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ACS Chemical Neuroscience

Prasenjit Mondal, Varsha Gupta, Gaurav Das, Krishnangsu Pradhan, Juhee Khan, Prabir Kumar Gharai, Surajit Ghosh
Design and development of acetylcholinesterase (AChE) inhibitor has tremendous implications in the treatment of Alzheimer's disease (AD). Here, we have adopted a computational approach for designing of peptide based AChE inhibitor from its active site. We identified an octapeptide, which interacts with the catalytic anionic site (CAS) of AChE enzyme and inhibits its activity. Interestingly, this peptide also inhibits amyloid aggregation through interacting at the 17-21 region of amyloid-beta (Aβ) and stabilizes microtubules by interacting with tubulin as well...
July 17, 2018: ACS Chemical Neuroscience
Antonietta Arcella, Sara Palchetti, Luca Digiacomo, Daniela Pozzi, Anna Laura Capriotti, Luigi Frati, Maria Antonietta Oliva, Georgia Tsaouli, Rossella Rota, Isabella Screpanti, Morteza Mahmoudi, Giulio Caracciolo
Temozolomide (TMZ) is the current first-line chemotherapy for treatment of glioblastoma multiforme (GBM). However, similar to other brain therapeutic compounds, access of TMZ to brain tumors is impaired by the blood-brain barrier (BBB) leading to poor response for GBM patients. To overcome this major hurdle, we have synthesized a set of TMZ-encapsulating nanomedicines made of four cationic liposome (CL) formulations with systematic changes in lipid composition and physical-chemical properties. The targeting nature of this nanomedicine is provided by the recruitment of proteins, with natural targeting capacity, in the biomolecular corona (BC) layer that forms around CLs after exposure to human plasma (HP)...
July 17, 2018: ACS Chemical Neuroscience
Hamed S Hayatshahi, Kuiying Xu, Suzy A Griffin, Michelle Taylor, Robert H Mach, Jin Liu, Robert R Luedtke
We have previously reported on the ability of arylamide phenylpiperazines to bind selectively to the D3 versus the D2 dopamine receptor subtype. For these studies we used LS-3-134 as the prototypic arylamide phenylpiperazine ligand because it binds with high affinity at D3 dopamine receptor (0.17 nM) and exhibits >150-fold D3 vs. D2 receptor binding selectivity. Our goal was to investigate how the composition and size of the nonaromatic ring structure at the piperazine position of substituted phenylpiperazine analogs might influence binding affinity at the human D2 and D3 dopamine receptors...
July 16, 2018: ACS Chemical Neuroscience
Lee E Dunlap, Anne M Andrews, David E Olson
Better known as "ecstasy", 3,4-methylenedioxymethamphetamine (MDMA) is a small molecule that has played a prominent role in defining the ethos of today's teenagers and young adults, much like lysergic acid diethylamide (LSD) did in the 1960s. Though MDMA possesses structural similarities to compounds like amphetamine and mescaline, it produces subjective effects that are unlike any of the classical psychostimulants or hallucinogens and is one of the few compounds capable of reliably producing prosocial behavioral states...
July 12, 2018: ACS Chemical Neuroscience
Yi Zheng, Samuel Obeng, Huiqun Wang, David L Stevens, Essie Komla, Dana E Selley, William L Dewey, Hamid I Akbarali, Yan Zhang
Two 6β-N-heterocyclic naltrexamine derivatives, NAP and NMP, have been identified as peripherally selective mu opioid receptor (MOR) antagonists. To further enhance the peripheral selectivity of both compounds, the 17-amino group and the nitrogen atom of the pyridine ring in both NAP and NMP were methylated to obtain dMNAP and dMNMP, respectively. Compared with NAP and NMP, the binding affinities of dMNAP and dMNMP shifted to MOR and KOR (kappa opioid receptor) dual selective and they acted as moderate efficacy partial agonists...
July 12, 2018: ACS Chemical Neuroscience
Alexander G Zestos, Hiram Luna-Munguia, William C Stacey, Robert T Kennedy
Epilepsy is a common neurological disease characterized by recurrent unpredictable seizures. For the last 30 years, microdialysis sampling has been used to measure changes in excitatory and inhibitory neurotransmitter concentrations before, during, and after seizures. These advances have fostered breakthroughs in epilepsy research by identifying neurochemical changes associated with seizures and correlating them to electrophysiological data. Recent advances in methodology may be useful in further delineating the chemical underpinnings of seizures...
July 12, 2018: ACS Chemical Neuroscience
Philipp Leippe, Nils Winter, Martin Sumser, Dirk Trauner
Photoswitchable blockers of potassium channels can be used to optically control neuronal excitability and hold great promise for vision restoration. Here, we report a series of improved photoswitchable blockers that feature a new pharmacophore based on the local anesthetic bupivacaine. These azobupivacaines (ABs) enable optical control over the delayed rectifier channel Kv2.1. and target the two-pore domain potassium channel TREK-1. For the first time, we have identified a compound that blocks conductance in the dark and potentiates it upon illumination...
July 12, 2018: ACS Chemical Neuroscience
Ravali Vinnakota, Deepthi Yedlapudi, Krishna Madhuri Manda, Keerti Bhamidipati, Kirthi Theja Bommakanti, G Sree RangaLakshmi, Shasi Vardhan Kalivendi
The presynaptic protein, α-synuclein (α-syn), has been shown to play a crucial role in multiple neurodegenerative diseases, such as, Parkinson's (PD), Alzheimer's (AD) and Dementia with Lewy bodies (DLB). The three major domains of α-syn protein were shown to govern its membrane interaction, protein fibrillation and chaperone activity. So far four different alternatively spliced isoforms of α-syn were identified which lack either exon 3 (syn-126) or 5 (syn-112) or both (syn-98) resulting in the altered function of proteins...
July 11, 2018: ACS Chemical Neuroscience
John P M Finberg, Miguel Schwartz, Raneen Jeries, Samih Badarny, Morad K Nakhleh, Enas Daoud, Yelena Ayubkhanov, Manal Aboud-Hawa, Yoav Y Broza, Hossam Haick
Early diagnosis of Parkinson's disease (PD) is important because it affects the choice of therapy and is subject to a relatively high degree of error. In addition, early detection of PD can potentially enable the start of neuroprotective therapy before extensive loss of dopaminergic neurons of the substantia nigra occurs. However, until now, studies for early detection of PD using volatile biomarkers sampled only treated and medicated patients. Therefore, there is a great need to evaluate untreated patients for establishing a real world screening\diagnostic technology...
July 10, 2018: ACS Chemical Neuroscience
Yanan Hou, Shoujiao Peng, Xinming Li, Juan Yao, Jianqiang Xu, Jianguo Fang
Honokiol (Hon), a polyphenol and main active ingredient from the bark of Magnolia officinalis, has been documented having multiple pharmacological functions, including neuroprotection. However, the mechanisms underlying its neuroprotective effects are not well defined. In the present study, we reported that Hon attenuates the H2O2- or 6-hydroxydopamine (6-OHDA)-induced apoptosis of PC12 cells via elevation of glutathione level and upregulation of a multitude of cytoprotective proteins, including heme oxygenase 1, NAD(P)H: quinone oxidoreductase 1, thioredoxin 1 and thioredoxin reductase 1...
July 10, 2018: ACS Chemical Neuroscience
Leonid Moroz
There is more than one way to develop neuronal complexity, and animals frequently use different molecular toolkits to achieve similar functional outcomes (=convergent evolution). Deciphering the evolutionary history of neuronal lineages requires the use of nontraditional reference species across the entire animal kingdom as the first step toward the phylogenetical classification of neuronal and glial cells or the field of NeuroSystematics. The second step is single-cell analyses of diverse neuronal populations including the scRNA-seq profiling of all neurons in an entire brain or Brain-seq...
July 10, 2018: ACS Chemical Neuroscience
Benedetta Mannini, Johnny Habchi, Sean Keng Rui Chia, Francesco Simone Ruggeri, Michele Perni, Tuomas P J Knowles, Christopher M Dobson, Michele Vendruscolo
Small oligomers formed during the aggregation of certain peptides and proteins are highly cytotoxic in numerous neurodegenerative disorders. Because of their transient nature and conformational heterogeneity, however, the structural and biological features of these oligomers are still poorly understood. Here we describe a method of generating stable oligomers formed by the Alzheimer's Aβ40 peptide by carrying out an aggregation reaction in the presence of zinc ions. The resulting oligomers are amenable to detailed biophysical and biological characterization, which reveals a homogenous population with small size, high cross-β sheet structure content and extended hydrophobic surface patches...
July 9, 2018: ACS Chemical Neuroscience
Yuxiang Mo, Sayanti Brahmachari, Jiangtao Lei, Sharon Gilead, Yiming Tang, Ehud Gazit, Guanghong Wei
Fibrillar deposits formed by the aggregation of the human islet amyloid polypeptide (hIAPP) are the major pathological hallmark of type 2 diabetes mellitus (T2DM). Inhibiting the aggregation of hIAPP is considered as the primary therapeutic strategy for the treatment of T2DM. Hydroxylated carbon nanoparticles have received great attention in impeding amyloid protein fibrillation owing to their reduced cytotoxicity compared to the pristine ones. In this study we investigated the influence of hydroxylated single-walled carbon nanotubes (SWCNT-OH) on the first step of hIAPP aggregation-the dimerization by performing explicit solvent replica exchange molecular dynamics (REMD) simulations...
July 9, 2018: ACS Chemical Neuroscience
Daixin Ye, Chaoyi Gu, Andrew G Ewing
Single cell amperometry and intracellular vesicle impact electrochemical cytometry were used to examine whether lidocaine can regulate neurotransmitter release or storage for PC12 cells to explain the biphasic effects whereby it can protect neurons and improve cognitive outcome at low concentration, but can cause neurotoxicity at high concentration. We show that lido-caine affects the behavior of PC12 cell exocytosis in a concentration dependent way, which exactly corresponds to its bipha-sic effects. At a relatively high concentration, it shows a much narrower pore size and a longer-duration fusion pore with less monoamine released than control cells...
July 6, 2018: ACS Chemical Neuroscience
Anzelle Delport, Brian H Harvey, Anél Petzer, Jacobus P Petzer
Methylene blue (MB) possesses diverse medical applications. Among these MB presents with antidepressant-like effects in animals and has shown promise in clinical trials for the treatment of mood disorders. As an antidepressant, MB may act via various mechanisms which include modulation of the nitric oxide cyclic guanosine monophosphate (NO-cGMP) cascade, enhancement of mitochondrial respiration and antioxidant effects. MB is also, however, a high potency inhibitor of monoamine oxidase (MAO) A, which most likely contributes to its antidepressant effect, but also to its adverse effects profile (eg...
July 6, 2018: ACS Chemical Neuroscience
Pallavi Rane, Deepaneeta Sarmah, Shashikala Bhute, Harpreet Kaur, Avirag Goswami, Kiran Kalia, Anupom Borah, Kunjan R Dave, Nutan Sharma, Pallab Bhattacharya
Parkinson's disease (PD) is a neurodegenerative disease that is pathologically characterized by degeneration of dopamine neurons in the substantia nigra pars compacta (SNpc).PD leads to clinical motor features that include rigidity, tremor and bradykinesia. Despite multiple available therapies for PD, the clinical features continue to progress, and patients suffer progressive disability. Many advances have been made in PD therapy which directly target the cause of the disease rather than providing symptomatic relief...
June 29, 2018: ACS Chemical Neuroscience
Haden A Geiger, Madeline G Wurst, R Nathan Daniels
Psilocybin is found in a family of mushrooms commonly known as "magic mushrooms" that have been used throughout history to induce hallucinations. In the late 1950s Albert Hofmann, of Sandoz Laboratories, identified and synthesized the psychoactive compounds psilocybin and psilocin which are found in psilocybe mushrooms. Psilocybin was marketed by Sandoz as Indocybin for basic psychopharmacological and therapeutic clinical research. Psilocybin saw a rapid rise in popularity during the 1960s and was classed as a schedule I drug in 1970...
June 29, 2018: ACS Chemical Neuroscience
Magnus Kjaergaard, Alexander J Dear, Franziska Kundel, Seema Qamar, Georg Meisl, Tuomas P J Knowles, David Klenerman
The molecular mechanism of protein aggregation is of both fundamental and clinical importance as amyloid aggregates are linked to a number of neurodegenerative disorders. Such protein aggregates include macroscopic insoluble fibrils as well as small soluble oligomeric species. Time-dependent resolution of these species is prerequisite for a detailed quantitative understanding of protein aggregation; this remains challenging due to the lack of methods for detecting and characterizing transient and heterogeneous protein oligomers...
June 28, 2018: ACS Chemical Neuroscience
Jeanette L Berton, Mabel Seto, Craig W Lindsley
Phencyclidine (PCP, "angel dust", an arylcyclohexylamine) was the first non-natural, man-made illicit drug of abuse, and was coined 'the most dangerous drug in America" in the late 1970s (amidst sensational horror stories of the drug's effects); however, few other illicit drugs have had such a significant and broad impact on society - both good and bad. Originally developed as a new class of anesthetic, PCP-derived psychosis gave way to the PCP hypothesis of schizophrenia (later coined the NMDA receptor hypofunction hypothesis or the glutamate hypothesis of schizophrenia), which continues to drive therapeutic discovery for schizophrenia today...
June 28, 2018: ACS Chemical Neuroscience
Xinyang Qi, Hua Xu, Liping Wang, Zhi-Jun Zhang
The animal model for depressive behavior due to chronic unpredicted mild stress (CUMS) is commonly used to evaluate antidepressant treatments. The CUMS model has faced some criticism due to the heterogeneity of behavioral effects. Spadin and SID1900 are TREK1 blockers with a quick antidepressant effect. However, to date their effectiveness and the long-term therapeutic mechanisms are not known. We hypothesize that early intervention with TREK1 blockers can fully reverse depressive-like behaviors, that the chronic administration of TREK1 blockers have a more pronounced effect than the SSRI fluoxetine, and that its long-term therapeutic effects may be mediated by improvement of impaired neurogenesis...
June 28, 2018: ACS Chemical Neuroscience
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