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ACS Chemical Neuroscience

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https://www.readbyqxmd.com/read/28644012/sigma-2-receptor-tmem97-agonists-produce-long-lasting-anti-neuropathic-pain-effects-in-mice
#1
James J Sahn, Galo L Mejia, Pradipta R Ray, Stephen F Martin, Theodore John Price
Neuropathic pain is an important medical problem with few effective treatments. The sigma 1 receptor (σ1R) is a potential target for neuropathic pain therapeutics, and antagonists for this receptor are effective in preclinical models and are currently in phase II clinical trials. Relatively little is known about the σ2R, which has recently been identified as transmembrane protein 97 (Tmem97). We generated a series of σ1R and σ2R/Tmem97 agonists and antagonists and tested them for efficacy in the mouse spared nerve injury (SNI) model...
June 23, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28640632/gut-microbiota-nitric-oxide-and-microglia-as-pre-requisites-for-neurodegenerative-disorders
#2
Joyce Ka Yu Tse
Regulating fluctuating endogenous nitric oxide (NO) levels is necessary for proper physiological functions. Aberrant NO pathways are implicated in a number of neurological disorders, including Alzheimer's Disease (AD) and Parkinson's Disease. The mechanism of NO in oxidative and nitrosative stress with pathological consequences involves reactions with reactive oxygen species (e.g. superoxide) to form the highly reactive peroxynitrite, hydrogen peroxide, hypochloride ions and hydroxyl radical. NO levels are typically regulated by endogenous nitric oxide synthases (NOS), and inflammatory iNOS is implicated in the pathogenesis of neurodegenerative diseases, in which elevated NO mediates axonal degeneration and activates cyclooxygenases to provoke neuroinflammation...
June 22, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28640596/drug-target-kinetics-in-drug-discovery
#3
Peter J Tonge
The development of therapies for the treatment of neurological cancer faces a number of major challenges including the synthesis of small molecule agents that can penetrate the blood brain barrier (BBB). Given the likelihood that in many cases drug exposure will be lower in the CNS than in systemic circulation, it follows that strategies should be employed that can sustain target engagement at low drug concentration. Time dependent target occupancy is a function of both the drug and target concentration as well as the thermodynamic and kinetic parameters that describe the binding reaction coordinate, and sustained target occupancy can be achieved through structural modifications that increase target (re)binding and/or that decrease the rate of drug dissociation...
June 22, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28640595/detection-and-characterization-of-small-molecule-interactions-with-fibrillar-protein-aggregates-using-microscale-thermophoresis
#4
Emily Fisher, Yanyan Zhao, Robert Richardson, Malgorzata Janik, Alexander K Buell, Franklin I Aigbirhio, Gergely Toth
Neurodegenerative diseases such as Parkinson's and Alzheimer's disease share the pathological hallmark of fibrillar protein aggregates. The specific detection of these protein aggregates by positron emission tomography (PET) in the patient brain can yield valuable information for diagnosis and disease progression. However, the identification of novel small compounds that bind fibrillar protein aggregates has been a challenge. In this study, microscale thermophoresis (MST) was applied to assess the binding affinity of known small molecule ligands of α-synuclein fibrils, which were also tested in parallel in a Thioflavin T fluorescence competition assay for further validation...
June 22, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28640591/managing-psychotropic-medications-in-complex-real-world-patients-using-comprehensive-therapeutic-drug-monitoring
#5
Jeffrey J Sutherland, Ryan D Morrison, J Scott Daniels, Stephen B Milne, Timothy P Ryan
There are multiple treatment options for depression, anxiety, psychosis, and other psychiatric disorders, and psychiatry patients are often comorbid with complex, polypharmacy treatment regimens. Unlike cardiovascular disease and diabetes, there are no readily available biomarkers to gauge treatment success with psychotropic medications, often resulting in subjective determination of medication therapy effectiveness. The physiochemical properties of psychiatric medications in general lend themselves to quantitative measurement in blood, offering an avenue to optimize treatment for each patient...
June 22, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28636360/proneurogenic-effects-of-trazodone-in-murine-and-human-neural-progenitors
#6
Valeria Bortolotto, Francesca Mancini, Giorgina Mangano, Rita Salem, Er Xia, Erika Del Grosso, Michele Bianchi, Pier Luigi Canonico, Lorenzo Polenzani, Mariagrazia Grilli
Several antidepressants increase adult hippocampal Neurogenesis (ahNG) in rodents, primates and, potentially, in humans. This effect may at least partially account for their therapeutic activity. The availability of antidepressants whose mechanism of action involves different neurotransmitter receptors represents an opportunity for increasing our knowledge on their distinctive peculiarities and for dissecting the contribution of receptor subtypes in ahNG modulation. The aim of this study was to evaluate, in vitro, the effects of the antidepressant trazodone (TZD) on ahNG by using primary cultures of adult hippocampal Neural Progenitor Cells (ahNPC) and human iPSC-derived NPC...
June 21, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28594546/neuropeptide-vgf-c-terminal-peptide-tlqp-62-alleviates-lipopolysaccharide-induced-memory-deficits-and-anxiety-like-and-depression-like-behaviors-in-mice-the-role-of-bdnf-trkb-signaling
#7
Chenli Li, Mengmeng Li, Hanjie Yu, Xinbei Shen, Jinting Wang, Xin Sun, Qinwen Wang, Chuang Wang
Peripheral inflammatory responses affect central nervous system (CNS) function, manifesting in symptoms of memory deficits, depression, and anxiety. Previous studies have revealed that neuropeptide VGF (nonacronymic) C-terminal peptide TLQP-62 rapidly reinforces brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB) signaling, regulating memory consolidation and antidepressant-like action. However, whether it is beneficial for lipopolysaccharide (LPS)-induced neuropsychiatric dysfunction in mice is unknown...
June 21, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28594540/noradrenergic-modulation-of-dopamine-transmission-evoked-by-electrical-stimulation-of-the-locus-coeruleus-in-the-rat-brain
#8
Jin W Park, Rohan V Bhimani, Jinwoo Park
Central norepinephrine (NE) and dopamine (DA) are involved in a variety of physiological functions and behaviors. Accumulating evidence suggests that NE neurons originating from the locus coeruleus (LC) innervate DA neurons of the ventral tegmental area (VTA) and influence VTA-DA neural activity. However, the underlying mechanisms of how LC-NE regulates DA transmission via VTA-DA neurons remain largely unexplored. Herein, we investigated how electrical stimulation of the LC modulates VTA-DA neurotransmission in the nucleus accumbens (NAc)...
June 21, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28628299/dihydropyrimidine-thiones-and-clioquinol-synergize-to-target-%C3%AE-amyloid-cellular-pathologies-through-a-metal-dependent-mechanism
#9
Daniel F Tardiff, Lauren E Brown, Xiaohui Yan, Richard Trilles, Nathan T Jui, M Inmaculada Barrasa, Kim A Caldwell, Guy A Caldwell, Scott E Schaus, Susan Lindquist
The lack of therapies for neurodegenerative diseases arises from our incomplete understanding of their underlying cellular toxicities and the limited number of predictive model systems. It is critical that we develop approaches to identify novel targets and lead compounds. Here, a phenotypic screen of yeast proteinopathy models identified dihydropyrimidine-thiones (DHPM-thiones) that selectively rescued the toxicity caused by β-amyloid (Aβ), the peptide implicated in Alzheimer's disease. Rescue of Aβ toxicity by DHPM-thiones occurred through a metal-dependent mechanism of action...
June 19, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28621929/kinetic-analysis-reveals-the-identity-of-a%C3%AE-metal-complex-responsible-for-the-initial-aggregation-of-a%C3%AE-in-the-synapse
#10
Thomas Branch, Mauricio Barahona, Charlotte A Dodson, Liming Ying
The mechanism of Aβ aggregation in the absence of metal ions is well established, yet the role that Zn(2+) and Cu(2+), the two most studied metal ions, released during neurotransmission, play in promoting Aβ aggregation in the vicinity of neuronal synapses remains elusive. Here we report the kinetics of Zn(2+) binding to Aβ and Zn(2+)/Cu(2+) binding to Aβ-Cu to form ternary complexes under near physiological conditions (nM Aβ, µM metal ions). We find that these reactions are several orders of magnitude slower than Cu(2+) binding to Aβ...
June 16, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28618224/design-synthesis-and-structure-activity-relationship-of-tetrahydropyrido-4-3-d-pyrimidine-derivatives-as-potent-smoothened-antagonists-with-in-vivo-activity
#11
Wenfeng Lu, Yongqiang Liu, Haikuo Ma, Jiyue Zheng, Sheng Tian, Zhijian Sun, Lusong Luo, Jiajun Li, Hongjian Zhang, Zeng-Jie Yang, Xiaohu Zhang
Medulloblastoma is one of the most prevalent brain tumors in children. Aberrant hedgehog (Hh) pathway signaling is thought to be involved in the initiation and development of medulloblastoma. Vismodegib, the first FDA-approved cancer therapy based on inhibition of aberrant hedgehog signaling, targets smoothened (Smo), a G-protein coupled receptor (GPCR) central to the Hh pathway. Although vismodegib exhibits promising therapeutic efficacy in tumor treatment, concerns have been raised from its non-linear pharmacokinetic (PK) profiles at high doses partly due to low aqueous solubility...
June 15, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28617576/ex-vivo-measurement-of-electrically-evoked-dopamine-release-in-zebrafish-whole-brain
#12
Mimi Shin, Thomas M Field, Chase S Stucky, Mia N Furgurson, Michael A Johnson
Zebrafish (Danio rerio) have recently emerged as useful model organism for the study of neuronal function. Here, fast-scan cyclic voltammetry at carbon-fiber microelectrodes (FSCV) was used to measure locally-evoked dopamine release and uptake in zebrafish whole brain preparations and results were compared with those obtained from brain slices. Evoked dopamine release ([DA]max) was similar in whole brain and sagittal brain slice preparations (0.49 ± 0.13 µM in whole brain and 0.59 ± 0.28 µM in brain slices)...
June 15, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28617575/external-influences-on-invertebrate-brain-histamine-and-related-compounds-via-an-automated-derivatization-method-for-capillary-electrophoresis
#13
Sandrine Parrot, Mónica Pavón Vergés, Marie-Jeanne Perrot-Minnot, Luc Denoroy
Histamine has been shown to modulate visual system and photic behavior in arthropods. However, few methods are available for the direct quantification of histamine and its precursor and metabolites in arthropod brain. In this work, a method for the separation of histamine, its precursor histidine and its metabolite N-methyl-histamine from brain extracts of a freshwater crustacean has been developed using capillary electrophoresis with laser-induced fluorescence detection. Molecules were tagged on their primary amine function with naphthalene-2,3-dicarboxaldehyde, but derivatized histamine and N-methyl-histamine exhibited poor stability in contrast to derivatized histidine...
June 15, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28574249/synthesis-and-characterization-of-novel-acyl-glycine-inhibitors-of-glyt2
#14
Shannon N Mostyn, Jane E Carland, Susan Shimmon, Renae M Ryan, Tristan Rawling, Robert J Vandenberg
It has been demonstrated previously that the endogenous compound N-arachidonyl-glycine inhibits the glycine transporter GlyT2, stimulates glycinergic neurotransmission, and provides analgesia in animal models of neuropathic and inflammatory pain. However, it is a relatively weak inhibitor with an IC50 of 9 μM and is subject to oxidation via cyclooxygenase, limiting its therapeutic value. In this paper we describe the synthesis and testing of a novel series of monounsaturated C18 and C16 acyl-glycine molecules as inhibitors of the glycine transporter GlyT2...
June 15, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28609096/identification-and-profiling-of-a-selective-and-brain-penetrant-radioligand-for-in-vivo-target-occupancy-measurement-of-casein-kinase-1-ck1-inhibitors
#15
Travis T Wager, Paul Galatsis, Ramalakshmi Y Chandrasekaran, Todd W Butler, Jianke Li, Lei Zhang, Scot Mente, Chakrapani Subramanyam, Shenping Liu, Angela C Doran, Cheng Chang, Katherine Fisher, Sarah Grimwood, Joseph R Hedde, Michael Marconi, Klaas Schildknegt
To enable the clinical development of our CNS casein kinase 1 delta/epsilon (CK1δ/ε) inhibitor project we investigated the possibility of developing a CNS positron emission tomography (PET) radioligand. For this effort, we focused our design and synthesis efforts on the initial CK1δ/ε inhibitor HTS hits with the goal of identifying a compound that would fulfill a set of recommended PET ligand criteria. We identified [3H]PF-5236216 (9) as a tool ligand that meets most of the key CNS PET attributes including high CNS MPO PET desirability score and kinase selectivity, CNS penetration and low non-specific binding...
June 13, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28605578/roflupram-a-phosphodiesterase-4-inhibitior-suppresses-inflammasome-activation-through-autophagy-in-microglial-cells
#16
Tingting You, Yu-Fang Cheng, Jiahong Zhong, Bingtian Bi, Bingqing Zeng, Wenhua Zheng, Hai-Tao Wang, Jiang-Ping Xu
Inhibition of phosphodiesterase 4 (PDE4) suppressed the inflammatory responses in the brain. However, the underlying mechanisms are poorly understood. Roflupram (ROF) is a novel PDE4 inhibitor. In the present study, we found that ROF enhanced the level of microtubule-associated protein 1 light chain 3 II (LC3-II) and decreased p62 in microglial BV-2 cells. Enhanced fluorescent signals were observed in BV-2 cells treated with ROF by Lysotracker red and acridine orange staining. In addition, immunofluorescence indicated a significant increase in punctate LC3...
June 12, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28603962/novel-opioid-analgesics-and-side-effects
#17
Giovanna Del Vecchio, Viola Spahn, Christoph Stein
Conventional opioids mediate analgesia as well as severe adverse effects via G-protein coupled opioid receptors (OR) in both inflamed (peripheral injured tissue) and healthy (brain, intestinal wall) environments. To exclude side effects, OR activation can be selectively achieved in damaged tissue by lowering the pKa of an opioid ligand to the acidic pH of inflammation. As a result, protonation of the ligand and consequent OR binding and activation of G-proteins is pH- and injury-specific. A novel compound (NFEPP) demonstrates the feasibility of this approach and displays blockade of pain transmission only at the peripheral site of injury, but with lack of central and gastrointestinal adverse effects...
June 12, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28594164/augmenting-glioblastoma-chemotherapy-with-polymers
#18
Matthew Skinner, Sarah M Ward, Carol L Nilsson, Todd Emrick
Chemotherapeutics are vital for treating brain tumors such as glioblastoma, an aggressive and prolific cancer predominantly treated with DNA alkylating agents. The efficacy of antiglioblastoma drugs, such as temozolomide, is limited by their rapid clearance and instability under normal physiological conditions. Both local and systemic polymer-based therapeutics have shown promise for treating many cancers, and as such there is a growing interest in applying polymer techniques to augment the efficacy and stability of glioblastoma chemotherapeutics...
June 8, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28590714/reaching-out-for-sensitive-evaluation-of-the-mu-opioid-receptor-in-vivo-positron-emission-tomography-imaging-of-the-agonist-11c-ah7921
#19
Waqas Rafique, Shivashankar Khanapur, Mona Milde Spilhaug, Patrick J Riss
Imaging of the mu-opioid receptor availability with PET is a pertinent challenge in Neuroscience. Both, regulation of receptor expression and occupancy by endogeneous opioids play into cognitive and behavioural phenotypes of healthy function and disease. Receptor expression in the active and inactive states can be measured using high affinity radioagonist and radioanatonist PET tracers, respectively. Occupancy assessment requires radioligands showing competitive and reversible binding with moderate affinity to the MOR, which may lead to physical extinction of the receptor specific signal in vivo...
June 7, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28586206/functionalized-fullerene-targeting-human-voltage-gated-sodium-channel-hnav1-7
#20
Tamsyn A Hilder, Anna Robinson, Shin-Ho Chung
Mutations of hNav1.7 that cause its activities to be enhanced contribute to severe neuropathic pain. Only a small number of hNav1.7 specific inhibitors have been identified, most of which interact with the voltage-sensing domain of the voltage-activated sodium ion channel. In our previous computational study, we demonstrated that a [Lys6]-C84 fullerene binds tightly (affinity of 46 nM) to NavAb, the voltage-gated sodium channel from the bacterium Arcobacter butzleri. Here, we extend this work and, using molecular dynamics simulations, demonstrate that the same [Lys6]-C84 fullerene binds strongly (2...
June 6, 2017: ACS Chemical Neuroscience
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