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  • 1.

    【2hr】In This Issue, Volume 5, Issue 1

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    机译 在本期中，第5卷，第1期
    • 作者：Jitesh Soares
    • 刊名：ACS Chemical Neuroscience
    • 2014年第1期
    摘要：
  • 2.

    【2hr】Ceftriaxone Blocks the Polymerization of α-Synucleinand Exerts Neuroprotective Effects in Vitro

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    机译 头孢曲松酮阻碍α-突触核蛋白的聚合并发挥神经保护作用
    摘要：The β-lactam antibiotic ceftriaxone was suggested as a therapeutic agent in several neurodegenerative disorders, either for its ability to counteract glutamate-mediated toxicity, as in cerebral ischemia, or for its ability to enhance the degradation of misfolded proteins, as in Alexander’s disease. Recently, the efficacy of ceftriaxone in neuroprotection of dopaminergic neurons in a rat model of Parkinson’s disease was documented. However, which characteristics of ceftriaxone mediate its therapeutic effects remains unclear. Since, at the molecular level, neuronal α-synuclein inclusions and pathological α-synuclein transmission play a leading role in initiation of Parkinson-like neurodegeneration, we thought of investigating, by circular dichroism spectroscopy, the capability of ceftriaxone to interact with α-synuclein. We found that ceftriaxone binds with good affinity to α-synuclein and blocks its in vitro polymerization. Considering this finding, we also documented that ceftriaxone exerts neuroprotective action in an in vitro model of Parkinson’s disease. Our data, in addition tothe findings on neuroprotective activity of ceftriaxone on Parkinson-likeneurodegeneration in vivo, indicates ceftriaxone as a potential agentin treatment of Parkinson’s disease.
  • 3.

    【2hr】Aging Related Changes of Retina and Optic Nerve of Uromastyx aegyptia and Falco tinnunculus

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    机译 视网膜色素变性和埃及鹰和视网膜神经的衰老相关变化
    摘要：Aging is a biological phenomenon that involves gradual degradation of the structure and function of the retina and optic nerve. To our knowledge, little is known about the aging-related ocular cell loss in avian (Falco tinnunculus) and reptilian species (Uromastyx aegyptia). A selected 90 animals of pup, middle, and old age U. aegyptia (reptilian) and F. tinnunculus (avian) were used. The retinae and optic nerves were investigated by light and transmission electron microscopy (TEM) and assessments of neurotransmitters, antioxidant enzymes (catalase, superoxide dismustase and glutathione s transferase), caspase-3 and -7, malonadialdhyde, and DNA fragmentation. Light and TEM observations of the senile specimens revealed apparent deterioration of retinal cell layers, especially the pigmented epithelium and photoreceptor outer segments. Their inclusions of melanin were replaced by lipofuscins. Also, vacuolar degeneration and demyelination of the optic nerve axons were detected. Concomitantly, there was a marked increase of oxidative stress involved reduction of neurotransmittersand antioxidant enzymes and an increase of lipid peroxidation, caspase-3and -7, subG0/G1 apoptosis, and P53. We conclude that aging showedan inverse relationship with the neurotransmitters and antioxidantenzymes and a linear relationship of caspases, malondialdhyde, DNAapoptosis, and P53 markers of cell death. These markers reflectedthe retinal cytological alterations and lipofuscin accumulation withininner segments.
  • 4.

    【2hr】Identifying the Cellular Targets of Drug Action inthe Central Nervous System Following Corticosteroid Therapy

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    机译 确定药物作用的细胞靶标皮质类固醇治疗后的中枢神经系统
    摘要：Corticosteroid (CS) therapy is used widely in the treatment of a range of pathologies, but can delay production of myelin, the insulating sheath around central nervous system nerve fibers. The cellular targets of CS action are not fully understood, that is, “direct” action on cells involved in myelin genesis [oligodendrocytes and their progenitors the oligodendrocyte precursor cells (OPCs)] versus “indirect” action on other neural cells. We evaluated the effects of the widely used CS dexamethasone (DEX) on purified OPCs and oligodendrocytes, employing complementary histological and transcriptional analyses. Histological assessments showed no DEX effects on OPC proliferation or oligodendrocyte genesis/maturation (key processes underpinning myelin genesis). Immunostaining and RT-PCR analyses show that both cell types express glucocorticoid receptor (GR; the target for DEX action), ruling out receptor expression as a causal factor in the lack of DEX-responsiveness. GRs function as ligand-activated transcription factors, so we simultaneously analyzed DEX-induced transcriptionalresponses using microarray analyses; these substantiated the histologicalfindings, with limited gene expression changes in DEX-treated OPCsand oligodendrocytes. With identical treatment, microglial cells showedprofound and global changes post-DEX addition; anunexpected finding was the identification of the transcription factor Olig1, a master regulator of myelination, as a DEX responsivegene in microglia. Our data indicate that CS-induced myelination delaysare unlikely to be due to direct drug action on OPCs or oligodendrocytes,and may occur secondary to alterations in other neural cells, suchas the immune component. To the best of our knowledge, this is thefirst comparative molecular and cellular analysis of CS effects inglial cells, to investigate the targets of this major class of anti-inflammatorydrugs as a basis for myelination deficits.
  • 5.

    【2hr】Wavelength-Selective One- and Two-Photon Uncagingof GABA

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    机译 波长选择一光子和二光子解笼GABA
    摘要：We have synthesized photolabile 7-diethylamino coumarin (DEAC) derivatives of γ-aminobutyric acid (GABA). These caged neurotransmitters efficiently release GABA using linear or nonlinear excitation. We used a new DEAC-based caging chromophore that has a vinyl acrylate substituent at the 3-position that shifts the absorption maximum of DEAC to about 450 nm and thus is named “DEAC450”. DEAC450-caged GABA is photolyzed with a quantum yield of 0.39 and is highly soluble and stable in physiological buffer. We found that DEAC450-caged GABA is relatively inactive toward two-photon excitation at 720 nm, so when paired with a nitroaromatic caged glutamate that is efficiently excited at such wavelengths, we could photorelease glutamate and GABA around single spine heads on neurons in brain slices with excellent wavelength selectivity using two- and one-photon photolysis, respectively. Furthermore, we found that DEAC450-caged GABA could be effectively released using two-photon excitation at 900 nm with spatial resolution of about 3 μm. Taken together, our experiments show that theDEAC450 caging chromophore holds great promise for the developmentof new caged compounds that will enable wavelength-selective, two-colorinterrogation of neuronal signaling with excellent subcellular resolution.
  • 6.

    【2hr】Mitigation of ROS Insults by Streptomyces Secondary Metabolites in Primary Cortical Neurons

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    机译 链霉菌次级代谢产物在原代皮层神经元中缓解ROS损伤
    摘要：Oxidative stress is a common point in neurodegenerative diseases, widely connected with mitochondrial dysfunction. In this study, we screened seven natural products from Streptomyces sources against hydrogen peroxide insult in primary cortical neurons, an oxidative stress in vitro model. We showed the ability of these compounds to inhibit neuronal cytotoxicity and to reduce ROS release after 12 h treatment. Among the tested compounds, the quinone anhydroexfoliamycin and the red pyrrole-type pigment undecylprodigiosin stand out. These two compounds displayed the most complete protection against oxidative stress with mitochondrial function improvement, ROS production inhibition, and increase of antioxidant enzyme levels, glutathione and catalase. Further investigations confirmed that anhydroexfoliamycin acts over the Nrf2-ARE pathway, as a Nrf2 nuclear translocation inductor, and is able to strongly inhibit the effect of the mitochondrial uncoupler FCCP over cytosolic Ca2+, pointing to mitochondria as a cellular target for this molecule. In addition, both compounds wereable to reduce caspase-3 activity induced by the apoptotic enhancerstaurosporine, but undecylprodigiosin failed to inhibit FCCP effectsand it did not act over the Nrf2 pathway as was the case for anhydroexfoliamycin.These results show that Streptomyces metabolites could be useful for the development of new drugs forprevention of neurodegenerative disorders such as Parkinson’sand Alzheimer’s diseases and cerebral ischemia.
  • 7.

    【2hr】Dendrimer Advances for the Central Nervous SystemDelivery of Therapeutics

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    机译 树枝状聚合物对中枢神经系统的影响提供治疗
    摘要：The effectiveness of noninvasive treatment for central nervous system (CNS) diseases is generally limited by the poor access of therapeutic agents into the CNS. Most CNS drugs cannot permeate into the brain parenchyma because of the blood-brain barrier (BBB), and overcoming this has become one of the most significant challenges in the development of CNS therapeutics. Rapid advances in nanotechnology have provided promising solutions to this challenge. This review discusses the latest applications of dendrimers in the treatment of CNS diseases with an emphasis on brain tumors. Dendrimer-mediated drug delivery, imaging, and diagnosis are also reviewed. The toxicity, biodistribution, and transport mechanisms in dendrimer-mediated delivery of CNS therapeutic agents bypassing or crossing the BBB are also discussed. Future directions and major challenges of dendrimer-mediated delivery of CNS therapeutic agents are included.
  • 8.

    【2hr】Classics in Chemical Neuroscience: Fluoxetine (Prozac)

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    机译 化学神经科学经典著作：氟西汀（Prozac）
    摘要：Fluoxetine (Prozac) was the first major breakthrough for the treatment of depression since the introduction of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) nearly 30 years earlier. It was the first selective serotonin reuptake inhibitor (SSRI) approved by the United States Food and Drug Administration, offering superior efficacy and reduced side effects relative to TCAs and MAOIs. Though a debate remains regarding the exact mechanism by which the clinical efficacy of fluoxetine is manifested, the importance of fluoxetine and related SSRIs to the field is unquestionable. The trade name Prozac has permeated popular culture, helping to raise awareness of depression and to diminish the prevalence of long-standing stigmas associated with this illness. In this Review, we will showcase the history and importance of fluoxetine to neuroscience in general, as well as for the treatment of depression, and review the synthesis, pharmacology, drug metabolism, and adverse effects of fluoxetine.
  • 9.

    【2hr】Clozapine, a Fast-Off-D2 Antipsychotic

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    机译 氯氮平，一种速效D2抗精神病药
    • 作者：Philip Seeman*
    • 刊名：ACS Chemical Neuroscience
    • 2014年第1期
    摘要：Ever since clozapine was first synthesized and tested, it showed the unique property of having antipsychotic action but no Parkinson-like motor side effects. The antipsychotic basis of clozapine is to transiently occupy dopamine D2 receptors in the human striatum, in contrast to haloperidol and chlorpromazine, which have a prolonged occupation of D2 receptors. The chemical structure of clozapine facilitates a relatively rapid dissociation from D2 receptors. After short-term occupation of D2 receptors, peak neural activity raises synaptic dopamine, which then displaces clozapine. While clozapine also occupies other types of receptors, they may not have a significant role in preventing parkinsonism. Clozapine’s transient occupation of D2 receptors permits patients to move easily and comfortably.
  • 10.

    【2hr】In This Issue, Volume 5, Issue 5

    包量

    机译 在本期中，第5卷，第5期
    • 作者：Jitesh Soares
    • 刊名：ACS Chemical Neuroscience
    • 2014年第5期
    摘要：
  • 11.

    【2hr】Label-Free Dopamine Imaging in Live Rat Brain Slices

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    机译 活大鼠脑切片中的无标签多巴胺成像
    摘要：Dopaminergic neurotransmission has been investigated extensively, yet direct optical probing of dopamine has not been possible in live cells. Here we image intracellular dopamine with sub-micrometer three-dimensional resolution by harnessing its intrinsic mid-ultraviolet (UV) autofluorescence. Two-photon excitation with visible light (540 nm) in conjunction with a non-epifluorescent detection scheme is used to circumvent the UV toxicity and the UV transmission problems. The method is established by imaging dopamine in a dopaminergic cell line and in control cells (glia), and is validated by mass spectrometry. We further show that individual dopamine vesicles/vesicular clusters can be imaged in cultured rat brain slices, thereby providing a direct visualization of the intracellular events preceding dopamine release induced by depolarization or amphetamine exposure. Our technique opens up a previously inaccessible mid-ultraviolet spectral regime (excitation ∼ 270 nm, emission < 320 nm) for label-free imaging of native molecules in live tissue.
  • 12.

    【2hr】The First CNS-Active Carborane: A Novel P2X7 Receptor Antagonist with Antidepressant Activity

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    机译 第一个中枢神经系统活性碳硼烷：具有抗抑郁活性的新型P2X7受体拮抗剂。
    摘要：Relative to other polycyclic frameworks (1–3), a carborane cage (4 and Cs·5) exerts a significant biological effect as an inhibitor of the purinergic P2X7 receptor (P2X7R) which allows one to target depression in vivo and thus demonstrate, for the first time, that a carborane has the capacity to modify CNS activity.
  • 13.

    【2hr】Interaction between Prion Protein and Aβ AmyloidFibrils Revisited

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    机译 Prion蛋白与Aβ淀粉样蛋白之间的相互作用重访原纤维
    摘要：Recent studies indicate that the pathogenesis of Alzheimer disease may be related to the interaction between prion protein (PrP) and certain oligomeric species of Aβ peptide. However, the mechanism of this interaction remains unclear and controversial. Here we provide direct experimental evidence that, in addition to previously demonstrated binding to Aβ oligomers, PrP also interacts with mature Aβ fibrils. However, contrary to the recent claim that PrP causes fragmentation of Aβ fibrils into oligomeric species, no evidence for such a disassembly could be detected in the present study. In contrast, our data indicate that the addition of PrP to preformed Aβ fibrils results in a lateral association of individual fibrils into larger bundles. These findings have potentially important implications for understanding the mechanism by which PrP might impact Aβ toxicity as well as for the emerging efforts to use PrP-derived compounds as inhibitors of Aβ-induced neurodegeneration.
  • 14.

    【2hr】Discovery of Potent Positive Allosteric Modulatorsof the α3β2 Nicotinic Acetylcholine Receptor by a ChemicalSpace Walk in ChEMBL

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    机译 发现强正构构调节剂化学方法测定α3β2烟碱乙酰胆碱受体ChEMBL中的太空漫步
    摘要：While a plethora of ligands are known for the well studied α7 and α4β2 nicotinic acetylcholine receptor (nAChR), only very few ligands address the related α3β2 nAChR expressed in the central nervous system and at the neuromuscular junction. Starting with the public database ChEMBL organized in the chemical space of Molecular Quantum Numbers (MQN, a series of 42 integer value descriptors of molecular structure), a visual survey of nearest neighbors of the α7 nAChR partial agonist N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-4-chlorobenzamide (PNU-282,987) pointed to N-(2-halobenzyl)-3-aminoquinuclidines as possible nAChR modulators. This simple “chemical space walk” was performed using a web-browser available at . Electrophysiological recordings revealed that these ligands represent a new and to date most potent class of positive allosteric modulators (PAMs) of the α3β2 nAChR, which also exert significant effects in vivo. The present discovery highlights the value of surveying chemical space neighbors of known drugs within public databases to uncover new pharmacology.
  • 15.

    【2hr】Investigation of a Calcium-Responsive Contrast Agentin Cellular Model Systems: Feasibility for Use as a Smart MolecularProbe in Functional MRI

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    机译 钙反应性造影剂的研究在细胞模型系统中：用作智能分子的可行性功能性MRI中的探针
    摘要：Responsive or smart contrast agents (SCAs) represent a promising direction for development of novel functional MRI (fMRI) methods for the eventual noninvasive assessment of brain function. In particular, SCAs that respond to Ca2+ may allow tracking neuronal activity independent of brain vasculature, thus avoiding the characteristic limitations of current fMRI techniques. Here we report an in vitro proof-of-principle study with a Ca2+-sensitive, Gd3+-based SCA in an attempt to validate its potential use as a functional in vivo marker. First, we quantified its relaxometric response in a complex 3D cell culture model. Subsequently, we examined potential changes in the functionality of primary glial cells following administration of this SCA. Monitoring intracellular Ca2+ showed that, despite a reduction in the Ca2+ level, transport of Ca2+ through the plasma membrane remained unaffected, while stimulation with ATP induced Ca2+-transients suggested normal cellular signaling in the presence of low millimolar SCA concentrations. SCAs merely lowered the intracellular Ca2+ level. Finally, we estimated the longitudinal relaxation times (T1) foran idealized in vivo fMRI experiment with SCA, for extracellular Ca2+ concentration level changes expected during intense neuronalactivity which takes place upon repetitive stimulation. The valueswe obtained indicate changes in T1 of around 1–6%,sufficient to be robustly detectable using modern MRI methods in highfield scanners. Our results encourage further attempts to developeven more potent SCAs and appropriate fMRI protocols. This would resultin novel methods that allow monitoring of essential physiologicalprocesses at the cellular and molecular level.
  • 16.

    【2hr】Neuronal Growth on l- and d-CysteineSelf-Assembled Monolayers Reveals Neuronal Chiral Sensitivity

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    机译 半胱氨酸和丁半胱氨酸的神经元生长自组装单层显示神经元手性敏感性。
    摘要：Studying the interaction between neuronal cells and chiral molecules is fundamental for the design of novel biomaterials and drugs. Chirality influences all biological processes that involve intermolecular interaction. One common method used to study cellular interactions with different enantiomeric targets is the use of chiral surfaces. Based on previous studies that demonstrated the importance of cysteine in the nervous system, we studied the effect of l- and d-cysteine on single neuronal growth. l-Cysteine, which normally functions as a neuromodulator or a neuroprotective antioxidant, causes damage at elevated levels, which may occur post trauma. In this study, we grew adult neurons in culture enriched with l- and d-cysteine as free compounds or as self-assembled monolayers of chiral surfaces and examined the effect on the neuronal morphology and adhesion. Notably, we have found that exposure to the l-cysteine enantiomer inhibited, and even prevented, neuronal attachment more severely than exposure to the d-cysteine enantiomer. Atop the l-cysteine surfaces, neuronal growth was reduced and degenerated. Since the cysteine molecules were attached to the surface via thethiol groups, the neuronal membrane was exposed to the molecular chiralsite. Thus, our results have demonstrated high neuronal chiral sensitivity,revealing chiral surfaces as indirect regulators of neuronal cellsand providing a reference for studying chiral drugs.
  • 17.

    【2hr】Acetylcholinesterase Inhibitors with PhotoswitchableInhibition of β-Amyloid Aggregation

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    机译 可光转换的乙酰胆碱酯酶抑制剂抑制β淀粉样蛋白聚集
    摘要：Photochromic cholinesterase inhibitors were obtained from cis-1,2-α-dithienylethene-based compounds by incorporating one or two aminopolymethylene tacrine groups. All target compounds are potent acetyl- (AChE) and butyrylcholinesterase (BChE) inhibitors in the nanomolar concentration range. Compound 11b bearing an octylene linker exhibited interactions with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Yet upon irradiation with light, the mechanism of interaction varied from one photochromic form to another, which was investigated by kinetic studies and proved “photoswitchable”. The AChE-induced β-amyloid (Aβ) aggregation assay gave further experimental support to this finding: Aβ1–40 aggregation catalyzed by the PAS of AChE might be inhibited by compound 11b in a concentration-dependent manner and seems to occur only with one photochromic form. Computational docking studies provided potential binding modes of the compound. Docking studies and molecular dynamics (MD) simulations for the ring-open and -closed form indicatea difference in binding. Although both forms can interact with thePAS, more stable interactions are observed for the ring-open formbased upon stabilization of a water molecule network within the enzyme,whereas the ring-closed form lacks the required conformational flexibilityfor an analogous binding mode. The photoswitchable inhibitor identifiedmight serve as valuable molecular tool to investigate the differentbiological properties of AChE as well as its role in pathogenesisof AD in in vitro assays.
  • 18.

    【2hr】p53 Functional InhibitorsBehaving Like Pifithrin-βCounteract the Alzheimer Peptide Non-β-amyloid Component Effectsin Human SH-SY5Y Cells

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    机译 p53功能抑制剂像菲菲菌素-β一样抵消阿尔茨海默氏症多肽的非β-淀粉样蛋白成分的影响SH-SY5Y细胞中的表达
    摘要：Alzheimer’s disease (AD) develops from a complex setting of genetic and biochemical alterations, including an increased level of p53 in the brain. Here, the robust and specific activation of p53 by the fibrillar non-β-amyloid component (NAC) of AD was demonstrated in human neuroblastoma SH-SY5Y cells. For the first time, the increase in the level of p53 target gene transcription, the cell cycle arrest, and the induction of apoptosis elicited by NAC were evidenced. These effects were counterbalanced by pifithrin-β, a small molecule interfering with the p53 functions. Using the structure of a pifithrin-β analogue as a reference, a pharmacophore-based virtual screening of the ZINC database was performed. Among the resulting hits, 20 druglike heterocyclic compounds were selected and evaluated for their neuroprotective activity against fibrillar NAC in the human SH-SY5Y cellular model. Three compounds exhibited neuroprotective effects. In particular, 2-(4-methoxyphenyl)-7-methyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine resulted in a promising lead compound for further development of anti-AD agentsin terms of neuroprotection, reducing the rate of NAC-induced celldeath with an activity higher than that of pifithrin-β, as aresult of a more effective functional inhibition of p53 target genetranscription.
  • 19.

    【2hr】Eye Movements as a Probe of Corollary Discharge Functionin Schizophrenia

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    机译 眼球运动作为推论放电功能的探针在精神分裂症
    摘要：Nearly every movement made by every animal is accompanied by a corollary discharge, a signal sent from the motor to sensory regions of its brain. Corollary discharges are a crucial mechanism by which the brain monitors its own actions, and there is some evidence that they are impaired in people with schizophrenia. Here, I briefly review this evidence and suggest that eye movements are a particularly valuable tool for assessing the role of corollary discharges in schizophrenia.
  • 20.

    【2hr】ACS Chemical Neuroscience in 2014

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    机译 2014年ACS化学神经科学
    摘要：
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