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  • Stereoselective Differences between the Reinforcing and Motivational Effects of Cathinone-Derived 4-Methylmethcathinone (Mephedrone) In Self-Administering Rats
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-22
    Helene L. Philogene-Khalid, Steven J. Simmons, Sunil Nayak, Rose M. Martorana, Shu H. Su, Yohanka Caro, Brona Ranieri, Kathryn DiFurio, Lili Mo, Taylor A. Gentile, Ali Murad, Allen B. Reitz, John W. Muschamp, Scott M. Rawls
    更新日期:2017-09-22
  • Comparison of α-Synuclein Fibril Inhibition by Four Different Amyloid Inhibitors
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-21
    Narendra Nath Jha, Rakesh Kumar, Rajlaxmi Panigrahi, Ambuja Navalkar, Dhiman Ghosh, Shruti Sahay, Mritunjoy Mondal, Ashutosh Kumar, Samir. K. Maji
    更新日期:2017-09-21
  • Caring about Power Analyses
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-21
    Jennifer E. Murray, Scott T. Barrett, Rebecca L. Brock, Rick A. Bevins
    更新日期:2017-09-21
  • Future Priorities in Tackling Infections Due to Brain-Eating Amoebae
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-21
    Naveed Ahmed Khan, Ayaz Anwar, Ruqaiyyah Siddiqui

    Brain-eating amoebae (Acanthamoeba spp., Balamuthia mandrillaris, and Naegleria fowleri) can cause opportunistic infections involving the central nervous system. It is troubling that the mortality rate is more than 90% despite advances in antimicrobial chemotherapy over the last few decades. Here, we describe urgent key priorities for improving outcomes from infections due to brain-eating amoebae.

    更新日期:2017-09-21
  • Identification of 5-(1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)thiophene-2-Carboxamides as Novel and Selective Monoamine Oxidase B Inhibitors Used to Improve Memory and Cognition
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-20
    Alan P. Kaplan, Terence Keenan, Roderick Scott, Xianbo Zhou, Rusiko Bourchouladze, Andrew J. McRiner, Mark E. Wilson, Darlene Romashko, Regina Miller, Matthew Bletsch, Gary Anderson, Jennifer Stanley, Adia Zhang, Dong Lee, John Nikpur
    更新日期:2017-09-20
  • Novel Vilazodone–Tacrine Hybrids as Potential Multitarget-Directed Ligands for the Treatment of Alzheimer’s Disease Accompanied with Depression: Design, Synthesis, and Biological Evaluation
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-19
    Xiaokang Li, Huan Wang, Yixiang Xu, Wenwen Liu, Qi Gong, Wei Wang, Xiaoxia Qiu, Jin Zhu, Fei Mao, Haiyan Zhang, Jian Li
    更新日期:2017-09-20
  • Two Distinct Polymorphic Folding States of Self-Assembly of the Non-amyloid-β Component Differ in the Arrangement of the Residues
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-19
    Maya Pollock-Gagolashvili, Yifat Miller
    更新日期:2017-09-19
  • 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 : 2017-09-19
    Ibrahim Kaya, Dimitri Brinet, Wojciech Michno, Mehmet Baskurt, Henrik Zetterberg, Kaj Blennow, Jörg Hanrieder

    Multimodal chemical imaging using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) can provide comprehensive molecular information in situ within the same tissue sections. This is of relevance for studying different brain pathologies such as Alzheimer’s Disease (AD), where recent data suggest a critical relevance of co-localizing Aβ peptides and neuronal lipids. We here developed a novel trimodal, high-resolution (10µm) MALDI imaging MS (IMS) paradigm for negative- and positive ion mode lipid analysis and subsequent protein ion imaging on the same tissue section. Matrix sublimation of 1,5-diaminonaphthalene (1,5-DAN) enabled dual polarity lipid MALDI IMS on the same pixel points at high spatial resolutions (10µm) and with high spectral quality. This was followed by 10µm resolution protein imaging on the same measurement area, which allowed correlation of lipid signals with protein distribution patterns within distinct cerebellar regions in mouse brain. The demonstrated trimodal imaging strategy (IMS3) was further shown to be an efficient approach for simultaneously probing Aβ plaque-associated lipids and Aβ peptides within the hippocampus of 18 month-old transgenic AD mice (tgArcSwe). Here, IMS3 revealed a strong co-localization of distinct lipid species including ceramides, phosphatidylinositols, sulfatides (Cer 18:0, PI 38:4, ST 24:0) and lysophosphatidylcholines (LPC 16:0, LPC 18:0) with plaque-associated Aβ isoforms (Aβ 1-37, Aβ 1-38, Aβ 1-40). This highlights the potential of IMS3 as an alternative, superior approach to consecutively performed immuno-based Aβ staining strategies. Furthermore, the IMS3 workflow allowed for multimodal in situ MS/MS analysis of both lipids and Aβ peptides. Altogether, the here presented IMS3 approach shows great potential for comprehensive, high-resolution molecular analysis of histological features at cellular length scales with high chemical specificity. It hence represents a powerful approach for probing the complex molecular pathology of e.g. neurodegenerative diseases that are characterized by neurotoxic protein aggregation.

    更新日期:2017-09-19
  • Experimental and Theoretical Insights into the Inhibition Mechanism of Prion Fibrillation by Resveratrol and its Derivatives
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-15
    Lanlan Li, Yongchang Zhu, Shuangyan Zhou, Xiaoli An, Yan Zhang, Qifeng Bai, Yong-Xing He, Huanxiang Liu, Xiaojun Yao
    更新日期:2017-09-15
  • The Medicinal Chemistry of Natural and Semisynthetic Compounds against Parkinson’s and Huntington’s Diseases
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-15
    Enrico Zanforlin, Giuseppe Zagotto, Giovanni Ribaudo
    更新日期:2017-09-15
  • Membrane Dynamics of γ-Secretase Provides a Molecular Basis for β-Amyloid Binding and Processing
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-25
    Arun Kumar Somavarapu, Kasper P. Kepp
    更新日期:2017-09-15
  • Two distinct polymorphic folding states of self-assembly of the non-amyloid β component differ in the arrangement of the residues
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-15
    Maya Pollock-Gagolashvili, Yifat Miller

    Parkinson’s disease is a degenerative disorder of the central nerves system. It is characterized by presence of Lew bodies (LBs), in which the main components of the LBs are α-synuclein (AS) aggregates. The central domain of AS, known as the “non-amyloid β component” (NAC) is responsible for the aggregation properties of AS. It is proposed that AS fibrillar structure is a well-packed cross-β structure of the NAC domains, while the N- and C-termini are disordered. Therefore, the study of the self-assembly of NAC domains are crucial in order to understand the molecular mechanisms of AS aggregation. This is a first study that illustrates two distinct polymorphic folding states of NAC that differ in the arrangement of the residues along the sequence. One of the polymorphic folding states reveals a conformational change that is similar to the other polymorphic folding state in the backbone shape, but differ in the arrangement of the residues along the backbone. This work provides insight into the molecular mechanisms through which AS can self-assembled in two different pathways yielding to a conformational change between the two polymorphic folding states.

    更新日期:2017-09-15
  • Angiostrongylus cantonensis: Agent of a Sometimes Fatal Globally Emerging Infectious Disease (Rat Lungworm Disease)
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-13
    Robert H. Cowie

    Angiostrongylus cantonensis, the rat lungworm, is a dangerous invasive species that is the agent of a potentially fatal globally emerging infectious disease. Humans are infected most commonly by ingestion, deliberately or inadvertently, of the parasite larvae in their intermediate snail hosts. The larvae make their way to the brain where they can cause severe neurological damage before eventually dying. Symptoms of the disease are diverse, making it difficult to diagnose. Treatment is primarily with corticosteroids to reduce inflammation, while treatment with anthelmintics to kill the worms remains controversial. There have been almost 3000 cases globally, the majority in southern China, but the parasite is spreading and now occurs much more widely. In the USA, almost all cases have been in Hawaii, but the parasite is also present in southeastern states. As the climate warms, this tropical/subtropical parasite is likely to spread further.

    更新日期:2017-09-14
  • Resolving the atomistic modes of anle138b inhibitory action on peptide oligomer formation.
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-14
    Dirk Matthes, Vytautas Gapsys, Christian Griesinger, Bert L. de Groot

    The di-phenyl-pyrazole compound anle138b is a known inhibitor of oligomeric aggregate formation in vitro and in vivo. Therefore, anle138b is considered a promising drug candidate to beneficially interfere with neurodegenerative processes causing devastating pathologies in humans. The atomistic details of the aggregation inhibition mechanism, however, are to date unknown since the ensemble of small nonfibrillar aggregates is structurally heterogeneous and inaccessible to direct structural characterization. Here, we set out to elucidate anle138b's mode of action using all-atom molecular dynamics simulations on the multi-microsecond timescale. By comparing simulations of dimeric to tetrameric aggregates from fragments of four amyloidogenic proteins (Aβ, hTau40, hIAPP and Sup35N) in the presence and absence of anle138b, we show that the compound reduces the overall number of intermolecular hydrogen bonds, disfavors the sampling of the aggregated state and remodels the conformational distributions within the small oligomeric peptide aggregates. Most notably, anle138b preferentially interacts with the disordered structure ensemble via its pyrazole moiety, thereby effectively blocking interpeptide main chain interactions and impeding the spontaneous formation of ordered β-sheet structures, in particular those with out-of-register anti-parallel β-strands. The structurally very similar compound anle234b was previously identified as inactive by in vitro experiments. Here, we show that anle234b has no significant effect on the aggregation process in terms of reducing the β-structure content. Moreover, we demonstrate that the hydrogen bonding capabilities are auto-inhibited due to steric effects imposed by the molecular geometry of anle234b and thereby indirectly confirm the proposed inhibitory mechanism of anle138b. We anticipate that the prominent binding of anle138b to partially disordered and dynamical aggregate structures is a generic basis for anle138b's ability to suppress toxic oligomer formation in a wide range of amyloidogenic peptides and proteins.

    更新日期:2017-09-14
  • Melatonin improves cognitive deficits via restoration of cholinergic dysfunction in a mouse model of scopolamine-induced amnesia.
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-13
    Bai Hui Chen, Joon Ha Park, Dae Won Kim, Jinseu Park, Soo Young Choi, In Hye Kim, Jeong Hwi Cho, Tae-Kyeong Lee, Jae Chul Lee, Choong-Hyun Lee, In Koo Hwang, Young-Myeong Kim, Bing Chun Yan, Il-Jun Kang, Bich Na Shin, Yun Lyul Lee, Myoung Cheol Shin, Jun Hwi Cho, Young Joo Lee, Yong Hwan Jeon, Moo-Ho Won, Ji Hyeon Ahn

    Melatonin is known to improve cognitive deficits and its functions have been studied in various disease models, including Alzheimer's disease. In this study, we investigated effects of melatonin on cognition and the cholinergic system of the septum and hippocampus in a mouse model of scopolamine-induced amnesia. Scopolamine (1 mg/kg) and melatonin (10 mg/kg) were administered intraperitoneally to mice for 2 and 4 weeks. The Morris water maze and passive avoidance tests revealed that both treatments of scopolamine significantly impaired spatial learning and memory; however, 2- and 4-week melatonin treatments significantly improved the spatial learning and memory. In addition, scopolamine treatments significantly decreased protein levels and immunoreactivities of choline acetyltransferase (ChAT), high-affinity choline transporter (CHT), vesicular acetylcholine transporter (VAChT), and muscarinic acetylcholine receptor M1 (M1R) in the septum and hippocampus. However, the treatments with melatonin resulted in increased ChAT-, CHT-, VAChT- and M1R-immunoreactivities and their protein levels in the septum and hippocampus. Our results demonstrate that melatonin treatment is effective in improving the cognitive deficits via restoration of the cholinergic system in the septum and hippocampus of a mouse model of scopolamine-induced amnesia.

    更新日期:2017-09-13
  • Effect of Alzheimer Familial Chromosomal Mutations on the Amyloid Fibril Interaction with Different PET Tracers- Insight from Molecular Modeling Studies
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-12
    Kanagasabai Balamurugan, Natarajan Arul Murugan, Bengt Långström, Agneta Nordberg, Hans Ågren

    Alzheimer’s disease (AD) is the most common neurodegenerative disorder. Along with an increasing number of elderly worldwide it poses a great challenge for the society and healthcare. Although sporadic AD is the common form of AD, 2-3% of the AD cases are expected to be due to mutations in the beta region of the amyloid precursor protein which is referred to as autosomal dominant AD (ADAD). These mutations may cause changes in the secondary structure of the amyloid beta fibrils and may alter the fibrillization rate leading to changes in the disease development and could also affect the binding to tracers used in diagnosis. In particular, from some recent clinical studies using PET tracers for detection of fibrillar amyloids it is evident that in ADAD patients with Arctic mutation no amyloid plaque binding can be detected with 11C-Pittsburgh Compound B (11C-PIB). However, for in vitro conditions, significant binding of 3H-PIB has been reported for the amyloid fibrils carrying the Arctic mutation. The aim of the present study is to investigate if there is any mutation specific binding of commonly used amyloid tracers, namely Florbetaben, Florbetapir, FPIB, AZD4694, AZD2184, by means of molecular modelling techniques. Other than Arctic, ADAD mutations, such as the Dutch, Italian, Iowa and Flemish mutations, are considered in this study. We report that all tracers except florbetapir show reduced binding affinity towards amyloid beta fibrils with the Arctic mutation when compared to the native type. Moreover, florbetapir is the only tracer that binds to all mutants with increased affinity when compared to the native fibril. The results obtained from these studies could increase the understanding of the structural changes, caused due by mutation and concomitant changes in the interaction pattern of the PET tracers with the mutated variants, which in turn can be useful in selecting the appropriate tracers for the diagnosis purpose as well as for designing new tracers with desirable properties.

    更新日期:2017-09-12
  • Multifunctional Analogs of Kynurenic Acid for the Treatment of Alzheimer’s Disease: Synthesis, Pharmacology, and Molecular Modeling Studies
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-08
    Girdhar Singh Deora, Srinivas Kantham, Stephen Chan, Satish N. Dighe, Suresh K. Veliyath, Gawain McColl, Marie-Odile Parat, Ross P. McGeary, Benjamin P. Ross
    更新日期:2017-09-08
  • Stereoselective differences between the reinforcing and motivational effects of cathinone-derived 4-methylmethcathinone (mephedrone) in self-administering rats
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-08
    Helene L Philogene-Khalid, Steven J Simmons, Sunil Nayak, Rose M Martorana, Shu H Su, Yohanka Caro, Brona Ranieri, Kathryn DiFurio, Lili Mo, Taylor A Gentile, Ali Murad, Allen B. Reitz, John W Muschamp, Scott M Rawls

    Mephedrone (4-methylmethcathinone (4-MMC)) (MEPH) is a new psychoactive substance (NPS) of the synthetic cathinone class. MEPH has a chiral center and exists as two enantiomers (R-,S-MEPH), yet stereospecific effects of MEPH have not been extensively investigated in preclinical assays. Because significant behavioral and neurochemical differences can exist between enantiomers, probing effects of stereochemistry on biological activity enables separation of adverse and therapeutic effects. Our prior work showed that R-MEPH, relative to S-MEPH, produced greater locomotor activation, place preference and facilitation of brain reward thresholds in rodents. The present study sought to determine if MEPH enantiomers display stereospecific reward and reinforcement in rat self-administration assays. In Experiment 1, rats were trained to self-administer racemic MEPH (0.50 mg/kg/inf), and dose substitution effects of R-MEPH (0.50 mg/kg/inf) and S-MEPH (0.25, 0.50, 2.00 mg/kg/inf) were examined. In Experiment 2, separate rats were trained to self-administer R-MEPH (0.25, 0.50, 2.00 mg/kg/inf) or S-MEPH (0.25, 0.50, 2.00 mg/kg/inf) and were thereafter evaluated under progressive-ratio access conditions. Within this cohort, 50-kHz ultrasonic vocalizations (USVs) were recorded to measure potential differences in subjective positive affect associated with MEPH enantiomer self-administration. We identified enantiomer- and dose-dependent effects on infusions earned during self-administration following acquisition of racemic MEPH, with greatest infusions under low-effort, fixed-ratio 1 access conditions from low-dose S-MEPH self-administration. When taxed with progressive-ratio access conditions, rats trained to self-administer R-MEPH showed higher breakpoints than those of rats trained to self-administer S-MEPH. Additionally, R-MEPH elicited greatest rates of 50-kHz USVs compared to S-MEPH. Taken together, these data suggest that the R-enantiomer of MEPH is primarily responsible for the rewarding, reinforcing, and motivational properties of racemic MEPH, which increases our understanding of stereospecific preferences pertaining to MEPH abuse.

    更新日期:2017-09-08
  • MitoNEET (CISD1) knockout mice show signs of striatal mitochondrial dysfunction and a Parkinson’s disease phenotype
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-07
    Werner J. Geldenhuys, Stanley A Benkovic, Li Lin, Heather M Yonutas, Samuel D Crish, Patrick G Sullivan, Altaf S Darvesh, Candice M Brown, Jason Richardson

    Mitochondrial dysfunction is thought to play a significant role in neurodegeneration observed in Parkinson’s disease (PD), yet the mechanisms underlying this pathology remain unclear. Here, we demonstrate that loss of mitoNEET (CISD1), an iron-sulfur containing protein which regulates mitochondrial bioenergetics, results in mitochondrial dysfunction and loss of striatal dopamine and tyrosine hydroxylase. Mitochondria isolated from mice lacking mitoNEET were dysfunctional as revealed by elevated reactive oxygen species (ROS) and reduced capacity to produce ATP. Gait analysis revealed a shortened stride length and decreased rotarod performance in knockout mice, consistent with the loss of striatal dopamine. Together, these data suggest mitoNEET KO mice exhibit many of the characteristics of early neurodegeneration in PD and may provide a novel drug discovery platform to evaluate compounds for enhancing mitochondrial function in neurodegenerative disorders.

    更新日期:2017-09-07
  • Vitamin B12 Inhibits Tau Fibrillization via Binding to Cysteine Residues of Tau
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-06
    Saharnaz Rafiee, Kazem Asadollahi, Gholamhossein Riazi, Shahin Ahmadian, Ali Akbar Saboury
    更新日期:2017-09-07
  • Novel Cell Model for Tauopathy Induced by a Cell-Permeable Tau-Related Peptide
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-06
    John R. Veloria, Lin Li, Gail A. M. Breen, Warren J. Goux
    更新日期:2017-09-07
  • Role of Sporadic Parkinson Disease Associated Mutations A18T and A29S in Enhanced α-Synuclein Fibrillation and Cytotoxicity
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-06
    Sanjay Kumar, Deepak Kumar Jangir, Roshan Kumar, Manisha Kumari, Neel Sarovar Bhavesh, Tushar Kanti Maiti
    更新日期:2017-09-06
  • Chemically Modified, α-Amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) Receptor RNA Aptamers Designed for in Vivo Use
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-05
    Zhen Huang, Wei Wen, Andrew Wu, Li Niu
    更新日期:2017-09-06
  • Revisiting the Quinoxalinedione Scaffold in the Construction of New Ligands for the Ionotropic Glutamate Receptors
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-05
    Charles S. Demmer, David Rombach, Na Liu, Birgitte Nielsen, Darryl S. Pickering, Lennart Bunch
    更新日期:2017-09-06
  • Comparison of Spreading Depolarizations in the Motor Cortex and Nucleus Accumbens: Similar Patterns of Oxygen Responses and the Role of Dopamine
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-05
    Caddy N. Hobbs, Gordon Holzberg, Akira S. Min, R. Mark Wightman
    更新日期:2017-09-06
  • Novel Vilazodone-Tacrine Hybrids as Potential Multitarget-Directed Ligands for the Treatment of Alzheimer’s Disease Accompanied with Depression: Design, Synthesis and Biological Evaluation
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-05
    Xiaokang Li, Huan Wang, Yixiang Xu, Wenwen Liu, Xiaoxia Qiu, Jin Zhu, Fei Mao, Haiyan Zhang, Jian Li

    Depression is one of the most frequent psychiatric complications of Alzheimer’s disease (AD), affecting up to 50% of the patients. A novel series of hybrid molecules were designed and synthesized by combining the pharmacophoric features of vilazodone and tacrine as potential multitarget-directed ligands for the treatment of AD with depression. In vitro biological assays were conducted to evaluate the compounds, among the 30 hybrids, compound 1e showed relatively balanced profiles between acetylcholinesterase inhibition (IC50 = 3.319 ± 0.708 μM), 5-HT1A agonist (EC50 = 107 ± 37 nM) and 5-HT reuptake inhibition (IC50 = 76.3 ± 33 nM). Compound 1e displayed tolerable hepatotoxicity and moderate hERG inhibition activity, and could penetrate the blood–brain barrier in vivo. Furthermore, an oral intake of 30 mg/kg of 1e·HCl could significantly improve the cognitive function of scopolamine-induced amnesia mice and alleviate the depressive symptom in tail suspension test. The effectivity of 1e validates the rationality of our design strategy.

    更新日期:2017-09-06
  • Comparison of α-synuclein fibril inhibition by four different amyloid inhibitors
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-05
    Narendra Nath Jha, Rakesh Kumar, Rajlaxmi Panigrahi, Ambuja Navalkar, Dhiman Ghosh, Shruti Sahay, Mrityunjoy Mondal, Ashutosh Kumar, Samir K. Maji

    Aggregation of α-synuclein (α-Syn) into toxic oligomers and fibrils leads to Parkinson’s disease (PD) pathogenesis. Molecules that can inhibit the fibrillization and oligomerization of α-Syn have potential therapeutic value. Here, we studied four selective amyloid inhibitors: Dopamine (Dopa), Amphotericin-B (Amph), Epigallocatechingallate (EGCG) and Quinacrinedihydrochloride (Quin) for their effect on oligomerization, fibrillization and preformed fibrils of α-Syn. The aggregation kinetics of α-Syn using ThT fluorescence and conformational transition by circular dichroism (CD) in the presence and absence of these four compounds suggest that, except Quin, remaining three molecules inhibit α-Syn aggregation in concentration dependent manner. In consistence with the aggregation kinetics data, the morphological study of aggregates formed in the presence of these compounds showed corresponding decrease in fibrillar size. The analysis of cell viability using MTT assay showed reduction in toxicity of α-Syn aggregates formed in the presence of these compounds, which also correlates with reduction of exposed hydrophobic surface as studied by ANS binding. Additionally, these inhibitors except Quin demonstrated reduction in size as well as the toxicity of oligomeric/fibrillar aggregates of α-Syn. The residue specific interaction to low molecular weight (LMW) species of α-Syn by 2D NMR study revealed that, the region and extent of binding are different for all these molecules. Furthermore, fibril-binding data using SPR suggested that there is no direct relationship between the binding affinity and fibril inhibition by these compounds. The present study suggests that sequence based interaction of small molecules to soluble α-Syn might dictate their inhibition or modulation capacity, which might be helpful in designing modulators of α-Syn aggregation

    更新日期:2017-09-05
  • Structural Determinants of the γ-8 TARP Dependent AMPA Receptor Antagonist
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-05
    Matthew R. Lee, Kevin M. Gardinier, Douglas L. Gernert, Douglas A. Schober, Rebecca A. Wright, He Wang, Yuewei Qian, Jeffrey M. Witkin, Eric S. Nisenbaum, Akihiko S. Kato
    更新日期:2017-09-05
  • Why I’m Not a Cognitive Psychologist... or a Behaviorist... or a Biologist
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-01
    Erik J. Garcia
    更新日期:2017-09-04
  • The Medicinal Chemistry of Natural and Semi-Synthetic Compounds Against Parkinson’s and Huntington’s Diseases
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-09-01
    Enrico Zanforlin, Giuseppe Zagotto, Giovanni Ribaudo

    Among the diseases affecting the Central Nervous System (CNS), neurodegenerations attract the interest of both the clinician and the medicinal chemist. The increasing average age of population, the growing number of patients and the lack of long-term effective remedies push ahead the quest for novel tools against this class of pathologies. We present a review on the state of the art of the molecules (or combination of molecules) of a natural origin which are currently under study against two well-defined pathologies: Parkinson’s Disease (PD) and Huntington’s Disease (HD). Nowadays, very few tools are available for preventing or counteracting the progression of such diseases. Two major parameters were considered for the preparation of this review: particular attention was reserved to these research works presenting well-defined molecular mechanisms for the studied compounds, and, where available, papers reporting in vivo data were preferred. A literature search for peer-reviewed articles using PubMed, Scopus and Reaxys databases was performed, exploiting different keywords and logical operators: 91 papers were considered (preferentially published after 2015). The review presents a brief overview on the aetiology of the studied neurodegenerations and the current treatments, followed by a detailed discussion of the natural and semi-synthetic compounds dividing them in different paragraphs considering their several mechanisms of action.

    更新日期:2017-09-04
  • Identification of 5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)thiophene-2-Carboxamides as Novel and Selective Monoamine Oxidase B Inhibitors Used to Improve Memory and Cognition
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-31
    Alan Kaplan, Terence Keenan, Roderick Scott, Xianbo Zhou, Rusiko Bourchouladze, Andrew J. McRiner, Mark E. Wilson, Darlene Romashko, Regina Miller, Matthew Bletsch, Gary Anderson, Jennifer Stanley, Adia Zhang, Dong Lee, John Nikpur

    Initial work in Drosophila and mice demonstrated that the transcription factor cAMP (cyclic adenosine monophosphate) response element binding protein (CREB) is a master control gene for memory formation. The relationship between CREB and memory has also been found to be true in other species, including aplysia and rats. It is thus well established that CREB activation plays a central role in memory enhancement and that CREB is activated during memory formation. Based on these findings, a phenotypic high throughput screening campaign, which utilized a CRE-luciferase (CRE-Luci) SK-N-MC cell line, was performed to identify compounds that enhance transcriptional activation of the CRE promoter with a suboptimal dose of forskolin. A number of small-molecule hits of unknown mechanisms of action were identified in the screening campaign, including HT-0411. Follow-on studies suggested that the CREB activation by HT-0411 is attributed to its specific and selective inhibition of monoamine oxidase B (MAO-B). Further, HT-0411 was shown to improve 24-hour memory in rodents in a contextual fear conditioning model. This report describes the lead optimization of a series of 5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl) thiophene-2-carboxamides that were identified as novel, potent and selective inhibitors of MAO-B. Extensive SAR studies and in vivo behavioral evaluations of this and other related analog series identified a number of potential clinical development candidates; ultimately, compound 8f was identified as a candidate molecule with high selectivity towards MAO-B (29-56 nM) over MAO-A (no inhibition at 10 μM), an excellent profile against a panel of other enzymes and receptors, good pharmacokinetic properties in rodents and dogs, and efficacy in multiple rodent memory models.

    更新日期:2017-08-31
  • Role of sporadic Parkinson disease associated mutations A18T and A29S in enhanced alpha synuclein fibrillation and cytotoxicity
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-25
    Sanjay Kumar, Deepak Kumar Jangir, Roshan Kumar, Manisha Kumari, Neel Bhavesh, Tushar Kanti Maiti

    Deposition of pre-synaptic protein α-synuclein in Lewy bodies and Lewy neurites in the substantia nigra region of brain has been linked with the clinical symptoms of the Parkinson’s disease (PD). Proteotoxic stress conditions and mutations that cause abnormal aggregation of α-synuclein have close association with onset of PD and its progression. Therefore, studies pertaining to α-synuclein mutations play important roles in mechanistic understanding of aggregation behaviour of the protein and subsequent pathology. Herein, guided by this fact, we have studied the aggregation kinetics, morphology and neurotoxic effects of the two newly discovered sporadic PD associated mutants A18T and A29S of α-synuclein. Our studies demonstrate that both of the mutants are aggregation prone and undergo rapid aggregation compared to wild type α-synuclein. Further, it was found that A18T mutant followed faster aggregation kinetics compared to A29S substitution. Additionally, we have designed three point mutations of α-synuclein for better understanding of the effects of substitutions on protein aggregation and demonstrated that substitution of alanine at 18th position is highly sensitive compared to adjacent positions. Our results provide better understanding on the effects of α-synuclein mutations on its aggregation behaviour that may be important in development of PD pathology.

    更新日期:2017-08-26
  • Membrane dynamics of γ-secretase provides a molecular basis for Aβ binding and processing
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-25
    Arun Kumar Somavarapu, Kasper P. Kepp

    γ-secretase produces β-amyloid (Aβ) within its presenilin (PS1) subunit, mutations in which cause Alzheimer’s disease, and current therapies thus seek to modulate its activity. While the general structure is known from recent electron microscopy studies, direct loop- and membrane-interactions and explicit dynamics relevant to substrate processing remain unknown. We report a modeled structure utilizing the optimal multi-template information available, including loops and missing side chains, account of maturation cleavage, and explicit all-atom molecular dynamics in the membrane. We observe three distinct conformations of γ-secretase (open, semi-open, and closed) that remarkably differ by tilting of helix 2 and 3 of PS1, directly controlling active site availability. The large hydrophilic loop of PS1 where maturation occurs reveals a new helix segment that parallels the likely helix character of other substrates. The semi-open conformation consistently shows the best fit of Aβ peptides, i.e. longer residence before release and by inference more trimming. In contrast, the closed, hydrophobic conformation is largely inactive and the open conformation is active but provides fewer optimal interactions and induces shorter residence time and by inference releases Aβ peptides of longer lengths. Our simulations thus provide a molecular basis for substrate processing and changes in the Aβ42/Aβ40 ratio. Accordingly, selective binding to protect the semi-open “innocent” conformation provides a molecular recipe for effective γ-secretase modulators; we provide the full atomic structures for these states that may play a key role in developing selective γ-secretase modulators for treatment of Alzheimer’s disease.

    更新日期:2017-08-26
  • Vitamin B12 Inhibits Tau Fibrillization via Binding to Cysteine Residues of Tau
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-25
    Saharnaz Rafiee, Kazem Asadollahi, Gholamhossein Riazi, Shahin Ahmadian, Ali Akbar Saboury

    Two mechanisms underlie the inhibitory/acceleratory action of chemical compounds on tau aggregation including the regulation of cellular kinases and phosphatases activity and direct binding to tau protein. Vitamin B12 is one of the tau polymerization inhibitors that its deficiency is linked to inactivation of protein phosphatase 2A and subsequently hyper phosphorylation and aggregation of tau protein. Regarding to the structure and function of vitamin B12 and tau protein we assumed that vitamin B12 is also able to directly bind to tau protein. Hence we investigated into the interaction of vitamin B12 with tau protein in vitro using fluorometry and circular dichrosim. Interaction studies was followed by investigation into the effect of vitamin B12 on tau aggregation using ThT fluorescence, Circular dichroism, transmission electron microscopy and SDS-PAGE. The results indicated that vitamin B12 interacts with tau protein and prevents fibrillization of tau protein. Blocking the cysteine residues of tau confirmed the cysteine-mediated binding of vitamin B12 to tau and showed that binding to cysteine is essential for inhibitory effect of vitamin B12 on tau aggregation. SDS-PAGE analysis indicated that vitamin B12 inhibits tau aggregation and tau oligomers formed in the presence of vitamin B12 are mostly SDS-soluble. We propose that direct binding of vitamin B12 is another mechanism underlying the inhibitory role of vitamin B12 on tau aggregation and neurodegeneration.

    更新日期:2017-08-26
  • Pharmacological Evaluation of Novel Bioisosteres of an Adamantanyl Benzamide P2X7 Receptor Antagonist
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-25
    Shane M. Wilkinson, Melissa L. Barron, James O’Brien-Brown, Bieneke Janssen, Leanne Stokes, Eryn L. Werry, Mansoor Chishty, Kristen K. Skarratt, Jennifer A. Ong, David E. Hibbs, Danielle J. Vugts, Stephen Fuller, Albert D. Windhorst, Michael Kassiou
    更新日期:2017-08-26
  • Receptor Targeted Polymeric Nanostructures Capable of Navigating across the Blood-Brain Barrier for Effective Delivery of Neural Therapeutics
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-25
    Taru Dube, Sonika Chibh, Jibanananda Mishra, Jiban Jyoti Panda
    更新日期:2017-08-25
  • Rational Design and Multibiological Profiling of Novel Donepezil–Trolox Hybrids against Alzheimer’s Disease, with Cholinergic, Antioxidant, Neuroprotective, and Cognition Enhancing Properties
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-25
    Pei Cai, Si-Qiang Fang, Xue-Lian Yang, Jia-Jia Wu, Qiao-Hong Liu, Hao Hong, Xiao-Bing Wang, Ling-Yi Kong
    更新日期:2017-08-25
  • Placement of Hydroxy Moiety on Pendant of Peptidomimetic Scaffold Modulates Mu and Kappa Opioid Receptor Efficacy
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-25
    Aubrie A. Harland, Irina D. Pogozheva, Nicholas W. Griggs, Tyler J. Trask, John R. Traynor, Henry I. Mosberg
    更新日期:2017-08-25
  • Microchip Circulation Drastically Accelerates Amyloid Aggregation of 1–42 β-amyloid Peptide from Felis catus
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-25
    Witold Gospodarczyk, Maciej Kozak
    更新日期:2017-08-25
  • A Novel Cell Model for Tauopathy Induced by a Cell-permeable Tau-related Peptide
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-24
    John Veloria, Lin Li, Warren J Goux

    In the present study a cell penetrating peptide (CPP)-amyloid conjugate was prepared (T-peptide), where the amyloid-forming sequence was homologous to a nucleating sequence from human Tau protein (306VQIVYK311). Kinetic and biophysical studies showed the peptide formed long-lived oligomers which were taken up by endocytosis and localized in perinuclear vesicles and in the cytoplasm of murine hippocampal neuroblastoma cells and human HeLa cells. Thioflavin S (ThS) staining of amyloid colocalized with pathological phosphorylated Tau, suggesting that the peptide was able to seed endogenous wild-type Tau. Subsequent experiments showed that aggregates present in the lysosomes mediated lysosome membrane permeability (LMP). We observed a decrease in total Tau, irrespective of phosphorylation state, consistent with Tau fragmentation by lysosomal proteases. We found cytotoxicity of T-peptide could be abrogated by inhibitors of lysosomal hydrolases and caspases, consistent with a model where Tau fragments processed by the lysosome leak into the cytoplasm and induce toxicity in subsequent downstream steps. It is our hope that the T-peptide system may prove amenable to the evaluation of small molecule inhibitors of cytotoxicity, either those which target Tau aggregation or the lysosomal/autophagy system.

    更新日期:2017-08-25
  • Using Chemistry to Target Neuroblastoma
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-24
    Jeanne N. Hansen, Xingguo Li, Y. George Zheng, Louis T. Lotta, Abhishek Dedhe, Nina F. Schor
    更新日期:2017-08-25
  • Label-Free Ratiometric Imaging of Serotonin in Live Cells
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-24
    Anand Kant Das, Barun Kumar Maity, Dayana Surendran, Umakanta Tripathy, Sudipta Maiti
    更新日期:2017-08-24
  • Discovery of Novel Pyrazolopyrimidinone Derivatives as Phosphodiesterase 9A Inhibitors Capable of Inhibiting Butyrylcholinesterase for Treatment of Alzheimer’s Disease
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-23
    Yan-Fa Yu, Ya-Dan Huang, Chen Zhang, Xu-Nian Wu, Qian Zhou, Deyan Wu, Yinuo Wu, Hai-Bin Luo
    更新日期:2017-08-24
  • Synthesis, Characterization, and Activity of a Triazine Bridged Antioxidant Small Molecule
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-22
    Paulina Gonzalez, Kristof Pota, Lara Su Turan, Viviana C. P. da Costa, Giridhar Akkaraju, Kayla N. Green
    更新日期:2017-08-23
  • Molecular Dynamics Simulation Study on the Binding and Stabilization Mechanism of Antiprion Compounds to the “Hot Spot” Region of PrPC
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-22
    Shuangyan Zhou, Xuewei Liu, Xiaoli An, Xiaojun Yao, Huanxiang Liu
    更新日期:2017-08-23
  • Delivering FLT to the Central Nervous System by Means of a Promising Targeting System: Synthesis, [11C]Radiosynthesis, and in Vivo Evaluation
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-22
    Fabienne Gourand, Mihaela-Liliana Ţînţaş, Axelle Henry, Méziane Ibazizène, Martine Dhilly, Fabien Fillesoye, Cyril Papamicaël, Vincent Levacher, Louisa Barré
    更新日期:2017-08-23
  • Structural Determinants of the γ-8 TARP Dependent AMPA Receptor Antagonist
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-21
    Matthew R Lee, Kevin M. Gardinier, Douglas L Gernert, Douglas A. Schober, Rebecca A Wright, He Wang, Yuewei Qian, Jeffrey M Witkin, Eric S. Nisenbaum, Akihiko S Kato

    The forebrain specific AMPA receptor antagonist, LY3130481/CERC-611, which selectively antagonizes the AMPA receptors associated with TARP γ-8, an auxiliary subunit enriched in the forebrain, has potent antiepileptic activities without motor side effects. We designated the compounds with such activities as γ-8 TARP dependent AMPA receptor antagonists (γ-8 TDAAs). In this work, we further investigated the mechanisms of action using a radio-labeled γ-8 TDAA and ternary structural modeling with mutational validations to characterize the LY3130481 binding to γ-8. The radio-ligand binding to the cells heterologously expressing GluA1 and / or γ-8 revealed that γ-8 TDAAs binds to γ-8 alone without AMPA receptors. Homology modeling of γ-8, based on the crystal structures of a distant TARP homologue, murine claudin 19, in conjunction with knowledge of two γ-8 residues previously identified as critical for the LY3130481 TARP-dependent selectivity provided the basis for a binding mode prediction. This allowed further rational mutational studies for characterization of the structural determinants in TARP γ-8 for LY3130481 activities, both thermodynamically as well as kinetically.

    更新日期:2017-08-22
  • Multifunctional analogs of kynurenic acid for the treatment of Alzheimer’s disease: Synthesis, pharmacology and molecular modeling studies
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-21
    Girdhar Singh Deora, Srinivas Kantham, Stephen Chan, SATISH NATHA N DIGHE, Suresh K. Veliyath, Gawain McColl, Marie-Odile Parat, Ross Peter McGeary, Benjamin P. Ross

    We report the synthesis and pharmacological investigation of analogs of the endogenous molecule kynurenic acid (KYNA) as multifunctional agents for the treatment of Alzheimer’s disease (AD). Synthesized KYNA analogs were tested for their N-methyl-D-aspartate (NMDA) receptor binding, mGluR5 binding and function, acetylcholinesterase (AChE) inhibition, DPPH radical scavenging, interference with the amyloid beta peptide (Aβ) fibrillation process, and protection against Aβ-induced toxicity in transgenic Caenorhabditis elegans strain GMC101 expressing full-length Aβ42. Molecular modeling studies were also performed to predict the binding modes of most active compounds with NMDAR, mGluR5 and Aβ42. Among the synthesized analogs, 3c, 5b and 5c emerged as multifunctional compounds that act via multiple anti-AD mechanisms including AChE inhibition, free radical scavenging, NMDA receptor binding, mGluR5 binding, inhibition of Aβ42 fibril formation, and disassembly of preformed Aβ42 fibrils. Interestingly, 5c showed protection against Aβ42-induced toxicity in transgenic C. elegans strain GMC101. Moreover, 5b and 5c displayed high permeability in an MDR1-MDCKII cell-based model of the blood-brain barrier (BBB). Compound 3b emerged with specific activity as a mi-cromolar AChE inhibitor, however it had low permeability in the BBB model. This study highlights the opportunities that exist to develop analogs of endogenous molecules from the kynurenine pathway for therapeutic uses.

    更新日期:2017-08-22
  • Reduction of NF-κB (p65) in Scrapie-Infected Cultured Cells and in the Brains of Scrapie-Infected Rodents
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-21
    Yue Ma, Qi Shi, Jing Wang, Kang Xiao, Jing Sun, Yan Lv, Man Guo, Wei Zhou, Cao Chen, Chen Gao, Bao-Yun Zhang, Xiao-Ping Dong
    更新日期:2017-08-21
  • Comparison of Spreading Depolarizations in the Motor Cortex and Nucleus Accumbens: Similar Patterns of Oxygen Responses and the Role of Dopamine
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-18
    Caddy Noahl Hobbs, Gordon Holzberg, Akira S. Min, R. Mark Wightman

    Spreading depolarizations (SD) are pathophysiological phenomena that spontaneously arise in traumatized neural tissue and can promote cellular death. Most investigations of SD are performed in the cortex, a brain region that is susceptible to these depolarizing waves and accessible via a variety of monitoring techniques. Here, we describe SD responses in the cortex and the deep brain region of the nucleus accumbens (NAc) of the anesthetized rat with a minimally invasive, implantable sensor. With high temporal resolution, we characterize the time course of oxygen responses to SD in relation to the electrophysiological depolarization signal. The predominant oxygen pattern consists of four phases: 1) a small initial decrease, 2) a large increase during the SD, 3) a delayed increase, and 4) a persistent decrease from baseline after the SD. Oxygen decreases during SD were also recorded. This response occurred more often in the NAc than the cortex (56% vs 20% of locations, respectively), which correlates to denser cortical vascularization. We also find that SDs travel more quickly in the cortex than NAc, likely affected by regional differences in cell type populations. Finally, we investigate the previously uncharacterized effects of dopamine release during SD in the NAc with dopamine receptor blockade. Our results support an inhibitory role of the D2 receptor on SD. As such, the data presented here expands the current understanding of within- and between-region variance in responses to SD.

    更新日期:2017-08-19
  • Enhanced Stress Response in 5-HT1AR Overexpressing Mice: Altered HPA Function and Hippocampal Long-Term Potentiation
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-18
    Fuencisla Pilar-Cuéllar, Rebeca Vidal, Álvaro Díaz, Emilio Garro-Martínez, Raquel Linge, Elena Castro, Robert Haberzettl, Heidrun Fink, Bettina Bert, Jan Brosda, Beatriz Romero, Benedicto Crespo-Facorro, Ángel Pazos
    更新日期:2017-08-19
  • Targeting Fatty-Acid Amide Hydrolase with Prodrugs for CNS-Selective Therapy
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-18
    J. Matthew Meinig, Skylar J. Ferrara, Tania Banerji, Tapasree Banerji, Hannah S. Sanford-Crane, Dennis Bourdette, Thomas S. Scanlan
    更新日期:2017-08-19
  • Angiostrongyliasis (Rat Lungworm Disease): Viewpoints from Hawai‘i Island
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-18
    Kathleen Howe, Susan I. Jarvi
    更新日期:2017-08-19
  • Experimental and Theoretical Insights into the Inhibition Mechanism of Prion Fibrillation by Resveratrol and its Derivatives
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-17
    Lanlan Li, Yongchang Zhu, Shuangyan Zhou, Xiaoli An, Yan Zhang, Qifeng Bai, Yong-Xing He, Huanxiang Liu, Xiao-Jun Yao

    Resveratrol and its derivatives have been shown to display beneficial effects to neurodegenerative diseases. However, the molecular mechanism of resveratrol and its derivatives on prion conformational conversion is poorly understood. In this work, the interaction mechanism between prion and resveratrol as well as its derivatives were investigated using steady-state fluorescence quenching, Thioflavin T binding assay, western blotting and molecular dynamics simulation. Protein fluorescence quenching method and Thioflavin T assay revealed that resveratrol and its derivatives could interact with prion and interrupt prion fibrils formation. Molecular dynamics simulation results indicated that resveratrol can stabilize the PrP127-147 peptide mainly through π-π stacking interactions between resveratrol and Tyr128. The hydrogen bonds interactions between resveratrol and the PrP127-147 peptide could further reduce the flexibility and the propensity to aggregate. The results of this study can not only provide useful information about the interaction mechanism between resveratrol and prion, but also provide useful clues for further design of new inhibitors inhibiting prion aggregation.

    更新日期:2017-08-17
  • Roflupram, a Phosphodiesterase 4 Inhibitior, Suppresses Inflammasome Activation through Autophagy in Microglial Cells
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-17
    Tingting You, Yufang Cheng, Jiahong Zhong, Bingtian Bi, Bingqing Zeng, Wenhua Zheng, Haitao Wang, Jiangping Xu
    更新日期:2017-08-17
  • Exhaled Breath Markers for Nonimaging and Noninvasive Measures for Detection of Multiple Sclerosis
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-16
    Yoav Y. Broza, Lior Har-Shai, Raneen Jeries, John C. Cancilla, Lea Glass-Marmor, Izabella Lejbkowicz, José S. Torrecilla, Xuelin Yao, Xinliang Feng, Akimitsu Narita, Klaus Müllen, Ariel Miller, Hossam Haick
    更新日期:2017-08-16
  • Opiates and Plasticity in the Ventral Tegmental Area
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-16
    Ludovic D. Langlois, Fereshteh S. Nugent
    更新日期:2017-08-16
  • The Importance of Mitophagy in Maintaining Mitochondrial Function in U373MG Cells. Bafilomycin A1 Restores Aminochrome-Induced Mitochondrial Damage
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-15
    Sandro Huenchuguala, Patricia Muñoz, Juan Segura-Aguilar
    更新日期:2017-08-15
  • Stochastic Simulation of Dopamine Neuromodulation for Implementation of Fluorescent Neurochemical Probes in the Striatal Extracellular Space
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-15
    Abraham G. Beyene, Ian R. McFarlane, Rebecca L. Pinals, Markita P. Landry
    更新日期:2017-08-15
  • Rational design and multi-biological profiling of novel donepezil-trolox hybrids against Alzheimer’s disease, with cholinergic, antioxidant, neuroprotective and cognition enhancing properties
    ACS Chem. Neurosci. (IF 3.883) Pub Date : 2017-08-14
    Pei Cai, Si-Qiang Fang, Xue-Lian Yang, Jia-Jia Wu, Qiao-Hong Liu, Hao Hong, Xiao-Bing Wang, Lingyi Kong

    A novel series of donepezil-trolox hybrids were designed, synthesized and evaluated as multifunctional ligands against Alzheimer's disease (AD). Biological assays showed that these derivatives possessed moderate to good inhibitory activities against acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) as well as remarkable antioxidant effects. The optimal compound 6d exhibited balanced functions with good inhibition against hAChE (IC50 = 0.54 μM) and hMAO-B (IC50 = 4.3 μM), significant antioxidant activity (41.33 μM of IC50 by DPPH method, 1.72 and 1.79 trolox equivalent by ABTS and ORAC methods), excellent copper chelation and Aβ1−42 aggregation inhibition effect. Furthermore, cellular tests indicated that 6d was very low toxic and capable of combating oxidative toxins (H2O2, rotenone and oligomycin-A) induced neurotoxicity. Most importantly, oral administration of 6d demonstrated notable improvements on cognition and spatial memory against scopolamine-induced acute memory deficit as well as D-galactose (D-gal) and AlCl3 induced chronic oxidative stress in mice model without acute toxicity and hepatotoxicity. In summary, both in vitro and in vivo results suggested that 6d is a valuable candidate for the development of safe and effective anti-Alzheimer’s drug.

    更新日期:2017-08-15
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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