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ACS Chemical Neuroscience

Kanta Pravalika, Deepaneeta Sarmah, Harpreet Kaur, Madhuri Wanve, Jackson Saraf, Kiran Kalia, Anupom Borah, Dileep R Yavagal, Kunjan R Dave, Pallab Bhattacharya
Myeloperoxidase (MPO) is a protein present in azurophilic granules, macrophages, and neutrophils that are released into extracellular fluid (ECF) during inflammation. MPO releases hypochlorous acid (HOCL) and other chlorinated species. It is derived from hydrogen peroxide (H2O2) showing response during inflammatory conditions and plays a role in the immune defense against pathogens. MPO may show unwanted effects by indirectly increasing the formation of reactive nitrogen species (RNS), reactive oxygen species (ROS), and tumor necrosis factor alpha (TNF-α) leading to inflammation and oxidative stress...
January 19, 2018: ACS Chemical Neuroscience
Uri Nimrod Ramírez-Jarquín, Ricardo Tapia
The complex neuronal networks of the spinal cord coordinate a wide variety of motor functions, including walking, running and voluntary and involuntary movements. This is accomplished by different groups of neurons, called center pattern generators, which control left-right alternation and flexor-extensor patterns. These spinal circuits, located in the ventral horns, are formed by several neuronal types, and the specific function of most of them has been identified by means of studies in vivo and in the isolated spinal cord of mice harboring genetically induced ablation of specific neuronal populations...
January 19, 2018: ACS Chemical Neuroscience
Marvin Villacrez, Karin Hellman, Tatsuya Ono, Yutaka Sugihara, Melinda Rezeli, Fredrik Ek, Gyorgy Marko-Varga, Roger Olsson
Studying how and where drugs are metabolized in the brain is challenging. In an entire organism, peripheral metabolism produces many of the same metabolites as those in the brain, and many of these metabolites can cross the blood-brain barrier from the periphery, thus making the relative contributions of hepatic and brain metabolism difficult to study in vivo. In addition, drugs and metabolites contained in ventricles and in the residual blood of capillaries in the brain may overestimate drugs' and metabolites' concentrations in the brain...
January 19, 2018: ACS Chemical Neuroscience
Dawid Panek, Anna Więckowska, Jakub Jończyk, Justyna Godyń, Marek W Bajda, Tomasz Wichur, Anna Pasieka, Damijan Knez, Anja Pislar, Jan Korabecny, Ondrej Soukup, Vendula Sepsova, Raimon Sabaté, Janko Kos, Stanislav Gobec, Barbara Malawska
The multitarget approach is a promising paradigm in drug discovery, potentially leading to new treatment options for complex disorders, such as Alzheimer's disease. Herein, we present the discovery of a unique series of 1-benzylamino-2-hydroxyalkyl derivatives combining inhibitory activity against butyrylcholinesterase, β-secretase, β-amyloid and tau protein aggregation, all related to mechanisms which underpin Alzheimer's disease. Notably, diphenylpropylamine derivative 10 showed balanced activity against both disease-modifying targets - inhibition of β-secretase (IC50 hBACE-1 = 41...
January 18, 2018: ACS Chemical Neuroscience
Schuyler A Chambers, Jenna M DeSousa, Eric D Huseman, Steven D Townsend
Humankind has used and abused psychoactive drugs for millennia. Formally, a psychoactive drug is any agent that alters cognition and mood. The term "psychotropic drug" is neutral and describes the entire class of substrates, licit and illicit, of interest to governmental drug policy. While these drugs are prescribed for issues ranging from pain management to anxiety, they are also used recreationally. In fact, the current opioid epidemic is the deadliest drug crisis in American history. While the topic is highly politicized with racial, gender, and socioeconomic elements, there's no denying the toll drug mis- and overuse is taking on this country...
January 17, 2018: ACS Chemical Neuroscience
Irina N Gaisina, Sue H Lee, Navneet A Kaidery, Manel Ben Aissa, Manuj Ahuja, Natalya N Smirnova, Sushama Wakade, Arsen Gaisin, Megan W Bourassa, Rajiv R Ratan, Sergey V Nikulin, Andrey A Poloznikov, Bobby Thomas, Gregory R J Thatcher, Irina G Gazaryan
Activation of HIF-1α and Nrf2 is a primary component of cellular response to oxidative stress, and activation of HIF-1α and Nrf2 provides neuroprotection in models of neurodegenerative disorders, including ischemic stroke, Alzheimer's and Parkinson's diseases. Screening a library of CNS-targeted drugs using novel reporters for HIF-1α and Nrf2 elevation in neuronal cells revealed histone deacetylase (HDAC) inhibitors as potential activators of these pathways. We report the identification of phenylhydroxamates as single agents exhibiting tripartite inhibition of HDAC6, inhibition of HIF-1 prolyl hydroxylase (PHD), and activation of Nrf2...
January 17, 2018: ACS Chemical Neuroscience
Elizabeth C Cropper, Jian Jing, Ferdinand S Vilim, Michael A Barry, Klaudiusz R Weiss
Neuropeptides are present in species throughout the animal kingdom and generally exert actions that are distinct from those of small molecule transmitters. It has, therefore, been of interest to define the unique behavioral role of this class of substances. Progress in this regard has been made in experimentally advantageous invertebrate preparations. We focus on one such system, the feeding circuit in the mollusc Aplysia. We review research conducted over several decades that played an important role in establishing that peptide cotransmitters are released under behaviorally relevant conditions...
January 8, 2018: ACS Chemical Neuroscience
George Devitt, Kelly Howard, Amrit Mudher, Sumeet Mahajan
The pathogenesis underlining many neurodegenerative diseases remains incompletely understood. The lack of effective biomarkers and disease preventative medicine demands the development of new techniques to efficiently probe the mechanisms of disease and to detect early biomarkers predictive of disease onset. Raman spectroscopy is an established technique that allows the label-free fingerprinting and imaging of molecules based on their chemical constitution and structure. While analysis of isolated biological molecules has been widespread in the chemical community, applications of Raman spectroscopy to study clinically relevant biological species, disease pathogenesis and diagnosis have been rapidly increasing since the last decade...
January 8, 2018: ACS Chemical Neuroscience
Lauri Nummenmaa, Lauri Tuominen, Jussi Hirvonen
Positron emission tomography (PET) and endogenous competition paradigms are widely used for studying neuroreceptor activation in humans in vivo. Changes in cerebral blood triggered by the experimentation, such as amphetamine administration, could influence both tracer delivery and washout, thus biasing the results. A recent study tested this assumption in baboons by measuring radiotracer binding with PET while measuring simultaneously cerebral blood flow with arterial spin labeled functional magnetic resonance imaging...
January 5, 2018: ACS Chemical Neuroscience
Andrea Renee Kelley, George Perry, Stephan B H Bach
The increase of insoluble senile plaques in the brain is a primary hallmark of Alzheimer's disease. The usefulness of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) with tandem MS for the characterization of senile plaques from AD brains and the relevance of the components identified to furthering AD research using MS is discussed. 33 components were reproducibly observed within tryptic aliquots of senile plaques from two different AD brains after sample preparation optimization...
January 4, 2018: ACS Chemical Neuroscience
Weiwei Xue, Fengyuan Yang, Panpan Wang, Guoxun Zheng, Yuzong Chen, Xiaojun Yao, Feng Zhu
Dual inhibition of serotonin and norepinephrine transporters (hSERT and hNET) gives greatly improved efficacy and tolerability for treating major depressive disorder (MDD) comparing with selective reuptake inhibitors. Pioneer studies provided valuable information of structure, function, and pharmacology of drugs dual-targeting hSERT and hNET (SNRIs), and the differential binding mechanism between SNRIs and selective inhibitors of 5-HT (SSRIs) / NE (sNRIs) to their corresponding target was expected to be able to facilitate the discovery of privileged drug-like scaffold with improved efficacy...
January 4, 2018: ACS Chemical Neuroscience
Tamara Fernández, Alberto Martínez-Serrano, Lorena Cussó, Manuel Desco, Milagros Ramos-Gómez
Early diagnosis in Alzheimer's disease (AD), prior to the appearance of marked clinical symptoms, is critical to prevent irreversible neuronal damage and neural malfunction that leads to dementia and death. Therefore, there is an urgent need to generate new contrast agents which reveal by a non-invasive method the presence of some of the pathological signs of AD. In the present study we demonstrate for the first time a new nanoconjugate composed of magnetic nanoparticles bound to an anti-ferritin antibody, which has been developed based on the existence of iron deposits and high levels of the ferritin protein present in areas with a high accumulation of amyloid plaques (particularly the subiculum in the hippocampal area) in the brain of a transgenic mouse model with five familial AD mutations...
January 3, 2018: ACS Chemical Neuroscience
Jianxiong Jiang, Tri Minh Van, Thota Ganesh, Raymond Dingledine
Prostaglandin E2 (PGE2) via its Gαs-coupled EP2 receptor protects cerebral cortical neurons from excitotoxic and anoxic injury, though EP2 receptor activation can also cause secondary neurotoxicity in chronic inflammation. We performed a high-throughput screen of a library of 292,000 small molecules and identified several compounds that have a 2-piperidinyl phenyl benzamide or trisubstituted pyrimidine core as positive modulators for human EP2 receptor. The most active compounds increased the potency of PGE2 on EP2 receptor 4 to 5-fold at 20 μM without altering efficacy, indicative of an allosteric mechanism...
January 2, 2018: ACS Chemical Neuroscience
Abdul Mannan Baig, Nuzair Waliani, Saiqa Karim
Neurotropic parasitic amoebal infections have imposed an enormous challenge to chemotherapy in patients who fall victims to the infections caused by them. Conventional antibiotics that are given to treat these infections have a low patient compliance because of the serious adverse effects that are associated with their use. Additionally, the growing incidence of the development of drug resistance by the neurotropic parasites like Naegleria fowleri, Balamuthia mandrillaris, and Acanthamoeba spp has made the drug therapy more challenging...
December 29, 2017: ACS Chemical Neuroscience
David Lankri, Dikla Haham, Adi Lahiani, Philip Lazarovici, Dmitry Tsvelikhovsky
One of the main symptoms in degenerative diseases is death of neuronal cell followed by the loss of neuronal pathways. In neuronal cultures, neurite outgrowths are cell sprouts capable of transforming into either axons or dendrites, to further form functional neuronal synaptic connections. Such connections have an important role in brain cognition, neuronal plasticity, neuronal survival, and regeneration. Therefore, drugs that stimulate neurite outgrowth may be found beneficial in ameliorating neural degeneration...
December 29, 2017: ACS Chemical Neuroscience
Jiyeon Han, Hyuck Jin Lee, Kyu Yeon Kim, Shin Jung C Lee, Jong-Min Suh, Jaeheung Cho, Junghyun Chae, Mi Hee Lim
Multiple pathogenic factors [e.g., amyloid-β (Aβ), metal ions, metal-bound Aβ (metal-Aβ), reactive oxygen species (ROS)] are found in the brain of patients with Alzheimer's disease (AD). In order to elucidate the roles of pathological elements in AD, chemical tools able to regulate their activities would be valuable. Due to the complicated link among multiple pathological factors, however, it has been challenging to invent such chemical tools. Herein, we report novel small molecules as chemical tools toward modulation of single or multiple target(s), designed via a rational structure-property-directed strategy...
December 28, 2017: ACS Chemical Neuroscience
Pham Dinh Quoc Huy, Nguyen Quoc Thai, Zuzana Bednarikova, Le Huu Phuc, Huynh Quang Linh, Zuzana Gazova, Mai Suan Li
No abstract text is available yet for this article.
December 28, 2017: ACS Chemical Neuroscience
Cesar de la Fuente-Nunez, Beatriz Torres Meneguetti, Octávio Luiz Franco, Timothy K Lu
We review here recent discoveries in the exciting new field of neuromicrobiology. This field encompasses the interactions between the microbiome and the central nervous system. The microbiome has a tremendous impact on human health. In particular, the gut microbiota may play a key role in many essential processes in health and disease via the activity of the gut-brain axis, possibly contributing to autism spectrum disorders, Alzheimer's disease, Parkinson's disease, depression, and anxiety disorder. Gut microbes may also be involved in nociception, complex host behaviors, and brain development...
December 28, 2017: ACS Chemical Neuroscience
Adriana Pietropaolo, Antonio Magrì, Valentina Greco, Valeria Losasso, Diego La Mendola, Sebastiano Sciuto, Paolo Carloni, Enrico Rizzarelli
The binding of the human nerve growth factor (NGF) protein to the tropomyosin-receptor-kinase A (TrkA) is associated with Alzhemeir's development. Owing to the large presence of zinc(II) ions in the synaptic compartments, the zinc ions might be bound to the complex in vivo. Here, we have identified a putative zinc binding site using a combination of computations and experiments. First, we have predicted structural features of the NGF/TrkA complex in aqueous solution by molecular simulation. Metadynamics free energy calculations suggest that these are very similar to those in the X-ray structure...
December 27, 2017: ACS Chemical Neuroscience
Xuehan Jiang, Yang Cao, Wei Han
The recent finding that the surface of amyloid-β (Aβ) fibril can recruit Aβ peptides and convert them into toxic oligomers has rendered fibril surfaces attractive as inhibition targets. Through extensive simulations with hybrid-resolution and all-atom models, we have investigated how Aβ1-40 recognizes its own fibril surfaces. These calculations give a ~2.6-5.6μM half-saturation concentration of Aβ on the surface (cf. experimental value ~6μM). Aβ was found to preferentially bind to region 16-24 of Aβ40 fibrils through both electrostatic and van der Waals forces...
December 27, 2017: ACS Chemical Neuroscience
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