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  • Design, Synthesis, and Biological Evaluation of Dual-Target Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 9A (PDE9A) for the Treatment of Alzheimer’s Disease
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-10-12
    Jinhui Hu, Ya-Dan Huang, Tingting Pan, Tianhua Zhang, Tao Su, Xingshu Li, Hai-Bin Luo, Ling Huang
    更新日期:2018-10-12
  • Comment on “In Vivo [18F]GE-179 Brain Signal Does Not Show NMDA-Specific Modulation with Drug Challenges in Rodents and Nonhuman Primates”
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-10-11
    Colm J. McGinnity, Erik Årstad, Katherine Beck, David J. Brooks, Jonathan P. Coles, John S. Duncan, Marian Galovic, Rainer Hinz, Ella Hirani, Oliver D. Howes, Paul A. Jones, Matthias J. Koepp, Feng Luo, Daniela A. Riaño Barros, Nisha Singh, William Trigg, Alexander Hammers

    Schoenberger and colleagues (Schoenberger et al.(2018) ACS Chem. Neurosci. 9, 298−305) recently reported attempts to demonstrate specific binding of the positron emission tomography (PET) radiotracer, [18F]GE-179, to NMDA receptors in both rats and Rhesus macaques. GE-179 did not work as expected in animal models; however, we disagree with the authors’ conclusion that “the [18F]GE-179 signal seems to be largely nonspecific”. It is extremely challenging to demonstrate specific binding for the use-dependent NMDA receptor intrachannel ligands such as [18F]GE-179 in animals via traditional blocking, due to its low availability of target sites (Bmax′). Schoenberger and colleagues anesthetized rats and Rhesus monkeys using isoflurane, which has an inhibitory effect on NMDA receptor function and thus would be expected to further reduce the Bmax′. The extent of glutamate release achieved in the provocation experiments is uncertain, as is whether a significant increase in NMDA receptor channel opening can be expected under anesthesia. Prior data suggest that the uptake of disubstituted arylguanidine-based ligands such as GE-179 can be reduced by phencyclidine binding site antagonists, if injection is performed in the absence of ketamine and isoflurane anesthesia, e.g., with GE-179’s antecedent, CNS 5161 (Biegon et al. (2007) Synapse 61, 577−586), and with GMOM (van der Doef et al. (2016) J. Cereb. Blood Flow Metab. 36, 1111−1121). However, the extent of nonspecific uptake remains uncertain.

    更新日期:2018-10-12
  • 更新日期:2018-10-12
  • Role of Rab GTPases in Alzheimer’s Disease
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-10-11
    Xian Zhang, Timothy Y. Huang, Joel Yancey, Hong Luo, Yun-wu Zhang
    更新日期:2018-10-12
  • Toxic Amyloid Tape: A Novel Mixed Antiparallel/Parallel β-Sheet Structure Formed by Amyloid β-Protein on GM1 Clusters
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-10-11
    Yuki Okada, Kaori Okubo, Keisuke Ikeda, Yoshiaki Yano, Masaru Hoshino, Yoshio Hayashi, Yoshiaki Kiso, Hikari Itoh-Watanabe, Akira Naito, Katsumi Matsuzaki
    更新日期:2018-10-12
  • Employment of Iron-Binding Protein from Haemophilus influenzae in Functional Nanopipettes for Iron Monitoring
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-10-11
    Gonca Bulbul, Goksin Liu, Namrata Rao Vithalapur, Canan Atilgan, Zehra Sayers, Nader Pourmand

    Because of the serious neurologic consequences of iron deficiency and iron excess in the brain, the interest in the iron status of central nervous system has increased significantly in the last decade. While iron plays an important role in many physiological processes, its accumulation may lead to diseases such as Huntington's, Parkinson's and Alzheimer's. Therefore, it is important to develop methodologies that can monitor the presence of iron in a selective and sensitive manner. In this paper, we first showed the synthesis and characterization of the iron-binding protein (FBP) from Haemophillus influenzae, specific for the ferrous ions. Subsequently, we employed this protein in our nanopipette platform, and utilized it in functionalized nanoprobes to monitor the presence of ferrous ions. A suite of characterization techniques: absorbance spectroscopy, dynamic light scattering, and small-angle X-ray scattering were used for FBP. The functionalized Fe-nanoprobe calibrated in ferrous chloride enabled detection from 0.05 to 10 µM, and the specificity of the modified iron probe was evaluated by using various metal ion solutions.

    更新日期:2018-10-12
  • Pathological Changes of Tau Related to Alzheimer’s Disease
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-10-11
    Dandan Chu, Fei Liu

    Alzheimer’s disease (AD), the most common form of dementia, is characterized by extracellular-amyloid plaques (Aβ) and the intracellular neurofibrillary tangles (NFTs), which are considered as major targets of AD therapies. However, no effective therapy is available to cure or to prevent the progression of AD up to now. Accumulation of NFTs, which consist of abnormally hyperphosphorylated tau, is directly correlated with the degree of dementia in AD patients. Emerging evidences indicate that the prion-like seeding and spreading of tau pathology may be the key driver of AD. In the past decades, intensive understanding of tau pathway reveals new targets for the development of specific therapies. Here, we review the recent research progresses in the mechanism underlying tau pathology in AD, and briefly introduce tau-based therapeutics.

    更新日期:2018-10-12
  • Local GABAA Receptor-Mediated Suppression of Dopamine Release within the Nucleus Accumbens
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-10-10
    Zachary D. Brodnik, Aashita Batra, Erik B. Oleson, Rodrigo A. España
    更新日期:2018-10-11
  • KA-11, a Novel Pyrrolidine-2,5-dione Derived Broad-Spectrum Anticonvulsant: Its Antiepileptogenic, Antinociceptive Properties and in Vitro Characterization
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-10-10
    Katarzyna Socała, Szczepan Mogilski, Mateusz Pieróg, Dorota Nieoczym, Michał Abram, Bartłomiej Szulczyk, Annamaria Lubelska, Gniewomir Latacz, Urszula Doboszewska, Piotr Wlaź, Krzysztof Kamiński
    更新日期:2018-10-11
  • Anti-TTR Nanobodies allow the identification of TTR neuritogenic epitope associated to TTR-megalin neurotrophic activities
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-10-10
    Joao Gomes, Zsuzsa Sàrkàny, Anabela Teixeira, Renata Nogueira, Ines Cabrito, Hugo Soares, Angela Wittelsberger, Catelijne Stortelers, Sandra Macedo-Ribeiro, Peter Vanlandschoot, Maria João M. Saraiva

    Transthyretin (TTR) has intrinsic neurotrophic physiological activities independent from its thyroxine ligands, which involve activation of signalling pathways through interaction with megalin. Still, the megalin binding motif on TTR is unknown. Nanobodies (Nb) have the ability to bind “hard to reach” epitopes being useful tools for protein/structure function. In this work we characterize two anti-TTR Nanobodies, with similar mouse TTR binding affinities, although only one is able to block its neuritogenic activity (169F7_Nb). Through epitope mapping we identified amino acids 14-18, at the entrance of the TTR central channel, to be important for interaction with megalin, and a stable TTR K15N mutant in that region was constructed. The TTR K15N mutant lacks neuritogenic activity indicating that K15 is critical for TTR neuritogenic activity. Thus, we identify the putative binding site for megalin and describe two Nanobodies that will allow research and clarification of TTR physiological properties, regarding its neurotrophic effects.

    更新日期:2018-10-11
  • Design, Synthesis and Pharmacological Characterization of Carbazole Based Dopamine Agonists as Potential Symptomatic and Neuroprotective Therapeutic Agents for Parkinson’s Disease
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-10-09
    Asma Elmabruk, Banibrata Das, DEEPTHI YEDLAPUDI, Liping Xu, Tamara Antonio, Maarten E.A. Reith, Aloke K. Dutta

    We have developed a series of carbazole-derived compounds based on our hybrid D2/D3 agonist template to design multifunctional compounds for the symptomatic and disease-modifying treatment of Parkinson’s disease (PD). The lead molecules (-)-11b, (-)-15a and (-)-15c exhibited high affinity for both D2 and D3 receptors where as in GTPγS functional assay, the compounds showed potent agonist activity at both D2 and D3 receptors (EC50 (GTPγS); D2 = 48.7 nM, D3 = 0.96 nM for 11b, D2 = 0.87 nM, D3 = 0.23 nM for 15a and D2 = 2.29 nM, D3 = 0.22 nM for 15c). In PD animal model study, the test compounds exhibited potent in vivo activity in reversing hypolocomotion in reserpinized rats with a long duration of action compared to the reference drug. In a cellular antioxidant assay, compounds (-)-11b, (-)-15a and (-)-15c exhibited potent activity in reducing oxidative stress induced by neurotoxin 6-hydroxydopamine (6-OHDA). Also, in a cell-based PD neuroprotection model, these lead compounds significantly increased cell survival from toxicity of 6-OHDA, thereby, producing neuroprotection effect. Additionally, compounds D636 and D653 inhibited aggregation and reduced toxicity of recombinant alpha synuclein protein in a cell based in vitro assays. These observations suggest that the lead carbazole-based dopamine agonists may be promising multifunctional molecules for a viable symptomatic and disease modifying therapy of PD and should be further investigated.

    更新日期:2018-10-10
  • DARK Classics in Chemical Neuroscience: Ibogaine
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-10-09
    Michael J. Wasko, Paula A. Witt-Enderby, Christopher K. Surratt
    更新日期:2018-10-09
  • 4,6-Diphenylpyrimidine Derivatives as Dual Inhibitors of Monoamine Oxidase and Acetylcholinesterase for the Treatment of Alzheimer’s Disease
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-10-08
    Bhupinder Kumar, Ashish Ranjan Dwivedi, Bibekananda Sarkar, Sukesh Kumar Gupta, Sairam Krishnamurthy, Anil K Mantha, Jyoti Prakash, Vinod Kumar

    Alzheimer’s disease (AD) is a neurodegenerative disorder with multifactorial pathogenesis. Monoamine oxidase (MAO) and acetylcholinesterase enzymes (AChE) are potential targets for the treatment of AD. A total of 15 new propargyl containing 4,6-diphenylpyrimidine derivatives were synthesized and screened for the MAO and AChE inhibition activities along with ROS production inhibition and metal chelation potential. All the synthesized compounds were found selective and potent inhibitors of MAO-A and AChE enzymes at nano molar concentrations. VB1 was found to be the most potent MAO-A and BuChE inhibitor with IC50 values of 18.34 ± 0.38 nM and 0.666 ± 0.03 μM, respectively. It also showed potent AChE inhibition with IC50 value of 30.46 ± 0.23 nM. Compound VB8 was found to be the most potent AChE inhibitor with IC50 value of 9.54 ± 0.07 nM and displayed IC50 value of 1010 ± 70.42 nM against MAO-A isoform. In the cytotoxic studies, these compounds were found non-toxic to the human neuroblastoma SH-SY5Y cells even at 25 μM concentration. All the compounds were found reversible inhibitors of MAO-A and AChE enzymes. In addition, these compounds also showed good neuroprotective properties against 6-OHDA and H2O2 induced neurotoxicity in SH-SY5Y cells. All the compounds accommodate nicely to the hydrophobic cavity of MAO-A and AChE enzymes. In the molecular dynamics simulation studies, both VB1 and VB8 were found stable in the respective cavities for 30 ns. Thus, 4,6-diphenylpyrimidine derivatives can act as promising leads in the development of dual acting inhibitors targeting MAO-A and AChE enzymes for the treatment of Alzheimer’s disease.

    更新日期:2018-10-09
  • Conformational-switch based Strategy Triggered by [18] Heteroannulenes towards Reduction of Alpha Synuclein (α-Syn) Oligomer Toxicity
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-10-08
    Ritobrita Chakraborty, Sumit Sahoo, Nyancy Halder, Harapriya Rath, Krishnananda Chattopadhyay

    Two water soluble meso-carboxy aryl substituted [18] heteroannulenes (porphyrins) and its Zn-complex have been found to be viable in targeting α-Syn aggregation at all its key micro-events, namely, primary nucleation, fibril elongation and secondary nucleation, by converting the highly heterogeneous and cytotoxic aggresome into a homogeneous population of minimally toxic off-pathway oligomers, that remained hitherto unexplored till date. With the EC50 and dissociation constants in the low micromolar range, these heteroannulenes induce a switch in the secondary structure of toxic prefibrillar on-pathway oligomers of α-Syn converting them into minimally toxic non-seeding off-pathway oligomers. The inhibition of the aggregation and the reduction of toxicity have been studied in vitro as well as inside neuroblastoma cells.

    更新日期:2018-10-09
  • DARK Classics in Chemical Neuroscience: Opium, a Historical Perspective
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-10-08
    Christopher C. Presley, Craig W. Lindsley
    更新日期:2018-10-08
  • Induction of Oxidative Stress and Cell Death in Neural Cells by Silica Nanoparticles
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-10-05
    Yuji Kamikubo, Tomohito Yamana, Yoshie Hashimoto, Takashi Sakurai
    更新日期:2018-10-06
  • DARK Classics in Chemical Neuroscience: Aminorex Analogues
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-10-05
    Julian Maier, Felix P. Mayer, Simon D. Brandt, Harald H. Sitte
    更新日期:2018-10-06
  • Real-time accumbal dopamine response to negative stimuli: Effects of ethanol
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-10-05
    Maria A Mikhailova, Alex Deal, Valentina P Grinevich, Keith D. Bonin, Raul R Gainetdinov, Evgeny A Budygin

    Activity in the mesolimbic dopamine (DA) pathway is known to have a role in reward processing and related behaviors. The mesolimbic DA response to reward has been well-examined, while the response to aversive or negative stimuli has been studied to a lesser extent and produced inconclusive results. However, a brief increase in the DA concentration in terminals during nociceptive activation has become an established but not well-characterized phenomenon. Consequently, the interpretation of the significance of this neurochemical response is still illusive. The present study was designed to further explore these increases in subsecond DA dynamics triggered by negative stimuli, using voltammetry in anesthetized rats. Our experiments revealed that repeated exposure to a tail pinch resulted in more efficacious DA release in rat nucleus accumbens. This fact may suggest a protective nature of immediate DA efflux. Furthermore, a sensitized DA response to a neutral stimulus, such as a touch, was discovered following several noxious pinches, while a touch applied before these pinches did not trigger DA release. Finally, it was found that the pinch-evoked DA efflux was significantly decreased by ethanol acutely administrated at an analgesic dose. Taken together, these results support the hypothesis that subsecond DA release in the nucleus accumbens may serve as an endogenous antinociceptive signal.

    更新日期:2018-10-06
  • Gene dysfunction mediates immune response to Dopaminergic degeneration in Parkinson’s disease
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-10-05
    Zhigang Jiao, Wenlong Zhang, Chaojun Chen, Xiaoqin Zhu, Xiang Chen, Miaomiao Zhou, Guoyou Peng, Hanqun Liu, Jiewen Qiu, Yuwan Lin, Shuxuan Huang, Mingshu Mo, Xinling Yang, Shaogang Qu, Pingyi Xu

    Many publications reported the genetic dysfunction mediates abnormal immune responses in brain, which is important for the development of neurodegenerative diseases, especially for Parkinson disease (PD). This immune disorder resulted in the subsequent inflammatory reaction which stimulates microglia or other immune cells to secrete cytokines and chemokines, disturbs the proportion of peripheral blood lymphocyte subsets contributing to Dopaminergic (DA) neuron apoptosis. Furthermore, the abnormal immune related signal pathways caused by genetic variants promotes chronic inflammatory to destroy the blood-brain barrier, which infiltrates different molecules and blood cells into the central nervous system (CNS) and exert neural toxicity on DA neurons. As a result, the inflammatory reaction in CNS accelerates the progression of Parkinson diseases and promotes α-synuclein aggregation and diffusion among DA neurons in the procession of Parkinson disease. Thus, for disease evaluation, the genetic mediated abnormal immune response in PD may be assessed on the multiple immune molecules, inflammatory factors, as well as the ratio of lymphocyte subsets from PD patient’s peripheral blood as potential biomarkers.

    更新日期:2018-10-06
  • Alpha-7 Nicotinic Receptor-Targeted Cinobufagin Induces Antinociception and Inhibits NF-κB Signaling Pathway in DRG Neurons
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-10-05
    Longsheng Xu, Xiaoping Zhang, Qingli Feng, Ying Zheng, Huadong Ni, Hui Shen, Ming Yao
    更新日期:2018-10-05
  • FAAH-Catalyzed C–C Bond Cleavage of a New Multitarget Analgesic Drug
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-10-04
    Alessia Ligresti, Cristoforo Silvestri, Rosa Maria Vitale, Jose L. Martos, Fabiana Piscitelli, Jenny W. Wang, Marco Allarà, Robert W. Carling, Livio Luongo, Francesca Guida, Anna Illiano, Angela Amoresano, Sabatino Maione, Pietro Amodeo, David F. Woodward, Vincenzo Di Marzo, Gennaro Marino
    更新日期:2018-10-04
  • Nanotechnology in Neuroscience Reveals Membrane Mobility Matters
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-10-04
    Sandra J. Rosenthal
    更新日期:2018-10-04
  • Surface Fouling of Ultrananocrystalline Diamond Microelectrodes During Dopamine Detection: Improving Lifetime Via Electrochemical Cycling
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-10-04
    An-Yi Chang, Gaurab Dutta, Shabnam Siddiqui, Prabhu Arumugam

    In this work, we report the electrochemical response of a boron-doped ultrananocrystalline diamond (BDUNCD) microelectrode during long-term dopamine (DA) detection. Specifically, changes to its electrochemical activity and electroactive area due to DA-by products and surface oxidation are studied via scanning electron microscopy, energy dispersive spectroscopy, electrochemical impedance spectroscopy and silver deposition imaging (SDI). The fouling studies with amperometry (AM) and fast scan cyclic voltammetry (FSCV) methods suggest that the microelectrodes are heavily fouled due to poor DA-dopamine-o-quinone cyclization rates followed by a combination of polymer formation and major changes in their surface chemistry. SDI data confirms the presence of the insulating polymer with sparsely-distributed tiny electroactive regions. This resulted in severely distorted DA signals and a 90% loss in signal starting as early as 3 hrs for AM and a 56% loss at 6.5 hrs for FSCV. This underscores the need for cleaning of the fouled microelectrodes if they have to be used long-term. Out of the three in vivo suitable electrochemical cycling cleaning waveforms investigated, the standard waveform (−0.4 V to +1.0 V) provides the best cleaned surface with a fully retained voltammogram shape, no hysteresis, no DA signal loss (a 90±0.72 nA increase) and the smallest charge transfer resistance value of 0.4±0.02 MΩ even after 6.5 hrs of monitoring. Most importantly, this is the same waveform that is widely used for in vivo detection with carbon fiber microelectrodes. Future work to test these microelectrodes for more than 24 hrs of DA detection is anticipated.

    更新日期:2018-10-04
  • Chronic social isolation stress during peri-adolescence alters presynaptic dopamine terminal dynamics via augmentation in accumbal dopamine availability
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-10-04
    Anushree N Karkhanis, Amy C. Leach, Jordan T Yorgason, Ayse Uneri, Samuel Barth, Farr Niere, Nancy J Alexander, J. L. Weiner, Brian A McCool, Kimberly F Raab-Graham, Mark John Ferris, Sara R Jones

    Chronic peri-adolescent stress in humans increases risk to develop a substance use disorder during adulthood. Rats reared in social isolation during peri-adolescence (aSI; 1 rat/cage) period, show greater ethanol and cocaine intake compared to group housed (aGH; 4 rats/cage) rats. In addition, aSI rats have a heightened dopamine response in the nucleus accumbens (NAc) to rewarding and aversive stimuli. Furthermore, single pulse electrical stimulation in slices containing NAc core elicits greater dopamine release in aSI rats. Here, we further investigated dopamine release kinetics and machinery following aSI. Dopamine release, across a wide range of stimulation intensities and frequencies, was significantly greater in aSI rats. Interestingly, subthreshold intensity stimulations also resulted in measurable dopamine release in accumbal slices from aSI, but not aGH rats. Extracellular [Ca+2] manipulations revealed augmented calcium sensitivity of dopamine release in aSI rats. The readily releasable pools of dopamine, examined by bath application of Ro-04-1284/000, a VMAT2 inhibitor, were depleted faster in aGH rats. Western blot analysis of release machinery proteins (VMAT2, Synaptogyrin-3, Syntaxin-1, and Munc13-3) showed no difference between the two groups. Tyrosine hydroxylase (TH) protein expression levels however, were elevated in aSI rats. The greater dopamine release could potentially be explained by higher levels of TH, the rate-limiting step for dopamine synthesis. This augmented responsivity of the dopamine system and heightened dopamine availability post-aSI may lead to an increased risk of addiction vulnerability.

    更新日期:2018-10-04
  • The Muscarinic Acetylcholine Receptor M5: Therapeutic Implications and Allosteric Modulation
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-10-03
    Aaron M. Bender, Aaron T Garrison, Craig W Lindsley

    The muscarinic acetylcholine receptor (mAChR) subtype 5 (M5) was the most recent mAChR to be cloned, and has since emerged as a potential therapeutic target for a number of indications. Early studies with knockout animals have provided clues to the receptor’s role in physiological processes related to Alzheimer’s disease, schizophrenia and addiction, and until recently, useful subtype-selective tools to further probe the pharmacology of M5 have remained elusive. Small molecule allosteric modulators have since gained traction as a means by which to selectively examine muscarinic pharmacology. This review will highlight the discovery and optimization of M5 positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs).

    更新日期:2018-10-03
  • Mechanistic insight into the binding profile of DCVJ and α-synuclein fibril revealed by multi-scale simulations
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-10-02
    Guanglin Kuang, Hans Arvid Ågren, N. Arul Murugan

    Parkinson’s disease (PD) is a serious neurodegenerative disease and is characterized by abnormal α-synuclein (α-syn) accumulation in Lewy bodies (LB) and Lewy neurites (LN), which makes α-syn an important imaging target for PD. An imaging probe that quantifies fibrillar α-syn can enhance the clinical diagnosis of PD and can also be used to evaluate the efficacy of therapeutics aimed at reducing the abnormal aggregation of the α-syn fibril in the brain. In this paper, we studied the binding profile of fibrillar α-syn with a fluorescent probe DCVJ, which is being explored for identifying α-syn imaging agents. A multi-scale simulation workflow including molecular docking, molecular dynamics, metadynamics, and QM/MM calculations was implemented. We find that DCVJ can bind to multiple sites of α-syn which are located either at the surface or in the core. Free energy calculations using implicit solvent models reveal that the most favourable binding mode for DCVJ is associated with the core binding site and is further confirmed by metadyamics simulation. Besides, a dynamic binding pathway is discovered, which reveals that DCVJ binds gradually into the core of the fibril passing through several intermediate states. The conformational arrest of the dicyano vinyl group in the fibrillar environment could explain the reason behind the fibril-specific fluorescence of DCVJ. Furthermore, based on hybrid QM/MM calculations, the molecular geometry of the dicyano vinyl group is found to be environment specific which explains why DCVJ serves as a staining agent for such fibrillar-like environments. Our results could be helpful for elucidating the binding mechanism of imaging tracers with the fibrillar form of α-syn and explain their fibrillar-specific optical properties, a knowledge that in turn can be used to guide the design and development of compounds with higher affinity and selectivity for α-syn using structure-based strategies.

    更新日期:2018-10-03
  • SLC30A10 mutation involved in parkinsonism results in manganese accumulation within nano-vesicles of the Golgi apparatus
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-10-01
    Asuncion Carmona, Charles E Zogzas, Stephane Roudeau, Francesco Porcaro, Jan Garrevoet, Kathryn Spiers, Murielle Salome, Peter Cloetens, Somshuvra Mukhopadhyay, Richard Ortega

    Manganese (Mn) is an essential metal that can be neurotoxic when elevated exposition occurs leading to parkinsonian-like syndromes. Mutations in the Slc30a10 gene have been identified in new forms of familial parkinsonism. SLC30A10 is a cell surface protein involved in the efflux of Mn protecting the cell against Mn toxicity. Disease causing mutations block the efflux activity of SLC30A10, resulting in Mn accumulation. Determining the intracellular localization of Mn when disease-causing SLC30A10 mutants are expressed is essential to elucidate the mechanisms of Mn neurotoxicity. Here, using organelle fluorescence microscopy and synchrotron X-ray fluorescence (SXRF) imaging we found that Mn accumulates in the Golgi apparatus of human cells transfected with the disease-causing SLC30A10-Δ105-107 mutant under physiological conditions and after exposure to Mn. In cells expressing the wild-type SLC30A10 protein, cellular Mn content was low after all exposure conditions, confirming efficient Mn efflux. In non-transfected cells that do not express endogenous SLC30A10, and in mock transfected cells, Mn was located in the Golgi apparatus, similarly to its distribution in cells expressing the mutant protein, confirming deficient Mn efflux. The newly developed SXRF cryogenic nano-imaging (<50 nm resolution) indicated that Mn was trapped in single vesicles within the Golgi apparatus. Our results confirm the role of SLC30A10 in Mn efflux and the accumulation of Mn in cells expressing the disease causing SLC30A10-Δ105-107 mutation. Moreover, we identified sub-organelle Golgi nano-vesicles as the main compartment of Mn accumulation in SLC30A10 mutants suggesting interactions with the vesicular trafficking machinery as a cause of the disease.

    更新日期:2018-10-02
  • 更新日期:2018-10-01
  • 更新日期:2018-09-29
  • Increased Cholinergic Response in α-Synuclein Transgenic Mice (h-α-synL62)
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-09-28
    Magdalena König, Beata Berlin, Karima Schwab, Silke Frahm, Franz Theuring, Claude M. Wischik, Charles R. Harrington, Gernot Riedel, Jochen Klein
    更新日期:2018-09-29
  • Reliability of docking-based virtual screening for GPCR ligands with homology modeled structures: a case study of angiotensin II type I receptor
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-09-28
    Haiyi Chen, Weitao Fu, Zhe Wang, Xuwen Wang, Tailong Lei, Feng Zhu, Dan Li, Shan Chang, Lei Xu, Tingjun Hou

    The number of solved G protein-coupled receptor (GPCR) crystal structures has expanded rapidly, but most GPCR structures remain unsolved. Therefore, computational techniques, such as homology modeling, have been widely used to produce the theoretical structures of various GPCRs for structure-based drug design (SBDD). Due to the low sequence similarity shared by the transmembrane domains of GPCRs, accurate prediction of GPCR structures by homology modeling is quite challenging. In this study, angiotensin II type I receptor (AT1R) was taken as a typical case to assess the reliability of class A GPCRs homology models for SBDD. Four homology models of angiotensin II type I receptor (AT1R) at the inactive state were built based on the crystal structures of CXCR4 chemokine receptor, CCR5 chemokine receptor and δ-opioid receptor, and refined through molecular dynamics (MD) simulations and induced fit docking, to allow for backbone and side-chain flexibility. Then, the quality of the homology models was assessed relative to the crystal structures in terms of two criteria commonly-used in SBDD: prediction accuracy of ligand binding poses and screening power of docking-based virtual screening. It was found that the crystal structures outperformed the homology models prior to any refinement in both assessments. MD simulations could generally improve the docking results for both the crystal structures and homology models. Moreover, the optimized homology model refined by MD simulations and induce fit docking even shows similar performance of docking assessment to the crystal structures. Our results indicate that it is possible to establish a reliable class A GPCR homology model for SBDD through the refinement by integrating multiple molecular modeling techniques.

    更新日期:2018-09-29
  • Stress-Induced Alterations of Norepinephrine Release in the Bed Nucleus of the Stria Terminalis of Mice
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-09-28
    Karl T. Schmidt, Viren H. Makhijani, Kristen M. Boyt, Elizabeth S. Cogan, Dipanwita Pati, Melanie M. Pina, Isabel M. Bravo, Jason L. Locke, Sara R. Jones, Joyce Besheer, Zoé A. McElligott
    更新日期:2018-09-28
  • Studies on the Activity of Selected Highly Lipophilic Compounds toward hGAT1 Inhibition. Part II
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-09-28
    Alicja Nowaczyk, Łukasz Fijałkowski, Magdalena Kowalska, Adrian Podkowa, Kinga Sałat
    更新日期:2018-09-28
  • Study of Electrical Stimulation with Different Electric-Field Intensities in the Regulation of the Differentiation of PC12 Cells
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-09-27
    Wei Jing, Yifan Zhang, Qing Cai, Guoqiang Chen, Lin Wang, Xiaoping Yang, Weihong Zhong
    更新日期:2018-09-27
  • A focused library of psychotropic analogs with neuroprotective and neuroregenerative potential
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-09-25
    Elisa Uliassi, Luis Emiliano Peña-Altamira, Aixa V. Morales, Francesca Massenzio, Sabrina Petralla, Michele Rossi, Marinella Roberti, Loreto Martínez-González, Ana Martínez, Barbara Monti, Maria Laura Bolognesi

    Overcoming the lack of effective treatments and the continuous clinical trial failures in neurodegenerative drug discovery might require a shift from the prevailing paradigm targeting pathogenesis to the one targeting simultaneously neuroprotection and neuroregeneration. In the studies reported herein, we sought to identify small molecules that might exert neuroprotective and neuroregenerative potential as tools against neurodegenerative diseases. In doing so, we started from the reported neuroprotective/neuroregenerative mechanisms of psychotropic drugs featuring a tricyclic alkylamine scaffold. Thus, we designed a focused-chemical library of 36 entries aimed at exploring the structural requirements for efficient neuroprotective/neuroregenerative cellular activity, without the manifestation of toxicity. To this aim, we developed a synthetic protocol which overcame the limited applicability of previously reported procedures. Next, we evaluated the synthesized compounds through a phenotypic screening pipeline, based on primary neuronal systems. Phenothiazine 2Bc showed improved neuroregenerative and neuroprotective properties with respect to reference drug desipramine (2Aa). Importantly, we have also shown that 2Bc outperformed currently available drugs in cell models of Alzheimer's and Parkinson's diseases and attenuates microglial activation by reducing iNOS expression.

    更新日期:2018-09-26
  • Caffeine modulates spontaneous adenosine and oxygen changes during ischemia and reperfusion
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-09-25
    Ying Wang, B. Jill Venton

    Adenosine is an endogenous neuroprotectant that modulates vasodilation in the central nervous system. Oxygen changes occur when there is an increase in local cerebral blood flow and thus are a measure of vasodilation. Transient oxygen events following rapid adenosine events have been recently discovered, but the relationship between adenosine and blood flow change during ischemia/reperfusion (I/R) has not been characterized. Caffeine is a nonselective adenosine receptor antagonist that can modulate the effects of adenosine in the brain, but how it affects adenosine and oxygen levels during I/R is also unknown. In this study, extracellular changes in adenosine and oxygen were simultaneously monitored using fast-scan cyclic voltammetry during bilateral common carotid artery occlusion (BCCAO) and the effects of a specific A2A antagonist, SCH 442416, or general antagonist, caffeine, were studied. Measurements were made in the caudate-putamen for one hour of normoxia, followed by 30 min of BCCAO and 30 min of reperfusion. The frequency and number of both adenosine and oxygen transient events significantly increased during I/R. The specific A2A antagonist, SCH 442416 (3 mg/kg, i.p.), eliminated the increase in adenosine and oxygen events caused by I/R. The general adenosine receptor antagonist, caffeine (100 mg/kg, i.p.), decreased the frequency of adenosine and oxygen transient events during I/R. These results demonstrate that during BCCAO, there are more rapid release events of the neuromodulator adenosine and correlated local oxygen changes, and these rapid, local effects are dampened by caffeine and other A2A antagonists.

    更新日期:2018-09-26
  • Computationally Guided Identification of Allosteric Agonists of the Metabotropic Glutamate 7 Receptor
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-09-25
    Jose María Cid, Hilde Lavreysen, Gary Tresadern, Laura Pérez-Benito, Fulgencio Tovar, Alberto Fontana, Andrés A. Trabanco
    更新日期:2018-09-25
  • Understanding CNS effects of deliriant hallucinogenic drugs through experimental animal models
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-09-25
    Andrey D. Volgin, Oleg V. Yakovlev, Konstantin A. Demin, Polina A. Alekseeva, Evan Kyzar, Christopher Collins, David E. Nichols, Allan Kalueff

    Hallucinogenic drugs potently alter human behavior and have a millennia-long history of use for medicinal and religious purposes. Interest is rapidly growing in their potential as CNS modulators and therapeutic agents for brain conditions. Anti-muscarinic cholinergic drugs, such as atropine and scopolamine, induce characteristic hyperactivity and dream-like hallucinations, and form a separate, group of hallucinogens known as ‘deliriants’. Although atropine and scopolamine are relatively well-studied drugs in cholinergic physiology, deliriants represent the least-studied class of hallucinogens in terms of their behavioral and neurological phenotypes. As such, novel approaches and new model organisms are needed to investigate the CNS effects of these compounds. Here, we comprehensively evaluate the preclinical effects of deliriant hallucinogens in various animal models, their mechanisms of action and potential interplay with other signaling pathways. We also parallel experimental and clinical findings on deliriant agents and outline future directions of translational research in this field.

    更新日期:2018-09-25
  • Bypassing Glutamic Acid Decarboxylase 1 (Gad1) Induced Craniofacial Defects with a Photoactivatable Translation Blocker Morpholino
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-09-24
    Matthew J. O’Connor, Lindsey L. Beebe, Davide Deodato, Rebecca E. Ball, A. Tyler Page, Ariel J. VanLeuven, Kyle T. Harris, Sungdae Park, Vani Hariharan, James D. Lauderdale, Timothy M. Dore
    更新日期:2018-09-25
  • Acetate Mediates Alcohol Excitotoxicity in Dopaminergic-Like PC12 Cells
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-09-24
    Andrew D. Chapp, Jessica E. Behnke, Kyle M. Driscoll, Yuanyuan Fan, Eileen Hoban, Zhiying Shan, Li Zhang, Qing-Hui Chen

    Neuronal excitotoxicity is the major cause of alcohol-related brain damage, yet the underlying mechanism remains poorly understood. Using dopaminergic like PC12 cells, we evaluated the effect of N-methyl-D-aspartate receptors (NMDAR) on acetate induced changes in PC12 cells: cell death, cytosolic calcium and expression levels of the pro-inflammatory cytokine, tumor necrosis factor alpha (TNFα). Treatment of PC12 cells with increasing concentrations of acetate for 4 hrs caused a dose-dependent increase in percent of cells staining positive for cell death using propidium iodide (PI) exclusion, and cytosolic reactive oxygen species (ROS) using Cell ROX detection, analyzed via flow cytometry. The EC50 value for acetate was calculated and found to be 4.40 mM for PI and 1.81 for ROS. Ethanol up to 100 mM had no apparent changes in the percent of cells staining positive for PI or ROS. Acetate (6 mM) treatment caused an increase in cytosolic calcium measured in real-time with Fluo-4AM which was abolished by co-application with NMDAR blocker, memantine (10 μM). Furthermore, cells treated with acetate (6 mM) for 4 hrs had increased expression levels of TNFα relative to control which was abolished by co-application of memantine (10 μM). Co-application of acetate (6 mM) and memantine had no apparent reduction in acetate induced cell death. These findings suggest that acetate is capable of increasing cytosolic calcium concentrations and expression levels of the pro-inflammatory cytokine TNFα through an NMDAR-dependent mechanism. Cell death from acetate was not reduced through NMDAR blockade, suggesting alternative pathways independent of NMDAR activation for excitotoxicity.

    更新日期:2018-09-25
  • 更新日期:2018-09-21
  • Diarylureas Containing 5-Membered Heterocycles as CB1 Receptor Allosteric Modulators: Design, Synthesis, and Pharmacological Evaluation
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-09-20
    Thuy Nguyen, Thomas F. Gamage, Ann M. Decker, Nadezhda German, Tiffany L. Langston, Charlotte E. Farquhar, Terry P. Kenakin, Jenny L. Wiley, Brian F. Thomas, Yanan Zhang
    更新日期:2018-09-20
  • Alpha-Synuclein Nitration and Its Implications in Parkinson’s Disease
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-09-17
    Yixi He, Zhongwang Yu, Shengdi Chen
    更新日期:2018-09-17
  • In Vivo Use of a Multi-DNA Aptamer-Based Payload/Targeting System To Study Dopamine Dysregulation in the Central Nervous System
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-09-17
    Erin M. McConnell, Katelyn Ventura, Zach Dwyer, Vernon Hunt, Anna Koudrina, Matthew R. Holahan, Maria C. DeRosa
    更新日期:2018-09-17
  • Huntingtin’s N-Terminus Rearrangements in the Presence of Membranes: A Joint Spectroscopic and Computational Perspective
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-09-17
    Geraldine R. Levy, Koning Shen, Yulian Gavrilov, Pieter E. S. Smith, Yaakov Levy, Rebecca Chan, Judith Frydman, Lucio Frydman
    更新日期:2018-09-17
  • 更新日期:2018-09-17
  • Synthesis and Biological Evaluation of Fentanyl Analogues Modified at Phenyl Groups with Alkyls
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-09-14
    Yajuan Qin, Luofan Ni, Jiawei Shi, Zhiying Zhu, Saijian Shi, Ai-leen Lam, Julia Magiera, Sunderajhan Sekar, Andy Kuo, Maree T. Smith, Tingyou Li
    更新日期:2018-09-14
  • Discovery and Characterization of VU0529331, a Synthetic Small-Molecule Activator of Homomeric G Protein-Gated, Inwardly Rectifying, Potassium (GIRK) Channels
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-09-13
    Krystian A. Kozek, Yu Du, Swagat Sharma, Francis J. Prael, Brittany D. Spitznagel, Sujay V. Kharade, Jerod S. Denton, Corey R. Hopkins, C. David Weaver
    更新日期:2018-09-14
  • Discrepancies in kappa opioid agonist binding revealed through PET imaging
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-09-13
    Michael Stephen Placzek, Frederick A. Schroeder, Tao Che, Hsiao-Ying Wey, Ramesh Neelamegam, Changning Wang, Bryan L Roth, Jacob M. Hooker

    Kappa opioid receptor (KOR) modulation has been pursued in many conceptual frameworks for the treatment of human pain, depression and anxiety. As such, several imaging tools have been developed to characterize the density of KORs in the human brain and its occupancy by exogenous drug-like compounds. While exploring the pharmacology of KOR tool compounds using positron emission tomography (PET), we observed discrepancies in the apparent competition binding as measured by changes in binding potential (BPND). This prompted us to systematically look at the relationships between baseline BPND maps for three common KOR PET radioligands, the antagonists [11C]LY2795050 and [11C]LY2459989, and the agonist [11C]GR103545. We then measured changes in BPND using kappa antagonists (naloxone, naltrexone, LY2795050, JDTic, nor-BNI), and found BPND was affected similarly between [11C]GR103545 and [11C]LY2459989. Longitudinal PET studies with nor-BNI and JDTic were also examined and we observed a persistent decrease in [11C]GR103545 BPND up to 25 days after drug administration for both nor-BNI and JDTic. Kappa agonists were also administered, and butorphan and GR89696 (racemic GR103545) impacted binding to comparable levels between the two radiotracers. Of greatest significance, kappa agonists salvinorin A and U-50488 caused dramatic reductions in [11C]GR103545 BPND but did not change [11C]LY2459989 binding. This discrepancy was further examined in dose response studies with each radiotracer as well as in vitro binding experiments.

    更新日期:2018-09-14
  • Interactions of Selective Serotonin Reuptake Inhibitors with β-Amyloid
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-09-11
    Gary Tin, Tarek Mohamed, Arash Shakeri, Amy Trinh Pham, Praveen P. N. Rao
    更新日期:2018-09-12
  • 更新日期:2018-09-12
  • 更新日期:2018-09-12
  • Mapping the Orthosteric Binding Site of the Human 5-HT3 Receptor Using Photo-cross-linking Antagonists
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-09-11
    Thomas Jack, Michele Leuenberger, Marc-David Ruepp, Sanjeev Kumar V. Vernekar, Andrew J. Thompson, Sophie Braga-Lagache, Manfred Heller, Martin Lochner
    更新日期:2018-09-11
  • Microdialysis Unveils the Role of the α2-Adrenergic System in the Basolateral Amygdala during Acquisition of Conditioned Odor Aversion in the Rat
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-09-10
    Lucile Estrade, Jean-Christophe Cassel, Sandrine Parrot, Patricia Duchamp-Viret, Barbara Ferry
    更新日期:2018-09-11
  • Importance of Theranostics in Rare Brain-Eating Amoebae Infections
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-09-10
    Ayaz Anwar, Ruqaiyyah Siddiqui, Naveed Ahmed Khan
    更新日期:2018-09-11
  • Classics in Neuroimaging: Radioligands for the Vesicular Monoamine Transporter 2
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-09-10
    Michael R. Kilbourn, Robert A. Koeppe

    Positron emission tomography (PET) studies of the monoamine neurotransmitter systems in the human brain employ a variety of radiotracers targeting the many receptors, transporters, and enzymes present in monoaminergic neurons. One of these is the vesicular monoamine transporter 2 (VMAT2), the protein responsible for the energy-dependent accumulation of monoamines into synaptic vesicles. The development of in vivo imaging radiotracers for VMAT2 is a story of starting with a well-characterized clinically used drug (tetrabenazine) which had a pharmacologically active metabolite: that metabolite that was in stepwise fashion refined and modified to provide both carbon-11 and fluorine-18 labeled VMAT2 radiotracers that are now used for human PET studies of neurodegenerative and psychiatric diseases. The design approach taken, which involved understanding the metabolism of the radiotracers and identification of the optimal ligand stereochemistry, are representative of important steps in the general concepts behind successful in vivo radiotracer design for brain imaging agents.

    更新日期:2018-09-11
  • Arsenic Exposure Contributes to the Bioenergetic Damage in an Alzheimer’s Disease Model
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-09-10
    Sandra Aurora Niño, Adriana Morales-Martínez, Erika Chi-Ahumada, Leticia Carrizales, Roberto Salgado-Delgado, Francisca Pérez-Severiano, Sofía Díaz-Cintra, María E. Jiménez-Capdeville, Sergio Zarazúa
    更新日期:2018-09-10
  • 更新日期:2018-09-07
  • Pharmacology and Therapeutic Potential of the 5-HT7 Receptor
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-09-04
    Kevin M. Blattner, Daniel J. Canney, Douglas A. Pippin, Benjamin E. Blass
    更新日期:2018-09-05
  • N-Methyl-d-aspartate Receptor Antibody Encephalitis: A Concise Review of the Disorder, Diagnosis, and Management
    ACS Chem. Neurosci. (IF 4.211) Pub Date : 2018-08-31
    Elizabeth M. Staley, Rabia Jamy, Allan Q. Phan, David A. Figge, Huy P. Pham
    更新日期:2018-09-01
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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