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https://www.readbyqxmd.com/read/28432778/cross-species-studies-of-cognition-relevant-to-drug-discovery-a-translational-approach
#1
REVIEW
T W Robbins
This Review advances the case that bidirectional, cross-species translation of findings from experimental animals to and from humans is an important strategy for drug discovery. Animal models of mental disorders require appropriate behavioural or cognitive outcome variables that can be generalized cross-species. One example is the treatment of impulsive behaviour in attention deficit hyperactivity disorder (ADHD) with stimulant drugs. Performance on the stop signal reaction task as an index of impulsivity is improved both in healthy human volunteers and in patients with adult ADHD by stimulant drugs and also by the selective noradrenergic reuptake blocker atomoxetine...
April 22, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28432601/neuropathic-pain-central-vs-peripheral-mechanisms
#2
REVIEW
Kathleen Meacham, Andrew Shepherd, Durga P Mohapatra, Simon Haroutounian
PURPOSE OF REVIEW: Our goal is to examine the processes-both central and peripheral-that underlie the development of peripherally-induced neuropathic pain (pNP) and to highlight recent evidence for mechanisms contributing to its maintenance. While many pNP conditions are initiated by damage to the peripheral nervous system (PNS), their persistence appears to rely on maladaptive processes within the central nervous system (CNS). The potential existence of an autonomous pain-generating mechanism in the CNS creates significant implications for the development of new neuropathic pain treatments; thus, work towards its resolution is crucial...
June 2017: Current Pain and Headache Reports
https://www.readbyqxmd.com/read/28432293/quiescence-of-adult-oligodendrocyte-precursor-cells-requires%C3%A2-thyroid-hormone-and-hypoxia-to-activate-runx1
#3
Yasuhito Tokumoto, Shinpei Tamaki, Yasuaki Kabe, Keiyo Takubo, Makoto Suematsu
The adult mammalian central nervous system (CNS) contains a population of slowly dividing oligodendrocyte precursor cells (OPCs), i.e., adult OPCs, which supply new oligodendrocytes throughout the life of animal. While adult OPCs develop from rapidly dividing perinatal OPCs, the mechanisms underlying their quiescence remain unknown. Here, we show that perinatal rodent OPCs cultured with thyroid hormone (TH) under hypoxia become quiescent and acquire adult OPCs-like characteristics. The cyclin-dependent kinase inhibitor p15/INK4b plays crucial roles in the TH-dependent cell cycle deceleration in OPCs under hypoxia...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28432176/a-phase-i-study-of-the-cdk4-6-inhibitor-ribociclib-lee011-in-pediatric-patients-with-malignant-rhabdoid-tumors-neuroblastoma-and-other-solid-tumors
#4
Birgit Geoerger, Franck Bourdeaut, Steven G DuBois, Matthias Fischer, James I Geller, Nicholas G Gottardo, Aurélien Marabelle, Andrew D J Pearson, Shakeel Modak, Thomas Cash, Giles W Robinson, Marlyane Motta, Alessandro Matano, Suraj G Bhansali, Jason R Dobson, Sudha Parasuraman, Susan N Chi
Purpose: The cyclin-dependent kinase (CDK) 4/6 inhibitor, ribociclib (LEE011), displayed preclinical activity in neuroblastoma and malignant rhabdoid tumor (MRT) models. In this phase I study, the maximum tolerated dose (MTD) and recommended phase II dose (RP2D), safety, pharmacokinetics (PK), and preliminary activity of single-agent ribociclib were investigated in pediatric patients with neuroblastoma, MRT, or other cyclin D-CDK4/6-INK4-retinoblastoma pathway-altered tumors.Experimental Design: Patients (aged 1-21 years) received escalating once-daily oral doses of ribociclib (3-weeks-on/1-week-off)...
April 21, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28431938/selective-inhibition-of-ezh2-by-a-small-molecule-inhibitor-regulates-microglial-gene-expression-essential-for-inflammation
#5
Sarder Arifuzzaman, Amitabh Das, Sun Hwa Kim, Taeho Yoon, Young Seek Lee, Kyoung Hwa Jung, Young Gyu Chai
Multiple studies have documented that Enhancer of zeste homolog 2 (EZH2) could play a role in inflammation and a wide range of malignancies; however, the underlying mechanisms remain largely unaddressed. Microglial activation is a key process in the production and release of numerous pro-inflammatory mediators that play important roles in inflammation and neurodegeneration in the central nervous system (CNS). Therefore, our aim was to investigate whether inhibition of EZH2 with the selective small molecule inhibitor EPZ-6438 protects against neonatal microglial activation...
April 18, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28431906/transgenic-mice-with-increased-astrocyte-expression-of-ccl2-show-altered-behavioral-effects-of-alcohol
#6
Jennifer G Bray, Amanda J Roberts, Donna L Gruol
Emerging research provides strong evidence that activation of CNS glial cells occurs in neurological diseases and brain injury and results in elevated production of neuroimmune factors. These factors can contribute to pathophysiological processes that lead to altered CNS function. Recently, studies have also shown that both acute and chronic alcohol consumption can produce activation of CNS glial cells and the production of neuroimmune factors, particularly the chemokine CCL2. The consequences of alcohol-induced increases in CCL2 levels in the CNS have yet to be fully elucidated...
April 18, 2017: Neuroscience
https://www.readbyqxmd.com/read/28430981/central-nervous-system-glp-1-receptors-regulate-islet-hormone-secretion-and-glucose-homeostasis-in-male-rats
#7
Lene Jessen, Eric P Smith, Yvonne Ulrich-Lai, James P Herman, Randy J Seeley, Darleen Sandoval, David D'Alessio
The glucagon-like peptide 1 (GLP-1) system plays an important role in blood glucose regulation, in great part through coordinate control of insulin and glucagon secretion. These effects are generally attributed to GLP-1 produced in peripheral sites, principally the intestine. GLP-1 is also produced in hindbrain neurons that signal through GLP-1 receptors (GLP-1r) expressed in brain regions involved in metabolic regulation. GLP-1 in the central nervous system (CNS) induces satiety, visceral illness, and stress responses...
April 18, 2017: Endocrinology
https://www.readbyqxmd.com/read/28428262/uncoupling-neurogenic-gene-networks-in-the-drosophila-embryo
#8
William A Rogers, Yogesh Goyal, Kei Yamaya, Stanislav Y Shvartsman, Michael S Levine
The EGF signaling pathway specifies neuronal identities in the Drosophila embryo by regulating developmental patterning genes such as intermediate neurons defective (ind). EGFR is activated in the ventral midline and neurogenic ectoderm by the Spitz ligand, which is processed by the Rhomboid protease. CRISPR/Cas9 was used to delete defined rhomboid enhancers mediating expression at each site of Spitz processing. Surprisingly, the neurogenic ectoderm, not the ventral midline, was found to be the dominant source of EGF patterning activity...
April 20, 2017: Genes & Development
https://www.readbyqxmd.com/read/28427812/synthesis-and-evaluation-of-4-6-disubstituted-pyrimidines-as-cns-penetrant-pan-muscarinic-antagonists-with-a-novel-chemotype
#9
Aaron M Bender, Rebecca L Weiner, Vincent B Luscombe, Hyekyung P Cho, Colleen M Niswender, Darren W Engers, Thomas M Bridges, P Jeffrey Conn, Craig W Lindsley
This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M4 antagonists, based on a 4,6-disubstituted core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at both human and rat M4 (IC50s<300nM), with no substantial species differences noted. Moreover, CNS penetration proved attractive for this series (brain:plasma Kp,uu=0.87), while other DMPK attributes were addressed in the course of the optimization effort, providing low in vivo clearance in rat (CLp=5...
April 4, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28427710/clinical-outcomes-and-predictive-factors-related-to-good-outcomes-in-plasma-exchange-in-severe-attack-of-nmosd-and-long-extensive-transverse-myelitis-case-series-and-review-of-the-literature
#10
Saharat Aungsumart, Metha Apiwattanakul
OBJECTIVE: To investigate the predictive factors associated with good outcomes of plasma exchange in severe attacks through neuromyelitis optica spectrum disorder (NMOSD) and long extensive transverse myelitis (LETM). In addition, to review the literature of predictive factors associated with the good outcomes of plasma exchange in central nervous system inflammatory demyelinating diseases (CNS IDDs). METHODS: Retrospective study in 27 episodes of severe acute attacks myelitis and optic neuritis in 24 patients, including 20 patients with NMOSD seropositive, 1 patient with NMOSD seronegative and 3 patients with LETM...
April 2017: Multiple Sclerosis and related Disorders
https://www.readbyqxmd.com/read/28427705/presence-of-central-veins-and-susceptibility-weighted-imaging-for-evaluating-lesions-in-multiple-sclerosis-and-leukoaraiosis
#11
Urška Lamot, Jernej Avsenik, Saša Šega, Katarina Šurlan Popovič
PURPOSE: The process of demyelination in multiple sclerosis (MS) is reflected in lesions of the central nervous system (CNS), which are found in an abundance of different diseases and are frequently radiographically indistinguishable. Our aim was to determine whether the perivenous distribution of MS lesions identified on susceptibility weighted images (SWI) could be used as a specific radiographic sign for MS, and also to determine whether the visibility of the central vein (CV) is affected by the activity of MS lesions...
April 2017: Multiple Sclerosis and related Disorders
https://www.readbyqxmd.com/read/28426967/an-intrinsic-epigenetic-barrier-for-functional-axon-regeneration
#12
Yi-Lan Weng, Ran An, Jessica Cassin, Jessica Joseph, Ruifa Mi, Chen Wang, Chun Zhong, Seung-Gi Jin, Gerd P Pfeifer, Alfonso Bellacosa, Xinzhong Dong, Ahmet Hoke, Zhigang He, Hongjun Song, Guo-Li Ming
Mature neurons in the adult peripheral nervous system can effectively switch from a dormant state with little axonal growth to robust axon regeneration upon injury. The mechanisms by which injury unlocks mature neurons' intrinsic axonal growth competence are not well understood. Here, we show that peripheral sciatic nerve lesion in adult mice leads to elevated levels of Tet3 and 5-hydroxylmethylcytosine in dorsal root ganglion (DRG) neurons. Functionally, Tet3 is required for robust axon regeneration of DRG neurons and behavioral recovery...
April 19, 2017: Neuron
https://www.readbyqxmd.com/read/28426956/amines-astrocytes-and-arousal
#13
Narges Bazargani, David Attwell
Amine neurotransmitters, such as noradrenaline, mediate arousal, attention, and reward in the CNS. New data suggest that, from flies to mammals, a major mechanism for amine transmitter action is to raise astrocyte [Ca(2+)]i and release gliotransmitters that modulate neuronal activity and behavior.
April 19, 2017: Neuron
https://www.readbyqxmd.com/read/28425493/characterization-of-different-microbubbles-in-assisting-focused-ultrasound-induced-blood-brain-barrier-opening
#14
Sheng-Kai Wu, Po-Chun Chu, Wen-Yen Chai, Shih-Tsung Kang, Chih-Hung Tsai, Ching-Hsiang Fan, Chih-Kuang Yeh, Hao-Li Liu
Microbubbles (MBs) serve as a critical catalyst to amplify local cavitation in CNS capillary lumen to facilitate focused ultrasound (FUS) to transiently open the blood-brain barrier (BBB). However, limited understanding is available regarding the effect of different microbubbles to induce BBB opening. The aim of this study is to characterize different MBs on their effect in FUS-induced BBB opening. Three MBs, SonoVue, Definity, and USphere, were tested, with 0.4-MHz FUS exposure at 0.62-1.38 of mechanical index (MI) on rats...
April 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28424694/immune-responses-in-the-central-nervous-system-are-anatomically-segregated-in-a-non-human-primate-model-of-human-immunodeficiency-virus-infection
#15
Barbara Tavano, Vicky Tsipouri, Gareth A D Hardy, Caroline M Royle, Michael R Keegan, Dietmar Fuchs, Steven Patterson, Neil Almond, Neil Berry, Claire Ham, Deborah Ferguson, Adriano Boasso
The human immunodeficiency virus (HIV) accesses the central nervous system (CNS) early during infection, leading to HIV-associated cognitive impairment and establishment of a viral reservoir. Here, we describe a dichotomy in inflammatory responses in different CNS regions in simian immunodeficiency virus (SIV)-infected macaques, a model for HIV infection. We found increased expression of inflammatory genes and perivascular leukocyte infiltration in the midbrain of SIV-infected macaques. Conversely, the frontal lobe showed downregulation of inflammatory genes associated with interferon-γ and interleukin-6 pathways, and absence of perivascular cuffing...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28424591/bcl11b-a-critical-neurodevelopmental-transcription-factor-roles-in-health-and-disease
#16
REVIEW
Matthew J Lennon, Simon P Jones, Michael D Lovelace, Gilles J Guillemin, Bruce J Brew
B cell leukemia 11b (Bcl11b) is a zinc finger protein transcription factor with a multiplicity of functions. It works as both a genetic suppressor and activator, acting directly, attaching to promoter regions, as well as indirectly, attaching to promoter-bound transcription factors. Bcl11b is a fundamental transcription factor in fetal development, with important roles for the differentiation and development of various neuronal subtypes in the central nervous system (CNS). It has been used as a specific marker of layer V subcerebral projection neurons as well as striatal interneurons...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28423185/functional-identification-of-activity-regulated-high-affinity-glutamine-transport-in-hippocampal-neurons-inhibited-by-riluzole
#17
Jeffrey D Erickson
Glutamine (Gln) is considered the preferred precursor for the neurotransmitter pool of glutamate (Glu), the major excitatory transmitter in the mammalian CNS. Here, an activity-regulated, high-affinity Gln transport system is described in developing and mature neuron-enriched hippocampal cultures that is potently inhibited by riluzole (IC50 1.3 +/- 0.5μM), an anti-glutamatergic drug, and is blocked by low concentrations of 2-(methylamino)isobutyrate (MeAIB), a system A transport inhibitor. K(+) -stimulated MeAIB transport displays an affinity (Km ) for MeAIB of 37 +/- 1...
April 19, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28420986/modulation-of-microglial-activity-by-rho-kinase-rock-inhibition-as-therapeutic-strategy-in-parkinson-s-disease-and-amyotrophic-lateral-sclerosis
#18
REVIEW
Anna-Elisa Roser, Lars Tönges, Paul Lingor
Neurodegenerative diseases are characterized by the progressive degeneration of neurons in the central and peripheral nervous system (CNS, PNS), resulting in a reduced innervation of target structures and a loss of function. A shared characteristic of many neurodegenerative diseases is the infiltration of microglial cells into affected brain regions. During early disease stages microglial cells often display a rather neuroprotective phenotype, but switch to a more pro-inflammatory neurotoxic phenotype in later stages of the disease, contributing to the neurodegeneration...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28420963/rna-seq-analysis-of-microglia-reveals-time-dependent-activation-of-specific-genetic-programs-following-spinal-cord-injury
#19
Harun N Noristani, Yannick N Gerber, Jean-Charles Sabourin, Marine Le Corre, Nicolas Lonjon, Nadine Mestre-Frances, Hélène E Hirbec, Florence E Perrin
Neurons have inherent competence to regrow following injury, although not spontaneously. Spinal cord injury (SCI) induces a pronounced neuroinflammation driven by resident microglia and infiltrating peripheral macrophages. Microglia are the first reactive glial population after SCI and participate in recruitment of monocyte-derived macrophages to the lesion site. Both positive and negative influence of microglia and macrophages on axonal regeneration had been reported after SCI, raising the issue whether their response depends on time post-lesion or different lesion severity...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28420695/adeno-associated-viral-9-mediated-cdk5-inhibitory-peptide-reverses-pathologic-changes-and-behavioral-deficits-in-the-alzheimer-s-disease-mouse-model
#20
Yong He, Suyue Pan, Miaojing Xu, Rongni He, Wei Huang, Pingping Song, Jianou Huang, Han-Ting Zhang, Yafang Hu
Cyclin-dependent kinase 5 (Cdk5), which binds to and is activated by p35, phosphorylates multiple substrates and plays an essential role in the development and function of the CNS; however, proteolytic production of p25 from p35 under stress conditions leads to the inappropriate activation of Cdk5 and contributes to hyperphosphorylation of τ and other substrates that are related to the pathogenesis of Alzheimer's disease. Selective inhibition of aberrant Cdk5 activity via genetic overexpression of Cdk5 inhibitory peptide (CIP) reduces pathologic changes and prevents brain atrophy and memory loss in p25-transgenic mice...
April 18, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
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