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ACS Chemical Neuroscience

Sandro Huenchuguala, Patricia Muñoz, Juan Segura-Aguilar
Aminochrome, an orthoquinone formed during the dopamine oxidation of neuromelanin, is neurotoxic because it induces mitochondria dysfunction, protein degradation dysfunction (both autophagy and proteasomal systems), α-synuclein aggregation to neurotoxic oligomers, neuroinflammation, and oxidative and endoplasmic reticulum stress. In this study, we investigated the relationship between aminochrome-induced autophagy/lysosome dysfunction and mitochondrial dysfunction in U373MGsiGST6 cells. Aminochrome (75 μM) induces mitochondrial dysfunction as determined by (i) a significant decrease in ATP levels (70%; P < 0...
August 15, 2017: ACS Chemical Neuroscience
Abraham G Beyene, Ian R McFarlane, Rebecca L Pinals, Markita P Landry
Imaging the dynamic behavior of neuromodulatory neurotransmitters in the extracelluar space that arise from individual quantal release events would constitute a major advance in neurochemical imaging. Spatial and temporal resolution of these highly stochastic neuromodulatory events requires concurrent advances in the chemical development of optical nanosensors selective for neuromodulators in concert with advances in imaging methodologies to capture millisecond neurotransmitter release. Herein, we develop and implement a stochastic model to describe dopamine dynamics in the extracellular space (ECS) of the brain dorsal striatum to guide the design and implementation of fluorescent neurochemical probes that record neurotransmitter dynamics in the ECS...
August 15, 2017: ACS Chemical Neuroscience
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...
August 14, 2017: ACS Chemical Neuroscience
Cassandra L Retzlaff, Amanda Kussrow, Tim Schorkopf, Phoonthawee Saetear, Darryl J Bornhop, J Andrew Hardaway, Sarah M Sturgeon, Jane Wright, Randy D Blakely
Ceftriaxone, a β-lactam antibiotic, has been reported to act independently of its antimicrobial actions to normalize perturbed central nervous system glutamate levels, principally by elevating expression of glial glutamate transporters. Identification of a specific, high-affinity target for ceftriaxone could significantly impact therapeutic development for multiple brain disorders, ranging from neurodegenerative disorders to addiction. Recently, we identified a glial-expressed Caenorhabditis elegans gene, swip-10, that encodes a metallo-β-lactamase domain-containing protein, and limits glutamate-dependent changes in dopamine neuron excitability...
August 14, 2017: ACS Chemical Neuroscience
Priyatosh Ranjan, Ashutosh Kumar
The characteristic cross-β-sheet-rich amyloid fibril formation by intrinsically disordered α-synuclein proteins is one of the pathological hallmarks of Parkinson's disease. Although unstructured in solution, the presence of autoinhibitory long-range contacts in monomeric form prevents protein aggregation. Out of the various factors that affect the rate of amyloid formation, familial mutations play an important role in α-synuclein aggregation. Even though these mutations are believed to form an aggregation-prone intermediate by perturbing these contacts, the correlation between perturbation and rate of fibril formation is not very straightforward...
August 14, 2017: ACS Chemical Neuroscience
Lizanne G Nilewski, Melissa Singh, David S Baskin, James M Tour, Martyn A Sharpe
Selective targeting of drug loaded nanovectors to specific epitopes highly expressed on the surface of cancer cells is a goal for nanotechnologists. We have modified our previously described PEGylated-hydrophilic carbon clusters (PEG-HCCs) so that the epidermal growth factor receptor (EGFR) binding peptide, GE11, is attached using click chemistry at the end of each PEG. The resulting nanosyringe, PepEGFR-PEG-HCC, can be loaded with a wide range of hydrophobic drugs and dyes. We show that, both in vitro and in vivo, this payload can be delivered to cancer cells expressing EGFR...
August 14, 2017: ACS Chemical Neuroscience
Jeanne N Hansen, Xingguo Li, Y George Zheng, Louis T Lotta, Abhishek Dedhe, Nina F Schor
Neuroblastoma is a cancer of the neural crest almost exclusively seen in childhood. While children with single, small primary tumors are often cured with surgery alone, the 65% of children with neuroblastoma whose disease has metastasized have less than a 50% chance of surviving five years after diagnosis. Innovative pharmacological strategies are critically needed for these children. Efforts to identify novel targets that afford ablation of neuroblastoma with minimal toxicity to normal tissues are underway...
August 11, 2017: ACS Chemical Neuroscience
Mitchell Longworth, Samuel D Banister, Rochelle Boyd, Richard C Kevin, Mark Connor, Iain S McGregor, Michael Kassiou
Synthetic cannabinoids (SC) are the largest class of new psychoactive substances (NPS), and are increasingly associated with serious adverse effects. The majority of SC NPS are 1,3-disubstituted indoles and indazoles featuring a diversity of subunits at the 1- and 3-positions. Most recently, cumyl-derived indole- and indazole-3-carboxamides have been detected by law enforcement agencies and by emergency departments. Herein we describe the synthesis, characterization, and pharmacology of SCs CUMYL-BICA, CUMYL-PICA, CUMYL-5F-PICA, CUMYL-PINACA, CUMYL-5F-PINACA, and related analogues...
August 11, 2017: ACS Chemical Neuroscience
Aubrie A Harland, Irina D Pogozheva, Nicholas W Griggs, Tyler J Trask, John R Traynor, Henry I Mosberg
In an effort to expand the structure-activity relationship (SAR) studies of a series of mixed-efficacy opioid ligands, peptidomimetics that incorporate methoxy and hydroxy groups around a benzyl or 2-methylindanyl pendant on a tetrahydroquinoline (THQ) core of the peptidomimetics were evaluated. Compounds containing a methoxy or hydroxy moiety in the o- or m- positions increased binding affinity to the kappa opioid receptor (KOR), whereas compounds containing methoxy or hydroxy groups in the p- position decreased KOR affinity and reduced or eliminated efficacy at the mu opioid receptor (MOR)...
August 10, 2017: ACS Chemical Neuroscience
Anand Kant Das, Barun Kumar Maity, Dayana Surendran, Umakanta Tripathy, Sudipta Maiti
Ratiometric imaging can quantitatively measure changes in cellular analyte concentrations using specially designed fluorescent labels. We describe a label-free ratiometric imaging technique for direct detection of changes in intravesicular serotonin concentration in live cells. At higher concentrations, serotonin forms transient oligomers whose ultraviolet emission is shifted to longer wavelengths. We access the ultraviolet/blue emission using relatively benign three-photon excitation and split it into two imaging channels, whose ratio reports the concentration...
August 10, 2017: ACS Chemical Neuroscience
Shuangyan Zhou, Xuewei Liu, Xiaoli An, Xiao-Jun Yao, Huanxiang Liu
Structural transitions in the prion protein from the cellular form, PrPC, into the pathological isoform, PrPSc, are regarded as the main cause of the transmissible spongiform encephalopathies, also known as prion diseases. Hence, discovering and designing effective antiprion drugs that can inhibit PrPC to PrPSc conversion is regarded as a promising way to cure prion disease. Among several strategies to inhibit PrPC to PrPSc conversion, to stabilize the native PrPC via specific binding is believed to be one of the valuable approach and many antiprion compounds have been reported based on this strategy...
August 10, 2017: ACS Chemical Neuroscience
Maria I Ayuso, Emma Martínez-Alonso, Mourad Chioua, Alejandro Escobar-Peso, Rafael Gonzalo-Gobernado, Joan Montaner, José Marco-Contelles, Alberto Alcázar
There is a need to develop additional effective therapies for ischemic stroke. Nitrones, which were first developed as reactive oxygen species (ROS)-trapping compounds, have been proposed as neuroprotective agents for ischemic stroke, a ROS-related disorder. The previous reported ROS-trapping compound, quinolyl nitrone RP19, is here being assayed to induce neuroprotection to ischemia-reperfusion injury in three experimental ischemia models: (i) oxygen-glucose deprivation (OGD) on primary neuronal cultures; (ii) transient global cerebral ischemia in four-vessel occlusion model; and (iii) transient focal cerebral ischemia in middle cerebral artery occlusion (tMCAO) model...
August 9, 2017: ACS Chemical Neuroscience
Brooke A Miller, Jason B Papke, Vytas P Bindokas, Amy B Harkins
Calcein, a fluorescent fluid phase marker, has been used to track and visualize cellular processes such as synaptic vesicle fusion. It is also the fluorophore for live cells in the commonly used Live/Dead viability assay. In pilot studies designed to determine fusion pore open size and vesicle movement in secretory cells, imaging analysis revealed that calcein reduced the number of vesicles released from the cells when stimulated with nicotine. Using amperometry to detect individual vesicle release events, we show that when calcein is present in the media, the number of vesicles that fuse with the cellular membrane is reduced when cells are stimulated with either nicotine or high K(+)...
August 9, 2017: ACS Chemical Neuroscience
Ayan Ghoshal, Sean P Moran, Jonathan W Dickerson, Max E Joffe, Brad A Grueter, Zixiu Xiang, Craig W Lindsley, Jerri M Rook, P Jeffrey Conn
Selective potentiation of the mGlu5 subtype of metabotropic glutamate (mGlu) receptor using positive allosteric modulators (PAMs) has robust cognition-enhancing effects in rodent models that are relevant for schizophrenia. Until recently, these effects were thought to be due to potentiation of mGlu5-induced modulation of NMDA receptor (NMDAR) currents and NMDAR-dependent synaptic plasticity. However, "biased" mGlu5 PAMs that do not potentiate mGlu5 effects on NMDAR currents show efficacy that is similar to that of prototypical mGlu5 PAMs, suggesting that NMDAR-independent mechanisms must be involved in these actions...
August 9, 2017: ACS Chemical Neuroscience
Fabienne Gourand, Mihaela-Liliana Ţînţaş, Axelle Henry, Méziane Ibazizène, Martine Dhilly, Fabien Fillesoye, Cyril Papamicaël, Vincent Levacher, Louisa Barre
The development of delivery systems to transport some specific radiotracers across the blood brain barrier (BBB) needs to be investigated for brain imaging. [18F]FLT (3'-deoxy-3'-18F-fluoro-L-thymidine), an analogue substrate of the nucleoside thymidine, has been developed as a proliferation tracer for oncological PET studies. Unfortunately, low-grade brain tumors are poorly visualised due to the low uptake of [18F]FLT in brain tissue, preventing its use in PET imaging to detect brain tumors at an early stage...
August 8, 2017: ACS Chemical Neuroscience
Swathi Sudhakar, Poornima Budime Santhosh, Ethayaraja Mani
Extracellular plaques of amyloid beta (Aβ) fibrils and neurofibrillary tangles are known to be associated with neurological diseases such as Alzheimer's disease. Studies have shown that spherical nanoparticles inhibit the formation of Aβ fibrils by intercepting the nucleation and growth pathways of fibrillation. In this report, gold nanorods (AuNRs) are used to inhibit the formation of Aβ fibrils and the shape-dependent plasmonic properties of AuNRs are exploited to faciliate faster dissolution of mature Aβ fibrils...
August 8, 2017: ACS Chemical Neuroscience
Yan-Fa Yu, Ya-Dan Huang, Chen Zhang, Xu-Nian Wu, Qian Zhou, Deyan Wu, Yinuo Wu, Hai-Bin Luo
Discovery of multi-target directed ligands (MTDLs) targeting at different factors simultaneously to control the complicated pathogenesis of Alzheimer's disease (AD), has become an important research area in recent years. Both PDE9A and BuChE inhibitors could participate in different processes of AD to attenuate neuronal injuries and improve cognitive impairments. However, research on the MTDLs combining the inhibition of PDE9A and BuChE simultaneously has not been reported yet. In this study, a series of novel pyrazolopyrimidinone-rivastigmine hydrids were designed, synthesized, and evaluated in vitro...
August 7, 2017: ACS Chemical Neuroscience
Yue Ma, Qi Shi, Jing Wang, Kang Xiao, Jing Sun, Yan Lv, Man Guo, Wei Zhou, Cao Chen, Chen Gao, Baoyun Zhang, Xiaoping Dong
Transcription factor NF-κB functions as a pleiotropic regulator of target genes controlling physiological function as well as pathological processes of many different diseases, including some neurodegeneration diseases. However, the role of NF-κB in the pathogenesis of prion disease remains ambiguous. In this study, the status of NF-κB (p65) in a prion infected cell line SMB-S15 was firstly evaluated. Significantly lower levels of p65 and phosphorylated form of p65 (p-p65) were detected in SMB-S15 cells, comparing with its normal partner cell line SMB-PS...
August 7, 2017: ACS Chemical Neuroscience
Fuencisla Pilar-Cuellar, Rebeca Vidal Casado, Alvaro Diaz, Emilio Garro-Martinez, Raquel Linge, Elena Castro, Robert Haberzettl, Heidrun Fink, Bettina Bert, Jan Brosda, Beatriz Romero, Benedicto Crespo Facorro, Angel Pazos
Postsynaptic 5-HT1A receptors (5-HT1AR) play an important role in anxiety and stress, although their contribution is still controversial. Previous studies report that mice overexpressing postsynaptic 5-HT1ARs show no changes in basal anxiety, though the influence of stress conditions has not been addressed yet. In this study, we used this animal model to evaluate the role of 5-HT1ARs in anxiety response after pre-exposition to an acute stressor. Under basal conditions, 5-HT1AR overexpressing animals presented high corticosterone levels and a lower mineralocorticoid/glucocorticoid receptor ratio...
August 4, 2017: ACS Chemical Neuroscience
Taru Dube, Sonika Chibh, Jibanananda Mishra, Jiban Jyoti Panda
The window of neurological maladies encompasses 600 known neurological disorders. In the last few years, an inordinate upsurge in the incidences of neuronal ailments with increased mortality rate has been witnessed globally. Despite noteworthy research in the discovery and development of neural therapeutics, brain drug delivery still encounters limited success due to meager perviousness of most of the drug molecules through the blood-brain barrier (BBB), a tight layer of endothelial cells that selectively impedes routing of the molecules across itself...
August 3, 2017: ACS Chemical Neuroscience
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