the bromopyridine precursor 7h with [18F]F- at 12 ± 3% radiochemical yield (n = 6, decay-corrected)...
April 19, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28420545/gqsar-modeling-and-combinatorial-library-generation-of-4-phenylquinazoline-2-carboxamide-derivatives-as-antiproliferative-agents-in-human-glioblastoma-tumors
#5
Debolina Goswami, Sukriti Goyal, Salma Jamal, Ritu Jain, Divya Wahi, Abhinav Grover
BACKGROUND: TSPO translocator protein, encoded in humans by the Tspo gene plays a crucial role in mitochondria mediated apoptosis and necrotic cell death through its association with Mitochondrial Permeability Transition pore (MPTP). It has been shown that this function can be exploited as a potential treatment for human Glioblastoma Multiforme. In this study, a novel robust fragment based QSAR model has been developed for a series of 4-phenylquinazoline-2-carboxamides experimentally known to be ligands for TSPO, thus triggering apoptotic mechanism cascade...
April 4, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28416580/a-tspo-ligand-attenuates-brain-injury-after-intracerebral-hemorrhage
#6
Minshu Li, Honglei Ren, Kevin N Sheth, Fu-Dong Shi, Qiang Liu
Intracerebral hemorrhage (ICH) is a devastating disease without effective treatment. After ICH, the immediate infiltration of leukocytes and activation of microglia are accompanied by a rapid up-regulation of translocator protein 18 kDa (TSPO). TSPO ligands have shown anti-inflammatory and neuroprotective properties in models of CNS injury. In this study, we determined the impact of a TSPO ligand, etifoxine, on brain injury and inflammation in 2 mouse models of ICH. TSPO was up-regulated in Iba1(+) cells from brains of patients with ICH and in CD11b(+)CD45(int) cells from mice subjected to collagenase-induced ICH...
April 17, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28405935/4-chlorodiazepam-protects-mitochondria-in-t98g-astrocyte-cell-line-from-glucose-deprivation
#7
Eliana Baez, Gina Paola Guio-Vega, Valentina Echeverria, Daniel Andres Sandoval-Rueda, George E Barreto
The translocator protein (TSPO), formerly known as the peripheral-type benzodiazepine receptor (PBR), is considered an important regulator of steroidogenesis and a potential therapeutic target in neurological disorders. Previous evidence suggests that TSPO ligands can protect cells during injury and prevent apoptosis in central nervous system (CNS) cells. However, its actions on astrocytic cells under metabolic injury are not well understood. In this study, we explored whether 4'-chlorodiazepam (Ro5-4864), a TSPO ligand, might protect astrocyte mitochondria under glucose deprivation...
April 13, 2017: Neurotoxicity Research
https://www.readbyqxmd.com/read/28398245/molecular-targets-for-pet-imaging-of-activated-microglia-the-current-situation-and-future-expectations
#8
REVIEW
Claire Tronel, Bérenger Largeau, Maria Joao Santiago Ribeiro, Denis Guilloteau, Anne-Claire Dupont, Nicolas Arlicot
Microglia, as cellular mediators of neuroinflammation, are implicated in the pathogenesis of a wide range of neurodegenerative diseases. Positron emission tomography (PET) imaging of microglia has matured over the last 20 years, through the development of radiopharmaceuticals targeting several molecular biomarkers of microglial activation and, among these, mainly the translocator protein-18 kDa (TSPO). Nevertheless, current limitations of TSPO as a PET microglial biomarker exist, such as low brain density, even in a neurodegenerative setting, expression by other cells than the microglia (astrocytes, peripheral macrophages in the case of blood brain barrier breakdown), genetic polymorphism, inducing a variation for most of TSPO PET radiopharmaceuticals' binding affinity, or similar expression in activated microglia regardless of its polarization (pro- or anti-inflammatory state), and these limitations narrow its potential interest...
April 11, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28387723/classical-and-novel-tspo-ligands-for-the-mitochondrial-tspo-can-modulate-nuclear-gene-expression-implications-for-mitochondrial-retrograde-signaling
#9
Nasra Yasin, Leo Veenman, Sukhdev Singh, Maya Azrad, Julia Bode, Alex Vainshtein, Beatriz Caballero, Ilan Marek, Moshe Gavish
It is known that knockdown of the mitochondrial 18 kDa translocator protein (TSPO) as well as TSPO ligands modulate various functions, including functions related to cancer. To study the ability of TSPO to regulate gene expression regarding such functions, we applied microarray analysis of gene expression to U118MG glioblastoma cells. Within 15 min, the classical TSPO ligand PK 11195 induced changes in expression of immediate early genes and transcription factors. These changes also included gene products that are part of the canonical pathway serving to modulate general gene expression...
April 7, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28387722/translocator-protein-18-kda-tspo-positron-emission-tomography-pet-imaging-and-its-clinical-impact-in-neurodegenerative-diseases
#10
REVIEW
Anne-Claire Dupont, Bérenger Largeau, Maria Joao Santiago Ribeiro, Denis Guilloteau, Claire Tronel, Nicolas Arlicot
In vivo exploration of activated microglia in neurodegenerative diseases is achievable by Positron Emission Tomography (PET) imaging, using dedicated radiopharmaceuticals targeting the translocator protein-18 kDa (TSPO). In this review, we emphasized the major advances made over the last 20 years, thanks to TSPO PET imaging, to define the pathophysiological implication of microglia activation and neuroinflammation in neurodegenerative diseases, including Parkinson's disease, Huntington's disease, dementia, amyotrophic lateral sclerosis, multiple sclerosis, and also in psychiatric disorders...
April 7, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28362078/the-anxiolytic-etifoxine-binds-to-tspo-ro5-4864-binding-site-with-long-residence-time-showing-a-high-neurosteroidogenic-activity
#11
Barbara Costa, Chiara Cavallini, Eleonora Da Pozzo, Sabrina Taliani, Federico Da Settimo, Claudia Martini
The low binding affinity of the approved anxiolytic drug etifoxine (Stresam) at the steroidogenic 18 kDa translocator protein (TSPO) has questioned the specific contribution of this protein in mediating the etifoxine neurosteroidogenic efficacy. Residence time (RT) at the binding site of the classical TSPO ligand PK11195 is emerging as a relevant neurosteroidogenic efficacy measure rather than the binding affinity. Here etifoxine was evaluated for (i) the in vitro neurosteroidogenic activity in comparison to poorly neurosteroidogenic reference TSPO ligands (PK11195 and Ro5-4864) and (ii) the affinity and RT at [(3)H]PK11195 and [(3)H]Ro5-4864 binding sites in rat kidney membranes...
April 4, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28358007/cholesterol-mediated-allosteric-regulation-of-the-mitochondrial-translocator-protein-structure
#12
Garima Jaipuria, Andrei Leonov, Karin Giller, Suresh Kumar Vasa, Łukasz Jaremko, Mariusz Jaremko, Rasmus Linser, Stefan Becker, Markus Zweckstetter
Cholesterol is an important regulator of membrane protein function. However, the exact mechanisms involved in this process are still not fully understood. Here we study how the tertiary and quaternary structure of the mitochondrial translocator protein TSPO, which binds cholesterol with nanomolar affinity, is affected by this sterol. Residue-specific analysis of TSPO by solid-state NMR spectroscopy reveals a dynamic monomer-dimer equilibrium of TSPO in the membrane. Binding of cholesterol to TSPO's cholesterol-recognition motif leads to structural changes across the protein that shifts the dynamic equilibrium towards the translocator monomer...
March 30, 2017: Nature Communications
https://www.readbyqxmd.com/read/28356120/in-vivo-tspo-and-cannabinoid-receptor-type-2-availability-early-in-post-stroke-neuroinflammation-in-rats-a-positron-emission-tomography-study
#13
Teruyo Hosoya, Dai Fukumoto, Takeharu Kakiuchi, Shingo Nishiyama, Shigeyuki Yamamoto, Hiroyuki Ohba, Hideo Tsukada, Takatoshi Ueki, Kohji Sato, Yasuomi Ouchi
BACKGROUND: Upregulated levels of 18-kDa translocator proteins (TSPO) and type 2 endocannabinoid receptors (CB2) are considered to reflect different aspects of microglia-related neuroinflammatory responses in the brain. Relative to the increase in the TSPO expression that occurs slightly later during neuroinflammation in a proinflammatory fashion, CB2 activation is considered to relate to the neuroprotective responses that occurs predominantly at an early stage of brain disorders. These findings, however, were deduced from studies with different animal samples under different experimental settings...
March 29, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28346358/genomic-evidence-for-bacterial-determinants-influencing-obesity-development
#14
Raphael D Isokpehi, Shaneka S Simmons, Matilda O Johnson, Marinelle Payton
Obesity is a major global public health problem requiring multifaceted interventional approaches including dietary interventions with probiotic bacteria. High-throughput genome sequencing of microbial communities in the mammalian gastrointestinal system continues to present diverse protein function information to understand the bacterial determinants that influence obesity development. The goal of the research reported in this article was to identify biological processes in probiotic bacteria that could influence the mechanisms for the extraction of energy from diet in the human gastrointestinal system...
March 26, 2017: International Journal of Environmental Research and Public Health
https://www.readbyqxmd.com/read/28337723/assessment-of-safety-efficacy-and-dosimetry-of-a-novel-18-kda-translocator-protein-ligand-11-c-cb184-in-healthy-human-volunteers
#15
Muneyuki Sakata, Kenji Ishibashi, Masamichi Imai, Kei Wagatsuma, Kenji Ishii, Kentaro Hatano, Kiichi Ishiwata, Jun Toyohara
BACKGROUND: N,N-di-n-propyl-2-[2-(4-[(11)C]methoxyphenyl)-6,8-dichloroimidazol[1,2-a]pyridine-3-yl]acetamide ([(11)C]CB184) is a novel selective radioligand for the 18-kD translocator protein (TSPO), which is upregulated in activated microglia in the brain, and may be useful in positron emission tomography (PET). We examined the safety, radiation dosimetry, and initial brain imaging with [(11)C]CB184 in healthy human volunteers. RESULTS: Dynamic [(11)C]CB184 PET scans (90 min) were performed in five healthy male subjects...
December 2017: EJNMMI Research
https://www.readbyqxmd.com/read/28336784/evaluation-of-the-effect-of-fingolimod-treatment-on-microglial-activation-using-serial-pet-imaging-in-multiple-sclerosis
#16
Marcus Sucksdorff, Eero Rissanen, Jouni Tuisku, Salla Nuutinen, Teemu Paavilainen, Johanna Rokka, Juha Rinne, Laura Airas
Traditionally, multiple sclerosis (MS) has been considered a white matter (WM) disease with focal inflammatory lesions. It is, however, becoming clear that significant pathology, such as microglial activation, also takes place outside the plaque areas, i.e. in areas of normal appearing white matter (NAWM) and gray matter (GM). Microglial activation can be detected in vivo using an 18 kDa translocator protein (TSPO) binding radioligands and positron emission tomography (PET). It is unknown whether fingolimod affects microglial activation in MS...
March 23, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/28322082/-11-c-dpa-713-has-much-greater-specific-binding-to-translocator-protein-18%C3%A2-kda-tspo-in-human-brain-than-11-c-r-pk11195
#17
Masato Kobayashi, Teresa Jiang, Sanjay Telu, Sami S Zoghbi, Roger N Gunn, Eugenii A Rabiner, David R Owen, Qi Guo, Victor W Pike, Robert B Innis, Masahiro Fujita
Positron emission tomography (PET) radioligands for translocator protein 18 kDa (TSPO) are widely used to measure neuroinflammation, but controversy exists whether second-generation radioligands are superior to the prototypical agent (11)C-( R)-PK11195 in human imaging. This study sought to quantitatively measure the "signal to background" ratio (assessed as binding potential ( BPND)) of (11)C-( R)-PK11195 compared to one of the most promising second-generation radioligands, (11)C-DPA-713. Healthy subjects had dynamic PET scans and arterial blood measurements of radioligand after injection of either (11)C-( R)-PK11195 (16 subjects) or (11)C-DPA-713 (22 subjects)...
January 1, 2017: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/28302760/-11-c-pbr28-or-18-f-pbr111-detect-white-matter-inflammatory-heterogeneity-in-multiple-sclerosis
#18
Gourab Datta, Alessandro Colasanti, Nicola Kalk, David R Owen, Gregory Scott, Eugenii Ilan A Rabiner, Roger Gunn, Anne Lingford-Hughes, Omar Malik, Olga Ciccarelli, Richard Nicholas, Lei Nie, Marco Battaglini, Nicola De Stefano, Paul Matthews
Objective: To assess microglial activation in lesions and in normal appearing white matter of multiple sclerosis (MS) patients using positron emission tomography (PET). Methods: 34 MS patients (7 with secondary progressive MS (SPMS), 27 with relapsing remitting MS (RRMS)) and 30 healthy volunteers, genetically stratified for translocator protein (TSPO), binding status underwent PET scanning with TSPO radioligands ((11)C-PBR28 or (18)F-PBR111). Regional TSPO availability was measured as a distribution volume ratio (DVR) relative to the caudate (a pseudo-reference region)...
March 16, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/28285077/multilayer-photodynamic-therapy-for-highly-effective-and-safe-cancer-treatment
#19
Ling Yang, Shaojuan Zhang, Xiaoxi Ling, Pin Shao, Ningyang Jia, Mingfeng Bai
Recent efforts to develop tumor-targeted photodynamic therapy (PDT) photosensitizers (PSs) have greatly advanced the potential of PDT in cancer therapy, although complete eradication of tumor cells by PDT alone remains challenging. As a way to improve PDT efficacy, we report a new combinatory PDT therapy technique that specifically targets multilayers of cells. Simply mixing different PDT PSs, even those that target distinct receptors (this may still lead to similar cell-killing pathways), may not achieve ideal therapeutic outcomes...
March 8, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28283959/neuroinflammation-in-neurodegenerative-disorders-a-review
#20
REVIEW
Martin Schain, William Charles Kreisl
The potential for positron emission tomography (PET) to detect neuroinflammation in vivo has sparked a remarkable interest in various disciplines of neuroscience. Early PET radioligands, such as [(11)C]PK(R)-11195 for the 18-kDa translocator protein (TSPO) and [(11)C]L-deprenyl for monoamine oxidase B, have been used in studies designed to clarify the role of neuroinflammation in a variety of psychiatric and neurological disorders. Recent years have witnessed the development of several second-generation PET radioligands for TSPO and radioligands to measure endogenous targets that are active in various stages of the inflammatory cascade, such as cyclooxygenase and arachidonic acid...
March 2017: Current Neurology and Neuroscience Reports
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