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  • 更新日期:2017-11-19
  • Higher Aminopeptidase Activity Determined by Electroosmotic Push–Pull Perfusion Contributes to Selective Vulnerability of the Hippocampal CA1 Region to Oxygen Glucose Deprivation
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-11-16
    Yangguang Ou, Stephen G. Weber

    It has been known for over a century that the hippocampus, the center for learning and memory in the brain, is selectively vulnerable to ischemic damage, with the CA1 being more vulnerable than the CA3. It is also known that leucine enkephalin, or YGGFL, is neuroprotective. We hypothesized that the extracellular hydrolysis of YGGFL may be greater in the CA1 than the CA3, which would lead to the observed difference in susceptibility to ischemia. In rat organotypic hippocampal slice cultures, we estimated the Michaelis constant and the maximum velocity for membrane-bound aminopeptidase activity in the CA1 and CA3 regions. Using electroosmotic push–pull perfusion and offline capillary liquid chromatography, we inferred enzyme activity based on the production rate of GGFL, a natural and inactive product of the enzymatic hydrolysis of YGGFL. We found nearly 3-fold higher aminopeptidase activity in the CA1 than the CA3. The aminopeptidase inhibitor bestatin significantly reduced hydrolysis of YGGFL in both regions by increasing apparent Km. Based on propidium iodide cell death measurements 24 h after oxygen–glucose deprivation, we demonstrate that inhibition of aminopeptidase activity using bestatin selectively protected CA1 against delayed cell death due to oxygen–glucose deprivation and that this neuroprotection occurs through enkephalin-dependent pathways.

    更新日期:2017-11-17
  • Identification of novel allosteric modulators of glutamate transporter EAAT2
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-11-15
    Sandhya Kortagere, Ole Valente Mortensen, Jingsheng Xia, William Lester, Yuhong Fang, Yellamelli V. V. Srikanth, Joseph M. Salvino, Andreia Cristina Karklin Fontana

    Dysfunction of excitatory amino acid transporters (EAATs) has been implicated in the pathogenesis of various neurological disorders, such as stroke, brain trauma, epilepsyand neurodegenerative diseases among others. EAAT2 is the main subtype responsible for glutamate clearance in the brain, having a key role in regulating transmission and preventing excitotoxicity. Therefore, compounds that increase the expression or activity of EAAT2 have therapeutic potential for neuroprotection. Previous studies identified molecular determinants for EAAT2 transport stimulation in a structural domain that lies at the interface of the rigid trimerization domain and the central substrate binding transport domain. In this work, a hybrid structure based approach was applied, based on this molecular domain, to create a high-resolution pharmacophore. Subsequently, a virtual screening of a library of small molecules was performed; identifying ten hit molecules that interact at the proposed domain. Among these, three compounds were determined to be activators, four were inhibitors and three had no effect on EAAT2-mediated transport in vitro. Further characterization of the two best ranking EAAT2 activators for efficacy, potency and selectivity for glutamate over monoamine transporters subtypes and NMDA receptors, and efficacy in cultured astrocytes is demonstrated. Mutagenesis studies suggest that the EAAT2 activators interact with residues forming the interface between the trimerization and the transport domains. These compounds enhance the glutamate translocation rate, with no effect on substrate interaction, suggesting an allosteric mechanism. The identification of these novel positive allosteric modulators of EAAT2 offer an innovative approach for the development of therapies based on glutamate transport enhancement.

    更新日期:2017-11-16
  • 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 3.883) Pub Date : 2017-11-14
    Matthias Schoenberger, Frederick A. Schroeder, Michael S. Placzek, Randall L. Carter, Bruce R. Rosen, Jacob M. Hooker, Christin Y. Sander
    更新日期:2017-11-15
  • Regional variations of spontaneous, transient adenosine release in brain slices
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-11-14
    Scott T Lee, B. Jill Venton

    Transient adenosine signaling has been recently discovered in vivo, where the concentration is on average 180 nM and the duration only 3-4 seconds. Characterizing transient adenosine release in brain slices would facilitate pharmacological experiments testing formation and function of adenosine. Here, the goal was to compare the frequency, concentration, and duration of transient events in rat brain slices from the pre-frontal cortex (PFC), hippocampus (CA1), and thalamus using fast-scan cyclic voltammetry. Adenosine transients in the PFC were similar to those found in vivo, with a concentration of 160 ± 10 nM, and occurred with the highest frequency, averaging one every 50 ± 5 s. In the thalamus, transients were infrequent, occurring every 280 ± 40 s, and lower concentration (110 ± 10 nM), but lasted twice as long as in the PFC. Adenosine transients in the hippocampus were less frequent than in the PFC, occurring every 79 ± 7 s, but the average concentration (240 ± 20 nM) was significantly higher than that of the other two regions. Adenosine A¬¬1 receptors have been implicated in modulating transient adenosine release and 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) was used to inhibit A1 receptors in each brain region. DPCPX had no significant effects on adenosine transients in the PFC, but increased the average transient concentration in the thalamus and both the transient frequency and concentration in the hippocampus. Thus, rapid adenosine signaling in brain slices differs in frequency, duration, and concentration between regions, showing that levels of adenosine modulation may be different among regions.

    更新日期:2017-11-15
  • 更新日期:2017-11-14
  • Discovery of a Novel Muscarinic Receptor PET Radioligand with Rapid Kinetics in the Monkey Brain
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-11-13
    Jonas Malmquist, Katarina Varnäs, Marie Svedberg, Frédéric Vallée, Jeffrey S. Albert, Sjoerd J. Finnema, Magnus Schou
    更新日期:2017-11-14
  • Endosulfan and Cypermethrin Pesticide Mixture Induces Synergistic or Antagonistic Effects on Developmental Exposed Rats Depending on the Analyzed Behavioral or Neurochemical End Points
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-11-13
    Belén Gómez-Giménez, Marta Llansola, Andrea Cabrera-Pastor, Vicente Hernández-Rabaza, Ana Agustí, Vicente Felipo
    更新日期:2017-11-14
  • A Crash Course in Calcium Channels
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-11-13
    Gerald W. Zamponi

    Much progress has been made in understanding the molecular physiology and pharmacology of calcium channels. Recently, there have been tremendous advances in learning about calcium channel structure and function through crystallography and cryo-electron microscopy studies. Here, I will give an overview of our knowledge about calcium channels, and highlight two recent studies that give important insights into calcium channel structure.

    更新日期:2017-11-14
  • Pharmacological characterization of [3H]ATPCA as a substrate for studying the functional role of the betaine/GABA transporter 1 and the creatine transporter
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-11-13
    Anas Al-Khawaja, Anne S Haugaard, Ales Marek, Rebekka Löffler, Louise Thiesen, Monica Santiveri, Maria Damgaard, Christoffer Bundgaard, Bente Frølund, Petrine Wellendorph

    The betaine/γ-aminobutyric acid (GABA) transporter 1 (BGT1) is one of the four GABA transporters (GATs) involved in the termination of GABAergic neurotransmission. Although suggested to be implicated in seizure management, the exact functional importance of BGT1 in the brain is still elusive. This is partly owing to the lack of potent and selective pharmacological tool compounds that can be used to probe its function. We previously reported the identification of 2-amino-1,4,5,6-tetrahydropyrimidine-5-carboxylic acid (ATPCA), a selective substrate for BGT1 over GAT1/GAT3, but also an agonist for GABAA receptors. With the aim of providing new functional insight into BGT1, we here present the synthesis and pharmacological characterization of the tritiated analogue, [3H]ATPCA. Using traditional uptake assays at recombinant transporters expressed in cell lines, [3HH]ATPCA displayed a striking selectivity for BGT1 among the four GATs (Km and Vmax values of 21 µM and 3.6 nmol ATPCA/(min×mg protein), respectively), but was also found to be a substrate for the creatine transporter (CreaT). In experiments with mouse cortical cell cultures, we observed a Na+H-dependent [3HH]ATPCA uptake in neurons, but not in astrocytes. The neuronal uptake could be inhibited by GABA, ATPCA and a non-competitive BGT1-selective inhibitor, indicating functional BGT1 in neurons. In conclusion, we report [3HH]ATPCA as a novel radioactive substrate for both BGT1 and CreaT. The dual activity should be taken into consideration when using this tool compound to study either target under native conditions.

    更新日期:2017-11-14
  • Synthesis and Evaluation of Orexin-1 Receptor Antagonists with Improved Solubility and CNS Permeability
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-11-11
    David A Perrey, Ann M. Decker, Yanan Zhang

    Orexins are hypothalamic neuropeptides playing important roles in many functions including the motivation of addictive behaviors. Blockade of the orexin-1 receptor has been suggested as a potential strategy for the treatment of drug addiction. We have previously reported OX1 receptor antagonists based on the tetrahydroisoquinoline scaffold with excellent OX1 potency and selectivity; however, these compounds had high lipophilicity (clogP > 5) and low to moderate solubility. In an effort to improve their properties, we have designed and synthesized a series of analogs where the 7-position substituents known to favor OX1 potency and selectivity were retained, and groups of different nature were introduced at the 1-position where substitution was generally tolerated as demonstrated in previous studies. Compound 44 with lower lipophilicity (clogP = 3.07) displayed excellent OX1 potency (Ke = 5.7 nM) and selectivity (> 1,760-fold over OX2) in calcium mobilization assays. In preliminary ADME studies, 44 showed excellent kinetic solubility (> 200 μM), good CNS permeability (Papp = 14.7 x 10-6 cm/sec in MDCK assay), and low drug efflux (efflux ratio = 3.3).

    更新日期:2017-11-13
  • 更新日期:2017-11-11
  • Development of μ-Low-Flow-Push–Pull Perfusion Probes for Ex Vivo Sampling from Mouse Hippocampal Tissue Slices
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-11-10
    Marissa R. Cabay, Alyssa McRay, David E. Featherstone, Scott A. Shippy
    更新日期:2017-11-11
  • Dendritic Polyglycerol Sulfates in the Prevention of Synaptic Loss and Mechanism of Action on Glia
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-11-10
    Dusica Maysinger, Jeff Ji, Alexandre Moquin, Shireen Hossain, Mark A. Hancock, Issan Zhang, Philip K.Y. Chang, Matthew Rigby, Madeleine Anthonisen, Peter Grütter, John Breitner, R. Anne McKinney, Sabine Reimann, Rainer Haag, Gerhard Multhaup
    更新日期:2017-11-11
  • 8-Nitro-cGMP Attenuates the Interaction between SNARE Complex and Complexin through S-Guanylation of SNAP-25
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-11-10
    Yusuke Kishimoto, Kohei Kunieda, Atsushi Kitamura, Yuki Kakihana, Takaaki Akaike, Hideshi Ihara
    更新日期:2017-11-11
  • Molecular Determinants for Substrate Interactions with the Glycine Transporter GlyT2
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-11-09
    Jane E. Carland, Michael Thomas, Shannon N. Mostyn, Nandhitha Subramanian, Megan Louise O'Mara, Renae M. Ryan, Robert J. Vandenberg

    Transporters in the SLC6 family play key roles in regulating neurotransmission and are the targets for a wide range of therapeutics. Important insights into the transport mechanisms and the specificity of drug interactions of SLC6 transporters have been obtained from the crystal structures of a bacterial homolog of the family, LeuTAa, and more recently the Drosophila dopamine transporter and the human serotonin transporter. However, there is disputed evidence that the bacterial leucine transporter, LeuTAa, contains two substrate binding sites that work cooperatively in the mechanism of transport, with the binding of a second substrate being required for the release of the substrate from the primary site. An alternate proposal is that there may be low affinity binding sites that serve to direct the flow of substrates to the primary site. We have used a combination of molecular dynamics simulations of substrate interactions with a homology model of GlyT2, together with radiolabelled amino acid uptake assays and electrophysiological analysis of wild type and mutant transporters, to provide evidence that substrate selectivity of GlyT2 is determined entirely by the primary substrate binding site; and furthermore, if a secondary site exists then it is a low affinity non-selective amino acid binding site.

    更新日期:2017-11-09
  • Aromatic Residues in the Fourth Transmembrane-Spanning Helix M4 Are Important for GABAρ Receptor Function
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-11-09
    James Cory-Wright, Mona Alqazzaz, Francesca Wroe, Jenny Jeffreys, Lu Zhou, Sarah C. R. Lummis
    更新日期:2017-11-09
  • Design, Synthesis, and Biological Evaluation of Orally Available First-Generation Dual-Target Selective Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5) for the Treatment of Alzheimer’s Disease
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-11-09
    Fei Mao, Huan Wang, Wei Ni, Xinyu Zheng, Manjiong Wang, Keting Bao, Dazheng Ling, Xiaokang Li, Yixiang Xu, Haiyan Zhang, Jian Li
    更新日期:2017-11-09
  • Targeting Heat Shock Protein 70 to Ameliorate c-Jun Expression and Improve Demyelinating Neuropathy
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-11-09
    Xinyue Zhang, Chengyuan Li, Stephen C. Fowler, Zheng Zhang, Brian S. J. Blagg, Rick T. Dobrowsky
    更新日期:2017-11-09
  • 更新日期:2017-11-09
  • Gastrodin and Isorhynchophylline Synergistically Inhibit MPP+-induced Oxidative Stress in SH-SY5Y Cells by Targeting ERK1/2 and GSK-3β Pathways: Involvement of Nrf2 Nuclear Translocation
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-11-08
    Qiang Li, Chengu Niu, Xiaojie Zhang, Miaoxian Dong

    Recently, the pathogenesis of Parkinson’s disease (PD) is multifactorial event. Combination therapies might be more effective in controlling the disease. Thus, the studies reported were designed to test the hypothesis that gastrodin (GAS)-induced de novo synthesis of nuclear factor E2-related factor 2 (Nrf2) and isorhynchophylline (IRN) inhibition of Nrf2 nuclear export contribute to their additive or synergistic neuroprotective effect. Here, we have demonstrated that the combination of GAS and IRN (GAS/IRN) protect SH-SY5Y cells against 1-methyl-4-phenylpyridinium (MPP+) toxicity in a synergistic manner. Concomitantly, GAS/IRN led to a statistically significant reduction of oxidative stress, as assessed by reactive oxygen species (ROS) and lipid hydroperoxides (LPO), and enhancement of both glutathione (GSH) and thioredoxin (Trx) systems compared with treatment with either agent alone in MPP+-challenged SH-SY5Y cells. Interestingly, GAS but not IRN activated extracellular signal-regulated kinases 1 and 2 (ERK1/2), leading to a increase in de novo synthesis of Nrf2 and nuclear import of Nrf2. Simultaneously, IRN but not GAS suppressed both constitutive glycogen synthase kinase (GSK)-3β and Fyn activation, which inhibited nuclear export of Nrf2. Importantly, simultaneous inhibition of GSK-3β pathway by IRN and activation of ERK1/2 pathway by GAS synergistically induced accumulation of Nrf2 in the nucleus in SH-SY5Y cells challenged with MPP+. Furthermore, the activation of the ERK1/2 pathway and inhibition of GSK-3β pathway by GAS/IRN are mediated by independent mechanisms. Collectively, these novel findings suggest an in vitro model of synergism between IRN and GAS in the induction of neuroprotection warrant further investigations in vivo.

    更新日期:2017-11-08
  • An overview of the clinical uses, pharmacology and safety of modafinil
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-11-08
    Eric Murillo-Rodriguez, André Barciela Veras, Nuno Barbosa Rocha, Henning Budde, Sérgio Machado

    Modafinil (MOD) is a drug used for the management of excessive daytime sleepiness observed in several sleep disturbances such as shift work sleep disorder, obstructive sleep apnea, restless leg syndrome and narcolepsy. Additionally, a wide scope of medical uses of MOD have been described such as fatigue in subjects with depression as well as patients under chemotherapy. Moreover, there also appear to be a cognitive enhancer drug. In contrast, recent reports have indicated the risk of developing addiction to MOD. Furthermore, interest of studying potential long-term effects of MOD have raised. Here, we highlight the evidence concerning the medical uses of MOD in the management of sleepiness, fatigue associated with depression and cancer as well as combat depletion.

    更新日期:2017-11-08
  • Glycosylation Changes in Brain Cancer
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-11-07
    Lucas Veillon, Christina Fakih, Hadi Abou-El-Hassan, Firas Kobeissy, Yehia Mechref
    更新日期:2017-11-08
  • Anti-NMDA-Receptor Encephalitis: From Bench to Clinic
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-11-07
    Arun Venkatesan, Krishma Adatia
    更新日期:2017-11-08
  • Positron Emission Tomography Assessment of the Intranasal Delivery Route for Orexin A
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-11-07
    Genevieve C. Van de Bittner, Kyle C. Van de Bittner, Hsiao-Ying Wey, Wayne Rowe, Ram Dharanipragada, Xiaoyou Ying, William Hurst, Andrew Giovanni, Kim Alving, Anurag Gupta, John Hoekman, Jacob M. Hooker
    更新日期:2017-11-08
  • Novel Bivalent 5-HT2A Receptor Antagonists Exhibit High Affinity and Potency in Vitro and Efficacy in Vivo
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-11-07
    Claudia A Soto, Matthew J. Shashack, Robert G Fox, Marcy J. Bubar, Kenner C. Rice, Cheryl S Watson, Kathryn A. Cunningham, Scott R. Gilbertson, Noelle C. Anastasio

    The 5-HT2AR plays an important role in various neuropsychiatric disorders including cocaine use disorder and schizophrenia. Homodimerization of this receptor has been suggested but tools that allow direct assessment of 5-HT2AR:5-HT2AR homodimer relevance in these disorders are necessary. We chemically modified the selective 5-HT2AR antagonist M100907 to synthesize a series of homobivalent ligands connected by ethylene glycol linkers of varying lengths that may be useful tools to probe 5-HT2AR:5-HT2AR homodimer function. We tested these molecules for 5-HT2AR antagonist activity in a cell line stably expressing the functional 5-HT2AR, and quantified a post-receptor signaling target, activation (phosphorylation) of extracellular regulated kinases 1/2 (ERK1/2), in comparison to in vivo efficacy to alter spontaneous or cocaine-evoked locomotor activity in rats. All of the synthetic compounds inhibited 5-HT-mediated phosphorylation of ERK1/2 in the cellular signaling assay; the potency of the bivalent ligands varied as a function of linker length with the intermediate linker lengths being the most potent. The Ki values for the binding of bivalent ligands to 5-HT2AR were only slightly lower than the values for the parent (+)-M100907 compound, but retained significant selectivity for 5-HT2AR over 5-HT2BR or 5-HT2CR binding. In addition, the 11-atom-linked bivalent 5-HT2AR antagonist (2 mg/kg, i.p.) demonstrated efficacy on par with (+)-M100907 to inhibit cocaine-evoked hyperactivity. As we develop further strategies for ligand-evoked receptor assembly and analyses of diverse signaling and functional roles, these novel homobivalent 5-HT2AR antagonist ligands will serve as useful in vitro and in vivo probes of 5-HT2AR structure and function.

    更新日期:2017-11-07
  • 8-Nitro-cGMP attenuates the interaction between SNARE complex and complexin through S-guanylation of SNAP-25
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-11-07
    Yusuke Kishimoto, Kohei Kunieda, Atsushi Kitamura, Yuki Kakihana, Takaaki Akaike, Hideshi Ihara

    8-Nitroguanosine 3′,5′-cyclic monophosphate (8-nitro-cGMP) is the second messenger in nitric oxide/reactive oxygen species redox signaling. This molecule covalently binds to protein thiol groups, called S-guanylation, and exerts various biological functions. Recently, we have identified synaptosomal-associated protein 25 (SNAP-25) as a target of S-guanylation, and demonstrated that S-guanylation of SNAP25 enhanced SNARE complex formation. In this study, we have examined the effects of S-guanylation of SNAP-25 on the interaction between the soluble SNARE complex and complexin (cplx), which binds to the SNARE complex with a high affinity. Pull-down assays and co-immunoprecipitation experiments have revealed that S-guanylation of Cys90 in SNAP-25 attenuates the interaction between the SNARE complex and cplx. In addition, blue native-PAGE followed by western blot analysis revealed that the amount of cplx detected at a high molecular weight decreased upon 8-nitro-cGMP treatment in SH-SY5Y cells. These results demonstrated for the first time that S-guanylation of SNAP-25 attenuates the interaction between the SNARE complex and cplx.

    更新日期:2017-11-07
  • Development of a PET Radiotracer for Imaging Elevated Levels of Superoxide in Neuroinflammation
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-11-03
    Catherine Hou, Chia-Ju Hsieh, Shihong Li, Hsiaoju Lee, Thomas J. A. Graham, Kuiying Xu, Chi-Chang Weng, Robert K. Doot, Wenhua Chu, Subhasish K. Chakraborty, Laura L. Dugan, Mark A. Mintun, Robert Mach

    Reactive oxygen species (ROS) are believed to play a major role in the proinflammatory, M1-polarized form of neuroinflammation. However, it has been difficult to assess the role of ROS and their role in neuroinflammation in animal models of disease because of the absence of probes capable of measuring their presence with the functional imaging technique positron emission tomography (PET). This study describes the synthesis and in vivo evaluation of [18F]ROStrace, a radiotracer for imaging superoxide in vivo with PET, in an LPS model of neuroinflammation. [18F]ROStrace was found to rapidly cross the blood-brain barrier (BBB) and was trapped in the brain of LPS-treated animals but not the control group. [18F]ox-ROStrace, the oxidized form of [18F]ROStrace, did not cross the BBB. These data suggest that [18F]ROStrace is a suitable radiotracer for imaging superoxide levels in the CNS with PET.

    更新日期:2017-11-05
  • A Novel Negative Allosteric Modulator Selective for GluN2C/2D-Containing NMDA Receptors Inhibits Synaptic Transmission in Hippocampal Interneurons
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-11-02
    Sharon A. Swanger, Katie M. Vance, Timothy M. Acker, Sommer S. Zimmerman, John O. DiRaddo, Scott J. Myers, Christoffer Bundgaard, Cara A. Mosley, Samantha L. Summer, David S. Menaldino, Henrik S. Jensen, Dennis C. Liotta, Stephen F. Traynelis
    更新日期:2017-11-02
  • ENDOSULFAN AND CYPERMETHRIN PESTICIDE MIXTURE INDUCES SYNERGISTIC OR ANTAGONISTIC EFFECTS ON DEVELOPMENTAL EXPOSED RATS DEPENDING ON THE ANALYZED BEHAVIORAL OR NEUROCHEMICAL ENDPOINTS
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-11-02
    Belén Gómez-Giménez, Marta Llansola, Andrea Cabrera-Pastor, VICENTE HERNÁNDEZ-RABAZA, Ana Agustí, Vicente Felipo

    Exposure to pesticides has been associated with neurodevelopmental toxicity. Usually people are exposed to mixtures of pesticides. However, most studies analyze the effects of individual pesticides. Developmental exposure to mixtures of pesticides may result in additive effects or in antagonistic or synergistic effects. The aim of this work was to compare the effects of developmental exposure of rats to cypermethrin or endosulfan with the effects of its mixture on cognitive and motor function and on some underlying mechanisms. Exposure to individual pesticides or the mixture was from gestational day 7 to post-natal day 21. We analyzed the effects, in males and females, on: spatial learning and memory, associative learning, anxiety, motor coordination and spontaneous motor activity. We also analyzed neuroinflammation and NMDA receptor subunits in hippocampus and extracellular GABA in cerebellum. Exposure to the mixture, but not to individual pesticides, impaired spatial memory in males, associative learning in females and increased motor activity in males and females. This indicates a synergistic effect of cypermethrin and endolsufan exposure on these endpoints. In contrast, motor coordination was impaired by individual exposure to endosulfan or cypermethrin, associated with increased extracellular GABA in cerebellum, but these effects were prevented in rats exposed to the mixture, indicating an antagonistic effect of cypermethrin and endolsufan exposure on these endpoints. The results show different interaction modes (synergism or antagonism) of the pesticides, depending on the endpoint analyzed and the sex of the rats

    更新日期:2017-11-02
  • 更新日期:2017-10-31
  • Dendritic Polyglycerol Sulfates in the Prevention of Synaptic Loss and Mechanism of Action on Glia
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-27
    Dusica Maysinger, Jeff Ji, Alexandre Moquin, Shireen Hossain, Mark A. Hancock, Issan Zhang, Philip K.Y. Chang, Matthew Rigby, Madeleine Anthonisen, Peter Grutter, John C.S. Breitner, R. Anne McKinney, Sabine Reimann, Rainer Haag, Gerhard Multhaup

    Dendritic polyglycerols (dPG), particularly dendritic polyglycerol sulfates (dPGS), have been intensively studied due to their intrinsic anti-inflammatory activity. As related to brain pathologies involving neuroinflammation, the current study examined if dPG and dPGS can (i) regulate neuroglial activation, and (ii) normalize the morphology and function of excitatory postsynaptic dendritic spines adversely affected by the neurotoxic 42 amino acid amyloid-β (Aβ42) peptide of Alzheimer disease (AD). The exact role of neuroglia, such as microglia and astrocytes, remains controversial especially their positive and negative impact on inflammatory processes in AD. To test dPGS effectiveness in AD models we used primary neuroglia and organotypic hippocampal slice cultures exposed to Aβ42 peptide. Overall, our data indicate that dPGS is taken up by both microglia and astrocytes in a concentration- and time-dependent manner. The mechanism of action of dPGS involves binding to Aβ42, i.e., a direct interaction between dPGS and Aβ42 species interfered with Aβ fibril formation and reduced the production of the neuroinflammagen lipocalin-2 (LCN2) mainly in astrocytes. Moreover, dPGS normalized the impairment of neuroglia and prevented the loss of dendritic spines at excitatory synapses in the hippocampus. In summary, dPGS has desirable therapeutic properties that may help reduce amyloid-induced neuroinflammation and neurotoxicity in AD.

    更新日期:2017-10-28
  • Higher aminopeptidase activity determined by electroosmotic push-pull perfusion contributes to selective vulnerability of the hippocampal CA1 region to oxygen-glucose deprivation
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-27
    Yangguang Ou, Stephen G Weber

    It has been known for over a century that the hippocampus, the center for learning and memory in the brain, is selectively vulnerable to ischemic damage, with the CA1 being more vulnerable than the CA3. It is also known that leucine enkephalin, or YGGFL, is neuroprotective. We hypothesized that the extracellular hydrolysis of YGGFL may be greater in the CA1 than the CA3, which would lead to the observed difference in susceptibility to ischemia. In rat organotypic hippocampal slice cultures, we estimated the Michaelis constant and the maximum velocity for membrane-bound aminopeptidase activity in the CA1 and CA3 regions. Using electroosmotic push-pull perfusion and offline capillary liquid chromatography we inferred enzyme activity based on the production rate of GGFL, a natural and inactive product of the enzymatic hydrolysis of YGGFL. Data were analyzed based on the integrated Michaelis-Menten equation. We found nearly three-fold higher aminopeptidase activity in the CA1 than the CA3. The aminopeptidase inhibitor bestatin significantly reduced hydrolysis of YGGFL in both regions by increasing apparent Km. Based on propidium iodide cell death measurements 24 hours after oxygen-glucose deprivation, we demonstrate that inhibition of aminopeptidase using bestatin selectively protected CA1 against delayed cell death due to oxygen-glucose deprivation and that this neuroprotection occurs through enkephalin-dependent pathways.

    更新日期:2017-10-28
  • A Detailed Model of Electroenzymatic Glutamate Biosensors to Aid in Sensor Optimization and in Applications in vivo
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-27
    Mackenzie Clay, Harold G. Monbouquette

    Simulations conducted with a detailed model of glutamate biosensor performance describe observed sensor performance well, illustrate the limits of sensor performance, and suggest a path toward sensor optimization. Glutamate is the most important excitatory neurotransmitter in the brain, and electroenzymatic sensors have emerged as a useful tool for the monitoring of glutamate signaling in vivo. However, the utility of these sensors currently is limited by their sensitivity and response time. A mathematical model of a typical glutamate biosensor consisting of a Pt electrode coated with a permselective polymer film and a top layer of crosslinked glutamate oxidase has been constructed in terms of differential material balances on glutamate, H2O2 and O2 in one spatial dimension. Simulations suggest that reducing thicknesses of the permselective polymer and enzyme layers can increase sensitivity ~6-fold and reduce response time ~7-fold, and thereby improve resolution of transient glutamate signals. At currently employed enzyme layer thicknesses, both intrinsic enzyme kinetics and enzyme deactivation likely are masked by mass transfer. However, O2 dependence studies show essentially no reduction in signal at the lowest anticipated O2 concentrations for expected glutamate concentrations in the brain, and that O2 transport limitations in vitro are anticipated only at glutamate concentrations in the mM range. Finally, the limitations of current biosensors in monitoring glutamate transients is simulated and used to illustrate the need for optimized biosensors to report glutamate signaling accurately on a subsecond timescale. This work demonstrates how a detailed model can be used to guide optimization of electroenzymatic sensors similar to that for glutamate and to ensure appropriate interpretation of data gathered using such biosensors.

    更新日期:2017-10-27
  • Development of µ-low-flow-push-pull perfusion probes for sampling from mouse hippocampal tissue slices
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-27
    Marissa R. Cabay, Alyssa McRay, David E. Featherstone, Scott A. Shippy

    This work demonstrates a reduced tip µ-low-flow-push-pull perfusion technique for ex vivo sampling of the extracellular space of mouse hippocampal brain slices. Concentric fused-silica capillary probes are pulled by an in-house gravity puller with a butane flame producing probe tips averaging an overall outer diameter of 30.3 ± 8 µm. The 10-30 nL/min perfusion flow rate through the probe generates an average recovery of 90%. Sampling was performed with mouse brain tissue slices to characterize basal neurotransmitter content in this model system. Samples were collected from hippocampal tissue slices (n=7) at a volume of 200 nL per sample. Sample arginine, histamine, lysine, glycine, glutamate, and aspartate content were quantified by micellar electrokinetic chromatography with laser induced fluorescence detection. Primary amine content was sampled over several hours to determine evidence for tissue damage and loss of extracellular content from the tissue slice. Overall, all amino acid concentrations trended lower as an effect of time relative to time of tissue slicing. There were significant concentration decreases seen for histamine, lysine, and aspartate between time points 0-2 and 2-6 hours (p<0.05) relative to tissue slicing. The work presented shows to the applicability of an 80% reduction of probe tip size relative to previous designs for the collection of extracellular content from thin tissue slices.

    更新日期:2017-10-27
  • Anti-NMDA-receptor encephalitis: from bench to clinic
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-27
    Arun Venkatesan, Krishma Adatia

    NMDAR encephalitis is a common cause of autoimmune encephalitis, predominantly affecting young adults. Current data supports the idea that autoantibodies targeting NMDARs are responsible for disease pathogenesis. While these autoantibodies occur in the setting of underlying malignancy in approximately half of all patients, initiating factors for the autoimmune response in the remainder of patients are unclear. While there is increasing evidence supporting viral triggers such as herpes simplex encephalitis, this association and the mechanism of action have not yet been fully described. Although the majority of patients achieve good outcomes, those without an underlying tumour consistently show worse outcomes, prolonged recovery and more frequent relapses. The cloning of patient-specific autoantibodies from affected individuals has raised important questions as to disease pathophysiology and clinical heterogeneity. Further advances in our understanding of this disease and underlying triggers are necessary to develop treatments which improve outcomes in patients presenting in the absence of tumours.

    更新日期:2017-10-27
  • Discovery of a Novel Muscarinic Receptor PET Radioligand with Rapid Kinetics in the Monkey Brain
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-26
    Jonas Malmquist, Katarina Varnas, Marie Svedberg, Frédéric Vallée, Jeffery S. Albert, Sjoerd J Finnema, Magnus Schou

    Positron emission tomography (PET), together with a suitable radioligand, is one of the more prominent methods for measuring changes in synaptic neurotransmitter concentrations in vivo. The radioligand of choice for such measurements on the cholinergic system has been the muscarinic antagonist N-[1-11C]propyl-3-piperidyl benzilate (PPB). In an effort to overcome the shortcomings with the technically cumbersome synthesis of [11C]PPB, we designed and synthesized four structurally related analogs of PPB, of which (S,R)-1-methylpiperidin-3-yl)2-cyclopentyl-2-hydroxy-2-phenylacetate (1) was found to bind muscarinic receptors with similar affinity as PPB (13.4 vs. 7.9 nM, respectively). (S,R)-1 was radiolabeled via N-11C-methylation at high radiochemical purity (>99%) and high specific radioactivity (>130 GBq/µmol). In vitro studies by autoradiography on human brain tissue and in vivo studies by PET in non-human primates demonstrated excellent signal to noise ratios and a kinetic profile in brain comparable to that of [11C]PBB. (S,R)-[11C]1 is a promising candidate for measuring changes in endogenous acetylcholine concentrations.

    更新日期:2017-10-27
  • Genetic and Pharmacological Discovery for Alzheimer’s Disease Using Caenorhabditis elegans
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-25
    Edward F. Griffin, Kim A. Caldwell, Guy A. Caldwell
    更新日期:2017-10-26
  • Design, Synthesis, and Biological Evaluation of Orally Available First-Generation Dual-Target Selective Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5) for the Treatment of Alzheimer’s Disease
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-25
    Fei Mao, Huan Wang, Wei Ni, Xinyu Zheng, Manjiong Wang, Keting Bao, Dazheng Ling, Xiaokang Li, Yixiang Xu, Haiyan Zhang, Jian Li

    Through drug discovery strategies of repurposing and redeveloping existing drugs, a series of novel tadalafil derivatives were rationally designed, synthesized and evaluated to seek dual-target AChE/PDE5 inhibitors as good candidate drugs for AD. Among these derivatives, 1p and 1w exhibited excellent selective dual-target AChE/PDE5 inhibitory activities and improved blood-brain barrier (BBB) penetrability. Importantly, 1w·Cit (citrate of 1w) could reverse the cognitive dysfunction of scopolamine-induced AD mice and exhibited an excellent effect on enhancing cAMP response element-binding protein (CREB) phosphorylation in vivo, a crucial factor in memory formation and synaptic plasticity. Moreover, the molecular docking simulations of 1w with hAChE and hPDE5A confirmed that our design strategy was rational. In summary, our research provides a potential selective dual-target AChE/PDE5 inhibitor as a good candidate drug for the treatment of AD, and it could also be regarded as a small molecule probe to validate the novel AD therapeutic approach in vivo.

    更新日期:2017-10-26
  • Traced on the Timeline: Discovery of Acetylcholine and the Components of the Human Cholinergic System in a Primitive Unicellular Eukaryote Acanthamoeba spp.
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-23
    Abdul Mannan Baig, Zohaib Rana, Sumayya Tariq, Salima Lalani, HR Ahmad

    Acetylcholine (ACh) is the neurotransmitter of cholinergic signal transduction that affects the target cells via muscarinic (mAChR) and nicotinic (nAChR) cholinergic receptors embedded in the cell membrane. Of the cholinergic receptors that bind to ACh, the mAChRs execute several cognitive and metabolic functions in the human central nervous system (CNS). Very little is known about the origins, autocrine and paracrine roles of the chemical ACh detected in primitive life forms on earth. With the recent report of the evidence of an acetylcholine binding mAChR1 like receptor in Acanthamoeba spp, it was tempting to investigate the origin and functional roles of cholinergic G-protein coupled receptors (GPCRs) in the biology of eukaryotes. We hypothesized the presence of ACh, its synthetic, degradation system and a signal transduction pathway in an approximately ~2.0 billion year old primitive eukaryotic cell Acanthamoeba castellanii. Bioinformatics analysis, ligand binding prediction and docking methods were used to establish the origins of enzymes involved in the synthesis and degradation of ACh. Notably, we provide evidence of the presence of ACh in Acanthamoeba castellanii by colorimetric analysis, which to date is the only report of its presence in this primitive unicellular eukaryote. We show evidence for the presence of homology of evolutionary conserved key enzymes of the cholinergic system like choline acetyltranferase (ChAT) and Acetylcholinesterase (AChE) in Acanthamoeba spp, which were found to be near identical to their human counterparts. Tracing the origin, functions of ACh and a primeval mAChRs in primitive eukaryotic cells has the potential of uncovering primitive cholinergic pathways that can be extended to understand the states of cholinergic deficiency in neurodegenerative diseases (ND).

    更新日期:2017-10-23
  • Single Cell Neurometabolomics
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-19
    Meng Qi, Marina C. Philip, Ning Yang, Jonathan V. Sweedler
    更新日期:2017-10-20
  • Altered Volatile Organic Compound Profile in Transgenic Rats Bearing A53T Mutation of Human α-Synuclein: Comparison with Dopaminergic and Serotonergic Denervation
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-19
    John P. M. Finberg, Yuval Aluf, Yelena Loboda, Morad K. Nakhleh, Raneen Jeries, Manal Abud-Hawa, Salman Zubedat, Avi Avital, Soliman Khatib, Jacob Vaya, Hossam Haick
    更新日期:2017-10-20
  • Comparative in Vivo Investigation of Intrathecal and Intracerebroventricular Administration with Melanocortin Ligands MTII and AGRP into Mice
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-19
    Danielle N. Adank, Mary M. Lunzer, Cody J. Lensing, Stacey L. Wilber, Amy M. Gancarz, Carrie Haskell-Luevano
    更新日期:2017-10-20
  • In vivo [18F]GE-179 brain signal does not show NMDA-specific modulation with drug challenges in rodents and non-human primates
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-19
    Matthias Schoenberger, Frederick A. Schroeder, Michael S. Placzek, Randall L. Carter, Bruce R. Rosen, Jacob M. Hooker, Christin Y. Sander

    As one of the major excitatory ion channels in the brain, NMDA receptors have been a leading research target for neuroscientists, physicians, medicinal chemists and pharmaceutical companies for decades. Molecular imaging of NMDA receptors by means of positron emission tomography (PET) with [18F]GE-179 quickly progressed to clinical PET studies but a thorough understanding of its binding specificity has been missing and has thus limited signal interpretation. Here, a preclinical study with [18F]GE-179 in rodents and non-human primates is presented, in an attempt to characterize [18F]GE-179 signal specificity. Rodent PET/CT was used to study drug occupancy and functional manipulation in rats by pretreating animals with drug/dose followed by a single bolus of [18F]GE-179. Binding competition with GE-179, MK801, PCP and ketamine, allosteric inhibition by ifenprodil as well as brain activation with methamphetamine did not alter the [18F]GE-179 brain signal in rats. In addition, multimodal imaging with PET/MRI in non-human primates (NHPs) was used to evaluate changes in radiotracer binding as a function of pharmacological challenges. Drug-induced hemodynamic changes were monitored simultaneously using functional MRI. Comparisons of baseline and signal after drug challenge in NHPs demonstrated that the [18F]GE-179 signal cannot be manipulated in a predictable fashion in vivo. fMRI data acquired simultaneously with PET supported this finding and provided evidence that radiotracer delivery is not altered by blood flow changes. In conclusion, the [18F]GE-179 brain signal is not readily interpretable in the context of NMDA receptor binding based on the results shown in this study.

    更新日期:2017-10-20
  • A novel negative allosteric modulator selective for GluN2C/2D-containing NMDA receptors inhibits synaptic transmission in hippocampal interneurons
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-18
    Sharon A Swanger, Katie M Vance, Timothy M Acker, Sommer S Zimmerman, John O DiRaddo, Scott J Myers, Christoffer Bundgaard, Cara A Mosley, Samantha L Summer, David S Menaldino, Henrik S. Jensen, Dennis C. Liotta, Stephen F. Traynelis

    N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors that mediate excitatory synaptic transmission and have been implicated in numerous neurological disorders. NMDARs typically comprise two GluN1 and two GluN2 subunits. The four GluN2 subtypes (GluN2A-GluN2D) have distinct functional properties and gene expression patterns, which contribute to diverse functional roles for NMDARs in the brain. Here, we present a series of GluN2C/2D-selective negative allosteric modulators built around a N-aryl benzamide (NAB) core. The prototypical compound, NAB-14, is >800-fold selective for recombinant GluN2C/GluN2D over GluN2A/GluN2B in Xenopus oocytes and has an IC50 value of 580 nM at recombinant GluN2D-containing receptors expressed in mammalian cells. NAB-14 inhibits triheteromeric (GluN1/GluN2A/GluN2C) NMDARs with modestly reduced potency and efficacy compared to diheteromeric (GluN1/GluN2C/GluN2C) receptors. Site-directed mutagenesis suggests that structural determinants for NAB-14 inhibition reside in the GluN2D M1 transmembrane helix. NAB-14 inhibits GluN2D-mediated synaptic currents in rat subthalamic neurons and mouse hippocampal interneurons, but has no effect on synaptic transmission in hippocampal pyramidal neurons, which do not express GluN2C or GluN2D. This series possesses some drug-like physical properties and modest brain permeability in rat and mouse. Altogether, this work identifies a new series of negative allosteric modulators that are valuable tools for studying GluN2C- and GluN2D-containing NMDAR function in brain circuits, and suggests that the series has the potential to be developed into therapies for selectively modulating brain circuits involving the GluN2C and GluN2D subunits.

    更新日期:2017-10-18
  • Positron Emission Tomography Assessment of the Intranasal Delivery Route for Orexin A
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-16
    Genevieve C. Van de Bittner, Kyle C. Van de Bittner, Hsiao-Ying Wey, Wayne Rowe, Ramalinga Dharanipragada, Xiaoyou Ying, William Hurst, Andrew Giovanni, Kim Alving, Anurag Gupta, John Hoekman, Jacob M. Hooker

    Intranasal drug delivery is a non-invasive drug delivery route that can enhance systemic delivery of therapeutics with poor oral bioavailability by exploiting the rich microvasculature within the nasal cavity. The intranasal delivery route has also been targeted as a method for improved brain uptake of neurotherapeutics, with a goal of harnessing putative, direct nose-to-brain pathways. Studies in rodents, non-human primates and humans have pointed to the efficacy of intranasally delivered neurotherapeutics, while radiolabeling studies have analyzed brain uptake following intranasal administration. In the present study, we employed carbon-11 radioactive methylation to assess the pharmacokinetic mechanism of intranasal delivery of Orexin A, a native neuropeptide and prospective anti-narcoleptic drug that binds the orexin receptor 1. Using physicochemical and pharmacological analysis, we identified the methylation sites and confirmed the structure and function of methylated Orexin A (CH3-Orexin A) prior to monitoring its brain uptake following intranasal administration in rodent and non-human primate. Through PET imaging of [11C]CH3-Orexin A, we determined that the brain exposure to Orexin A is poor after intranasal administration. Additional ex vivo analysis of brain uptake using [125I]Orexin A indicated intranasal administration of Orexin A affords similar brain uptake when compared to intravenous administration across most brain regions, with possible increased brain uptake localized to the olfactory bulbs.

    更新日期:2017-10-17
  • 更新日期:2017-10-17
  • Identification of FDA-Approved Small Molecules Capable of Disrupting the Calmodulin–Adenylyl Cyclase 8 Interaction through Direct Binding to Calmodulin
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-16
    Michael P. Hayes, Monica Soto-Velasquez, C. Andrew Fowler, Val J. Watts, David L. Roman
    更新日期:2017-10-17
  • DMSO: A Mixed-Competitive Inhibitor of Human Acetylcholinesterase
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-16
    Amit Kumar, Taher Darreh-Shori
    更新日期:2017-10-16
  • Genetic and pharmacological discovery for Alzheimer’s Disease using C. elegans
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-12
    Edward F Griffin, Kim A Caldwell, Guy A Caldwell

    The societal burden presented by Alzheimer’s disease warrants both innovative and expedient means by which its underlying molecular causes can be both identified and mechanistically exploited to discern novel therapeutic targets and strategies. The conserved characteristics, defined neuroanatomy and advanced technological application of Caenorhabditis elegans render this metazoan an unmatched tool for probing neurotoxic factors. In addition, its short lifespan and importance in the field of aging make it an ideal organism for modeling age-related neurodegenerative disease. As such, this nematode system has demonstrated its value in predicting functional modifiers of human neurodegenerative disorders. Here, we review how C. elegans has been utilized to model Alzheimer’s disease. Specifically, we present how the causative neurotoxic peptides, amyloid-β and tau, contribute to disease-like neurodegeneration in C. elegans and how they translate to human disease. Furthermore, we describe how a variety of transgenic animal strains, each with distinct utility, have been used to identify both genetic and pharmacological modifiers of toxicity in C. elegans. As technological advances improve the prospects for intervention, the rapidity, unparalleled accuracy, and scale that C. elegans offers researchers for defining functional modifiers of neurodegeneration should speed the discovery of improved therapies for Alzheimer's disease.

    更新日期:2017-10-12
  • Studies on 16,17-pyrazoline substituted heterosteroids as anti-Alzheimer and anti-Parkinsonian agents using LPS induced neuroinflammation models of mice and rats
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-11
    Ranjit Singh, Sridhar Thota, Ranju Bansal

    Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common forms of neurodegenerative disorders. Dehydroepiandrosterone (DHEA) has been reported as a neuroprotective steroid useful in the therapeutic management of neurodegenerative disorders such as AD and PD. Herein we report the synthesis and evaluation of a new series of 16,17-pyrazolinyl DHEA analogues 2-4a-d as neuroprotective agents using LPS-induced neuroinflammation animal models. Treatment with the pyrazoline substituted steroids considerably improved the LPS-induced learning, memory and movement deficits in animal models. Suppression of biochemical parameters of oxidative and nitrosative stress, acetylcholinesterase activity and TNF-α levels was also observed. 16,17-Pyrazolinyl steroids 2c-4c substituted with a 4-pyridyl moiety at 5-position of heterocyclic ring were found to be the most potent agents and produced neuroprotective effects better than standard drugs celecoxib and dexamethasone. Of these pyrazoline substituted steroids, the N-acetyl analogue 3c displayed neuroprotective effects better than N-phenyl (4c), which in turn showed potency more than N-unsubstituted analogue 2c.

    更新日期:2017-10-11
  • Altered Volatile Organic Compounds Profile in Transgenic Rats Bearing A53T Mutation of Human Alpha-Synuclein: Comparison with Dopaminergic and Serotonergic Denervation
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-10
    John P. M. Finberg, Yuval Aluf, Yelena Loboda, Morad K. Nakhleh, Raneen Jeries, Manal Aboud, Salman Zubedat, Avi Avital, soliman khatib, Jacob Vaya, Hossam Haick

    Early diagnosis of Parkinson’s disease (PD) is of great importance due its progressive phenotype. Neuroprotective drugs could potentially slow down disease progression if used at early stages. Previously, we have reported an altered content of volatile organic compounds (VOCs) in the breath of rats following a 50% reduction in striatal dopamine (DA) content induced by 6-hydroxydopamine. We now report on the difference in the breath-print and content of VOCs between rats with mild and severe lesions of DA neurons, serotonergic neuronal lesions, and transgenic (Tg) rats carrying the PD-producing A53T mutation of the SNCA (alpha-synuclein) gene. The Tg rats had an increased content of 3-octen-1-ol and 4-chloro-3-methyl phenol in blood, while in brain tissue, hexanal, hexanol and 2,3-octanedione were present in controls but absent in Tg rats. Levels of 1-heptyl-2-methyl cyclopropane were increased in brain tissue of Tg rats. The data confirm the potential of breath analysis for detection of human- idiosyncratic as well as autosomal dominant PD.

    更新日期:2017-10-11
  • DMSO: A Mixed-Competitive Inhibitor of Human Acetylcholinesterase
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-10
    Amit Kumar, Taher Darreh-Shori

    Dimethyl sulfoxide (DMSO) is the most common organic solvent used in biochemical and cellular assays during drug discovery programs. In spite of its wide use, the effect of DMSO on several enzyme classes, which are crucial targets of the new therapeutic agents, are still unexplored. Here, we report the detailed biochemical analysis of the effects of DMSO on the human acetylcholine-degrading enzyme, acetylcholinesterase (AChE), the primary target of current Alzheimer’s therapeutics. Our analysis showed that DMSO is a considerably potent and highly selective irreversible mixed-competitive inhibitor of human AChE with IC50 values in the lower millimolar range, corresponding to 0.88 to 2.6% DMSO (v/v). Most importantly, 1-4% (v/v) DMSO, the commonly used experimental concentrations, showed ~ 37-80% inhibition of human AChE activity. We believe that our results will assist in developing stringent protocols and help in the better interpretation of experimental outcomes during screening and biological evaluation of new drugs.

    更新日期:2017-10-11
  • The Analgesic Acetaminophen and the Antipsychotic Clozapine Can Each Redox-Cycle with Melanin
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-09
    Zülfikar Temoçin, Eunkyoung Kim, Jinyang Li, Lucia Panzella, Maria Laura Alfieri, Alessandra Napolitano, Deanna L. Kelly, William E. Bentley, Gregory F. Payne
    更新日期:2017-10-10
  • Integrating Transcriptomic Data with Mechanistic Systems Pharmacology Models for Virtual Drug Combination Trials
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-06
    Anne Marie Barrette, Mehdi Bouhaddou, Marc R. Birtwistle
    更新日期:2017-10-07
  • Is There a Cholinergic Survival Incentive for Neurotropic Parasites in the Brain?
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-06
    Abdul Mannan Baig

    The reason why some parasites specifically target the brain remains a mystery. Often, it is seen that the primary site of infection is quite remote from the brain, but an eventual involvement of the cerebral tissue is seen to occur that becomes the cause of death of the majority of the patients. In the absence of a clear preferential reason for targeting the brain, chemicals produced by the nervous system, which have miniature concentrations in the blood, appear to set up a chemical attraction that eventually causes them to migrate to the neural tissue. We studied the possible chemicals of neural origin that can lure the parasite toward the brain, enabling them to cause meningoencephalitis. The identification of these chemicals could be of enormous prophylactic significance as blocking the chemotaxis of neurotropic parasite by antagonist drugs and chemicals can prevent cerebral infection and provide ample time to eradicate the parasites at the primary site of infection.

    更新日期:2017-10-07
  • Glycosylation Changes in Brain Cancer
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-05
    Lucas Veillon, Christina Fakih, Hadi Abou-El-Hassan, firas kobeissy, Yehia Mechref

    Protein glycosylation is a posttranslational modification that affects more than half of all known proteins. Glycans covalently bound to biomolecules modulate their functions by both direct interactions, such as the recognition of glycan structures by binding partners, and indirect mechanisms that contribute to the control of protein conformation, stability, and turnover. The focus of this review is the discussion of aberrant glycosylation related to brain cancer. Altered sialylation and fucosylation of N- and O-glycans play a role in the development and progression of brain cancer. Additionally, aberrant O-glycan expression has been implicated in brain cancer. This review also addresses the clinical potential and applications of aberrant glycosylation for the detection and treatment of brain cancer. The viable roles glycans may play in the development of brain cancer therapeutics are addressed as well as cancer-glycoproteomics and personalized medicine. Glycoprotein alterations are considered as a hallmark of cancer while high expression in body fluids represents an opportunity for cancer assessment.

    更新日期:2017-10-05
  • Single Cell Neurometabolomics
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-05
    Meng Qi, Marina Philip, Ning Yang, Jonathan V. Sweedler

    Metabolomics, the characterization of metabolites and their changes within biological systems, has seen great technological and methodological progress over the past decade. Most metabolomic experiments involve the characterization of the small-molecule content of fluids or tissue homogenates. While these microliter and larger volume metabolomic measurements can characterize hundreds to thousands of compounds, the coverage of molecular content decreases as sample sizes are reduced to the nanoliter and even to the picoliter volume range. Recent progress has enabled the ability to characterize the major molecules found within specific individual cells. Especially within the brain, a myriad of cell types are colocalized and oftentimes only a subset of these cells undergo changes in both healthy and pathological states. Here we highlight recent progress in mass spectrometry-based approaches used for single cell metabolomics, emphasizing their application to neuroscience research. Single cell studies can be directed to measuring differences between members of populations of similar cells (i.e., oligodendrocytes), as well as characterizing differences between cell types (i.e., neurons and astrocytes), and are especially useful for measuring changes occurring during different behavior states, exposure to diets and drugs, neuronal activity, and disease. When combined with other -omics approaches such as transcriptomics, and with morphological and physiological measurements, single cell metabolomics aids fundamental neurochemical studies, has great potential in pharmaceutical development, and should improve the diagnosis and treatment of brain diseases.

    更新日期:2017-10-05
  • 更新日期:2017-10-05
  • Novel Trimodal MALDI Imaging Mass Spectrometry (IMS3) at 10 μm Reveals Spatial Lipid and Peptide Correlates Implicated in Aβ Plaque Pathology in Alzheimer’s Disease
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-10-04
    Ibrahim Kaya, Dimitri Brinet, Wojciech Michno, Mehmet Başkurt, Henrik Zetterberg, Kaj Blenow, Jörg Hanrieder
    更新日期:2017-10-04
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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