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ACS Chemical Neuroscience

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https://www.readbyqxmd.com/read/28103441/enantio-specific-allosteric-modulation-of-cannabinoid-1-receptor
#1
Robert B Laprairie, Pushkar M Kulkarni, Jeffrey R Deschamps, Melanie E M Kelly, David R Janero, Maria G Cascio, Lesley A Stevenson, Roger G Pertwee, Terry Kenakin, Eileen M Denovan-Wright, Ganesh A Thakur
The cannabinoid 1 receptor (CB1R) is one of the most widely expressed metabotropic G protein-coupled receptors in brain, and its participation in various (patho)physiological processes has made CB1R activation a viable therapeutic modality. Adverse psychotropic effects limit the clinical utility of CB1R orthosteric agonists and have promoted the search for CB1R positive allosteric modulators (PAMs) with the promise of improved drug-like pharmacology and enhanced safety over typical CB1R agonists. In this study, we describe the synthesis and in vitro and ex vivo pharmacology of the novel allosteric CB1R modulator GAT211 (racemic) and its resolved enantiomers, GAT228 (R) and GAT229 (S)...
January 19, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28033462/the-pharmacological-heterogeneity-of-nepenthone-analogs-in-conferring-highly-selective-and-potent-%C3%AE%C2%BA-opioid-agonistic-activities
#2
Wei Li, Jian-Dong Long, Yuan-Yuan Qian, Yu Long, Xue-Jun Xu, Yu-Jun Wang, Qing Shen, Zuo-Neng Wang, Xi-Cheng Yang, Li Xiao, Hong-Peng Sun, Yu-Long Xu, Yi-Yi Chen, Qiong Xie, Yong-Hui Wang, Li-Ming Shao, Jing-Gen Liu, Zhui-Bai Qiu, Wei Fu
To develop novel analgesics with no side effects or less side effects than traditional opioids is highly demanded to treat opioid receptor mediated pain and addiction issues. Recently, κ-opioid receptor (KOR) has been established as an attractive target, although its selective agonists could bear heterogeneous pharmacological activities. In this study, we designed and synthesized two new series of nepenthone derivatives by inserting a spacer (carbonyl) between 6α,14α-endo-ethenylthebaine and the 7α-phenyl substitution of the skeleton and by substituting the 17-N-methyl group with a cyclopropylmethyl group...
January 19, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28029782/a-tph2-gfp-reporter-stem-cell-line-to-model-in-vitro-and-in-vivo-serotonergic-neuron-development-and-function
#3
Giulia Pacini, Attilio Marino, Sara Migliarini, Elisa Brilli, Barbara Pelosi, Giacomo Maddaloni, Marta Pratelli, Mario Pellegrino, Aldo Ferrari, Massimo Pasqualetti
Modeling biological systems in vitro has contributed to clarification of complex mechanisms in simplified and controlled experimental conditions. Mouse embryonic stem (mES) cells can be successfully differentiated toward specific neuronal cell fates, thus representing an attractive tool to dissect, in vitro, mechanisms that underlie complex neuronal features. In this study, we generated and characterized a reporter mES cell line, called Tph2(GFP), in which the vital reporter GFP replaces the tryptophan hydroxylase 2 (Tph2) gene...
January 19, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28097868/development-of-phenothiazine-based-theranostic-compounds-that-act-both-as-inhibitors-of-%C3%AF-amyloid-aggregation-and-imaging-probes-for-amyloid-plaques-in-alzheimer-s-disease
#4
Pascal Dao, Feifei Ye, Yan Liu, Zhiyun Du, Kun Zhang, Chang-Zhi Dong, Bernard Meunier, Huixiong Chen
Early detection of Alzheimer's disease (AD) is imperative in enabling the understanding and clinical treatment of this disorder, as well as in preventing its progression. Imaging agents specifically targeting Aβ plaques in the brain and the retina may lead to the early diagnosis of AD. Among them, near infrared fluorescent imaging has emerged as an attractive tool to noninvasively identify and monitor diseases during the preclinical and early stages. In the present study, we report the design, synthesis and evaluation of a series of new near-infrared fluorescent probes...
January 18, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28094974/monitoring-dopamine-responses-to-potassium-ion-and-nomifensine-by-in-vivo-microdialysis-with-online-liquid-chromatography-at-one-minute-resolution
#5
Khanh Thieu Ngo, Erika L Varner, Adrian Charles Michael, Stephen G Weber
Recently, our laboratory has demonstrated the technical feasibility of monitoring dopamine at one-min temporal resolution with microdialysis and online liquid chromatography. Here, we monitor dopamine in the rat striatum during local delivery of potassium ion and nomifensine in awake-behaving rats. Microdialysis probes were implanted and dopamine was monitored one or four Days later under basal conditions, during 10-min applications of 60 mM or 100 mM K+, and during 15-min applications of 10 µM nomifensine: K+ and nomifensine were delivered locally by adding them to the microdialysis perfusion fluid...
January 17, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28094500/chronic-mild-stress-induced-alterations-of-local-protein-synthesis-a-role-for-cognitive-impairment
#6
Francesca Calabrese, Paola Brivio, Piotr Gruca, Magdalena Lason-Tyburkiewicz, Mariusz Papp, Marco A Riva
Depression, a major cause of disability worldwide, is characterized by a complex and heterogeneous symptomatology. With this respect, cognitive deterioration represents a major problem that has a strong impact on patient's function. Thus, within the context of a depressive phenotype, it is important to characterize the mechanisms that sustain cognitive dysfunctions and may represent an important target for pharmacological intervention. Here, using the chronic mild stress (CMS) paradigm of depression, we found that, independently from the anhedonic phenotype, CMS rats showed a deficit in the novel object recognition (NOR) test, which is associated with an inability to phosphorylate GluN2B subunit on Ser1303 and to activate the mTOR pathway...
January 17, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28094495/bacoside-a-an-indian-traditional-medicine-substance-inhibits-beta-amyloid-cytotoxicity-fibrillation-and-membrane-interactions
#7
Ravit Malishev, Shira Shaham-Niv, Sukhendu Nandi, Sofiya Kolusheva, Ehud Gazit, Raz Jelinek
Bacoside-A, a family of compounds extracted from the Bacopa monniera plant, is a folk-medicinal substance believed to exhibit therapeutic properties, particularly enhancing cognitive functions and improving memory. We show that bacoside-A exerted significant inhibitory effects upon cytotoxicity, fibrillation, and particularly membrane interactions of amyloid-beta (1-42) (Aβ42), the peptide playing a prominent role in Alzeheimer's disease progression and toxicity. Specifically, pre-incubation of bacoside-A with Aβ42 significantly reduced cell toxicity and inhibited fibril formation both in buffer solution and, more significantly, in the presence of membrane vesicles...
January 17, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/27984698/simultaneous-voltammetric-measurements-of-glucose-and-dopamine-demonstrate-the-coupling-of-glucose-availability-with-increased-metabolic-demand-in-the-rat-striatum
#8
Samantha K Smith, Christie A Lee, Matthew E Dausch, Brian M Horman, Heather B Patisaul, Gregory S McCarty, Leslie A Sombers
Cerebral blood flow ensures delivery of nutrients, such as glucose, to brain sites with increased metabolic demand. However, little is known about rapid glucose dynamics at discrete locations during neuronal activation in vivo. Acute exposure to many substances of abuse elicits dopamine release and neuronal activation in the striatum; however, the concomitant changes in striatal glucose remain largely unknown. Recent developments have combined fast-scan cyclic voltammetry with glucose oxidase enzyme modified carbon-fiber microelectrodes to enable the measurement of glucose dynamics with subsecond temporal resolution in the mammalian brain...
January 17, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28076682/effect-of-maternal-%C3%A2-citalopram-exposure-on-p11-expression-and-neurogenesis-in-the-mouse-fetal-brain
#9
Jennifer R King, Juan C Velasquez, Masaaki Torii, Alexandre Bonnin
Fetal exposure to selective serotonin reuptake inhibitors (SSRI) has been associated with increased risk of adverse neurodevelopmental outcomes. In the adult brain, SSRI therapy regulates p11 (s100a10) expression and alters neurogenesis. The protein p11 indirectly regulates 5-HT signaling through 5-HT1B/D receptors. In the fetal brain, signaling through these receptors modulates axonal circuit formation. We determined whether p11 is expressed in the fetal mouse brain, and whether maternal SSRI exposure affects fetal p11 expression and neurogenesis...
January 13, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28026168/synthetic-models-of-quasi-stable-amyloid-%C3%AE-40-oligomers-with-significant-neurotoxicity
#10
Yumi Irie, Kazuma Murakami, Mizuho Hanaki, Yusuke Hanaki, Takashi Suzuki, Yoko Monobe, Tomoyo Takai, Ken-Ichi Akagi, Taiji Kawase, Kenji Hirose, Kazuhiro Irie
The formation of soluble oligomers of amyloid β42 and 40 (Aβ42, Aβ40) is the initial event in the pathogenesis of Alzheimer's disease (AD). Based on previous systematic proline replacement and solid-state NMR, we proposed a toxic dimer structure of Aβ42, a highly aggregative alloform, with a turn at positions 22 and 23, and a hydrophobic core in the C-terminal region. However, in addition to Aβ42, Aβ40 dimers can also contribute to AD progression because of the more abundance of Aβ40 monomer in biological fluids...
January 12, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28076681/computational-modeling-of-neurotransmitter-release-evoked-by-electrical-stimulation-non-linear-approaches-to-predicting-stimulation-evoked-dopamine-release
#11
James K Trevathan, Ali Yousefi, Hyung Ook Park, John J Bartoletta, Kip A Ludwig, Kendall H Lee, J Luis Lujan
Neurochemical changes evoked by electrical stimulation of the nervous system have been linked to both therapeutic and undesired effects of neuromodulation therapies used to treat obsessive-compulsive disorder, depression, epilepsy, Parkinson's disease, stroke, hypertension, tinnitus, and many other indications. In fact, interest in better understanding the role of neurochemical signaling in neuromodulation therapies has been a focus of recent government- and industry-sponsored programs whose ultimate goal is to usher in an era of personalized medicine by creating neuromodulation therapies that respond to real-time changes in patient status...
January 11, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28075555/familial-mutations-may-switch-conformational-preferences-in-%C3%AE-synuclein-fibrils
#12
Liang Xu, Buyong Ma, Ruth Nussinov, Damien Thompson
The pathogenesis of Parkinson's disease is closely associated with the aggregation of the α-synuclein protein. Several familial mutants have been identified and shown to affect the aggregation kinetics of α-synuclein through distinct molecular mechanisms. Quantitative evaluation of the relative stabilities of the wild type and mutant fibrils is crucial for understanding the aggregation process and identifying the key component steps. In this work, we examined two topologically different α-synuclein fibril structures that are either determined by solid-state NMR method or modelled based on solid-state NMR data, and characterized their conformational properties and thermodynamic stabilities using molecular dynamics simulations...
January 11, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28071892/transient-adenosine-release-is-modulated-by-nmda-and-gabab-receptors
#13
Michael D Nguyen, Ying Wang, Mallikarjunarao Ganesana, B Jill Venton
Adenosine is a neuroprotective agent that modulates neurotransmission and is modulated by other neurotransmitters. Spontaneous, transient adenosine is a recently discovered mode of signaling where adenosine is released and cleared from the extracellular space quickly, in less than three seconds. Spontaneous adenosine release is regulated by adenosine A1 and A2a receptors, but regulation by other neurotransmitter receptors has not been studied. Here, we examined the effect of glutamate and GABA receptors on the concentration and frequency of spontaneous, transient adenosine release by measuring adenosine with fast-scan cyclic voltammetry in the rat caudate-putamen...
January 10, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28001356/diverse-effects-on-m1-signaling-and-adverse-effect-liability-within-a-series-of-m1-ago-pams
#14
Jerri M Rook, Masahito Abe, Hyekyung P Cho, Kellie D Nance, Vincent B Luscombe, Jeffrey J Adams, Jonathan W Dickerson, Daniel H Remke, Pedro M Garcia-Barrantes, Darren W Engers, Julie L Engers, Sichen Chang, Jarrett J Foster, Anna L Blobaum, Colleen M Niswender, Carrie K Jones, P Jeffrey Conn, Craig W Lindsley
Both historical clinical and recent preclinical data suggest that the M1 muscarinic acetylcholine receptor is an exciting target for the treatment of Alzheimer's disease and the cognitive and negative symptom clusters in schizophrenia; however, early drug discovery efforts targeting the orthosteric binding site have failed to afford selective M1 activation. Efforts then shifted to focus on selective activation of M1 via either allosteric agonists or positive allosteric modulators (PAMs). While M1 PAMs have robust efficacy in rodent models, some chemotypes can induce cholinergic adverse effects (AEs) that could limit their clinical utility...
January 10, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/27984697/delineating-amyloid-plaque-associated-neuronal-sphingolipids-in-transgenic-alzheimer-s-disease-mice-tgarcswe-using-maldi-imaging-mass-spectrometry
#15
Ibrahim Kaya, Dimitri Brinet, Wojciech Michno, Stina Syvänen, Dag Sehlin, Henrik Zetterberg, Kaj Blennow, Jörg Hanrieder
The major pathological hallmarks of Alzheimer's disease (AD) are the progressive aggregation and accumulation of beta-amyloid (Aβ) and hyperphosphorylated tau protein into neurotoxic deposits. Aβ aggregation has been suggested as the critical early inducer, driving the disease progression. However, the factors that promote neurotoxic Aβ aggregation remain elusive. Imaging mass spectrometry (IMS) is a powerful technique to comprehensively elucidate the spatial distribution patterns of lipids, peptides, and proteins in biological tissue sections...
January 10, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28067492/the-polyphenol-altenusin-inhibits-in-vitro-fibrillization-of-tau-and-reduces-induced-tau-pathology-in-primary-neurons
#16
Sook Wern Chua, Alberto Cornejo, Janet van Eersel, Claire H Stevens, Inmaculada Vaca, Mercedes Cueto, Michael Kassiou, Amadeus Gladbach, Alex Macmillan, Lev Lewis, Renee Megan Whan, Lars Matthias Ittner
In Alzheimer´s disease the microtubule-associated protein tau forms intracellular neurofibrillary tangles (NFTs). A critical step in the formation of NFTs is the conversion of soluble tau into insoluble filaments. Accordingly, a current therapeutic strategy in clinical trials is aimed at preventing tau aggregation. Here, we assessed altenusin, a bioactive polyphenolic compound, for its potential to inhibit tau aggregation. Altenusin inhibits aggregation of tau protein into paired helical filaments in vitro...
January 9, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28067045/neurotoxicity-of-%C3%AE-keto-amphetamines-deathly-mechanisms-elicited-by-methylone-and-mdpv-in-human-dopaminergic-sh-sy5y-cells
#17
Maria Joao Valente, Maria Lourdes Bastos, Eduarda Fernandes, Félix Carvalho, Paola Guedes de Pinho, Marcia Carvalho
Synthetic cathinones (β-keto amphetamines) act as potent CNS stimulants similarly to classical amphetamines, which raise concerns about their potential neurotoxic effects. The present in vitro study aimed to explore and compare the mechanisms underlying the neurotoxicity of two commonly abused cathinone derivatives, 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxypyrovalerone (MDPV), with those of 3,4-methylenedioxymethamphetamine (MDMA), using undifferentiated and differentiated SH-SY5Y cells...
January 9, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28061031/inhibition-and-degradation-of-amyloid-beta-a%C3%AE-40-fibrillation-by-designed-small-pep-tide-a-combined-spectroscopy-microscopy-and-cell-toxicity-study
#18
Anirban Ghosh, Nibedita Pradhan, Swapna Bera, Aritreyee Datta, Janarthanan Krishnamoorthy, Nikhil R Jana, Anirban Bhunia
A designed non-toxic, non-hemolytic 11-residue peptide, NF11 (NAVRWSLMRPF) not only inhibits the aggregation of Amyloid beta (Aβ40) protein but also disaggregates the pre-formed oligomers and mature Aβ fibrils thereby reducing associated-toxicity. NMR experiments provide evidence of NF11's ability to inhibit fibril formation, primarily through interaction with the N-terminus region as well as the central hydrophobic cluster of Aβ40. NF11 has micro molar binding affinity towards both monomeric and aggregated species for efficient clearance of toxic aggregates...
January 6, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28044440/ethylatropine-bromide-as-a-peripherally-restricted-muscarinic-antagonist
#19
Asheebo Rojas, Thota Ganesh, Alec Walker, Raymond Dingledine
Quaternary ammonium analogues of atropine that are unable to cross the blood-brain barrier are used to alleviate peripheral muscarinic toxicity in animal models of epilepsy produced by systemic administration of pilocarpine or diisopropylfluorophosphate (DFP). Currently, methylatropine is the most popular and potent of these quaternary derivatives; however, it is expensive and produced in limited quantity. Here, we propose the use of ethylatropine bromide as an alternative to methylatropine. The synthesis of ethylatropine bromide is simple, inexpensive and has low environmental impact...
January 6, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28029766/neuroprotective-effects-of-a-structurally-new-family-of-high-affinity-imidazoline-i2-receptor-ligands
#20
Sònia Abás, Amaia M Erdozain, Benjamin Keller, Sergio Rodríguez-Arévalo, Luis F Callado, Jesús A García-Sevilla, Carmen Escolano
The imidazoline I2 receptors (I2-IRs) are widely distributed in the brain, and I2-IR ligands may have therapeutic potential as neuroprotective agents. Since structural data for I2-IR remains unknown, the discovery of selective I2-IR ligands devoid of α2-adrenoceptor (α2-AR) affinity is likely to provide valuable tools in defining the pharmacological characterization of these receptors. We report the pharmacological characterization of a new family of (2-imidazolin-4-yl)phosphonates. Radioligand binding studies showed that they displayed a higher affinity for I2-IRs than idazoxan, and high I2/α2 selectivity...
January 4, 2017: ACS Chemical Neuroscience
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