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https://www.readbyqxmd.com/read/29161500/a-small-molecule-mimetic-of-the-humanin-peptide-as-a-candidate-for-modulating-nmda-induced-neurotoxicity
#1
Mohammad Parvez Alam, Tina Bilousova, Patricia Spilman, Kanagasabai Vadivel, Dongsheng Bai, Denis Evseenko, Varghese John
Humanin (HN), a 24-amino acid bioactive peptide, has been shown to increase cell survival of neurons after exposure to Aβ and NMDA-induced toxicity and thus could be beneficial in the treatment of Alzheimer's disease (AD). The neuroprotection by HN is reported to be primarily through its agonist binding properties to the gp130 receptor. However, peptidic nature of HN presents challenges in its development as a therapeutic for AD. We report here for the first time the elucidation of the binding site of Humanin (HN) peptide to gp130 receptor extracellular domain through modeling and the synthesis of small molecule mimetics that interact with the HN binding site on the gp130 receptor that provides protection against NMDA-induced neurotoxicity in primary hippocampal neurons...
November 21, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29158578/ketamine-and-its-metabolite-2r-6r-hydroxynorketamine-induce-lasting-alterations-in-glutamatergic-synaptic-plasticity-in-the-mesolimbic-circuit
#2
N Yao, O Skiteva, X Zhang, P Svenningsson, K Chergui
Low doses of ketamine trigger rapid and lasting antidepressant effects after one injection in treatment-resistant patients with major depressive disorder. Modulation of AMPA receptors (AMPARs) in the hippocampus and prefrontal cortex is suggested to mediate the antidepressant action of ketamine and of one of its metabolites (2R,6R)-hydroxynorketamine ((2R,6R)-HNK). We have examined whether ketamine and (2R,6R)-HNK affect glutamatergic transmission and plasticity in the mesolimbic system, brain regions known to have key roles in reward-motivated behaviors, mood and hedonic drive...
November 21, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29154925/membrane-cholesterol-depletion-in-cortical-neurons-highlights-altered-nmda-receptor-functionality-in-a-mouse-model-of-amyotrophic-lateral-sclerosis
#3
Alessia Antonini, Silvia Caioli, Luana Saba, Giulia Vindigni, Silvia Biocca, Nadia Canu, Cristina Zona
Amyotrophic Lateral Sclerosis (ALS) is a chronic neurodegenerative disease affecting upper and lower motor neurons, with unknown aetiology. Lipid rafts, cholesterol enriched microdomains of the plasma membrane, have been linked to neurodegenerative disorders like ALS. The NMDA-receptor subcellular localization in lipid rafts is known to play many roles, from modulating memory strength to neurotoxicity. In this study, performed on the widely used G93A mouse model of ALS, we have shown an equal content of total membrane cholesterol in Control and G93A cortical cultures...
November 14, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29151189/the-environmental-pollutant-bde-209-regulates-no-cgmp-signaling-through-activation-of-nmda-receptors-in-neurons
#4
Jingsi Chen, Xiuying Li, Xiaomei Li, Dunjin Chen
The common flame retardant decabrominated diphenyl ether (BDE-209) is a persistent organic pollutant. Epidemiological studies have revealed that prenatal or postnatal exposure to BDE-209 can result in delayed cognitive development, and BDE-209 has been shown to be toxic to cultured neurons with maturation interference effects. However, its neurotoxic mechanism remains unclear. Nitric oxide/cyclic guanosine monophosphate (NO/cGMP) signaling plays an important role in regulating neuronal maturation. We examined the influence of BDE-209 (100, 200, and 400 nM) on NO production and cGMP levels signaling in rodent neurons in vitro, with or without pretreatment N-methyl-D-aspartate (NMDA) receptor antagonism...
November 18, 2017: Environmental Science and Pollution Research International
https://www.readbyqxmd.com/read/29150590/subtype-specific-effects-of-dopaminergic-d2-receptor-activation-on-synaptic-trains-in-layer-v-pyramidal-neurons-in-the-mouse-prefrontal-cortex
#5
Jonna M Leyrer-Jackson, Mark P Thomas
In humans, prefrontal cortical areas are known to support executive functions. In mice, these functions are mediated by homologous regions in the medial prefrontal cortex (mPFC). Executive processes are critically dependent on optimal levels of dopamine (DA), but the cellular mechanisms of DA modulation are incompletely understood. Stable patterns of neuronal activity may be sensitive to frequency-dependent changes in synaptic transmission. We characterized the effects of D2 receptor (D2R) activation on short-term excitatory postsynaptic potential (EPSP) dynamics evoked at varying frequencies in the two subtypes of layer V pyramidal neurons in mouse mPFC We isolated NMDA receptor and non-NMDA receptor-mediated components of EPSP trains evoked by stimulating fibers within layer V or layer I...
November 2017: Physiological Reports
https://www.readbyqxmd.com/read/29143219/glutamatergic-gabaergic-and-endocannabinoid-neurotransmissions-within-the-dorsal-hippocampus-modulate-the-cardiac-baroreflex-function-in-rats
#6
Nilson Carlos Ferreira-Junior, Davi Campos Lagatta, Leonardo Barbosa Moraes Resstel
The dorsal hippocampus (DH) is involved in the modulation of the cardiac baroreflex function. There is a wide expression of the NMDA and AMPA/Kainate receptors within the DH. Glutamate administration into the DH triggers both tachycardia and pressor responses. Moreover, GABAergic interneurons and endocannabinoid system play an important role in modulation of the activity of glutamatergic neurons within the DH. Therefore, the present work aimed to evaluate the involvement of the glutamatergic, GABAergic, and endocannabinoid neurotransmissions within the DH in cardiac baroreflex function in rats...
November 15, 2017: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/29140675/identification-of-novel-allosteric-modulators-of-glutamate-transporter-eaat2
#7
Sandhya Kortagere, Ole Valente Mortensen, Jingsheng Xia, William Lester, Yuhong Fang, Yellamelli V V Srikanth, Joseph M Salvino, Andreia Cristina Karklin Fontana
Dysfunction of excitatory amino acid transporters (EAATs) has been implicated in the pathogenesis of various neurological disorders, such as stroke, brain trauma, epilepsyand neurodegenerative diseases among others. EAAT2 is the main subtype responsible for glutamate clearance in the brain, having a key role in regulating transmission and preventing excitotoxicity. Therefore, compounds that increase the expression or activity of EAAT2 have therapeutic potential for neuroprotection. Previous studies identified molecular determinants for EAAT2 transport stimulation in a structural domain that lies at the interface of the rigid trimerization domain and the central substrate binding transport domain...
November 15, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29138490/bidirectional-modulation-of-hippocampal-synaptic-plasticity-by-dopaminergic-d4-receptors-in-the-ca1-area-of-hippocampus
#8
Sheeja Navakkode, Katherine C M Chew, Sabrina Jia Ning Tay, Qingshu Lin, Thomas Behnisch, Tuck Wah Soong
Long-term potentiation (LTP) is the persistent increase in the strength of the synapses. However, the neural networks would become saturated if there is only synaptic strenghthening. Synaptic weakening could be facilitated by active processes like long-term depression (LTD). Molecular mechanisms that facilitate the weakening of synapses and thereby stabilize the synapses are also important in learning and memory. Here we show that blockade of dopaminergic D4 receptors (D4R) promoted the formation of late-LTP and transformed early-LTP into late-LTP...
November 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29127015/oxotremorine-m-potentiates-nmda-receptors-by-muscarinic-receptor-dependent-and-independent-mechanisms
#9
Ruud Zwart, Hannah Reed, Emanuele Sher
Muscarinic acetylcholine M1 receptors play an important role in synaptic plasticity in the hippocampus and cortex. Potentiation of NMDA receptors as a consequence of muscarinic acetylcholine M1 receptor activation is a crucial event mediating the cholinergic modulation of synaptic plasticity, which is a cellular mechanism for learning and memory. In Alzheimer's disease, the cholinergic input to the hippocampus and cortex is severely degenerated, and agonists or positive allosteric modulators of M1 receptors are therefore thought to be of potential use to treat the deficits in cognitive functions in Alzheimer's disease...
November 7, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29124300/xanthoceraside-modulates-nr2b-containing-nmda-receptors-at-synapses-and-rescues-learning-memory-deficits-in-app-ps1-transgenic-mice
#10
Lin Zhu, Lei Yang, Xuemei Zhao, Danyang Liu, Xiaoli Guo, Peng Liu, Tianyan Chi, Xuefei Ji, Libo Zou
RATIONALE: Alzheimer's disease (AD) is characterized by memory loss and synaptic damage. Previous studies suggested that xanthoceraside decreases glutamate-induced PC12 cell death, ameliorates memory deficits, and increases the number of dendritic spines in AD mice. These results indicated that xanthoceraside might have activities that protect synaptic plasticity. Herein, we detected the effect of xanthoceraside on synaptic function. MATERIALS AND METHODS: Three-month-old APP/PS1 transgenic mice were orally treated with xanthoceraside (0...
November 9, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/29121962/direct-interaction-with-14-3-3%C3%AE-promotes-surface-expression-of-best1-channel-in-astrocyte
#11
Soo-Jin Oh, Junsung Woo, Young-Sun Lee, Minhee Cho, Eunju Kim, Nam-Chul Cho, Jae-Yong Park, Ae Nim Pae, C Justin Lee, Eun Mi Hwang
BACKGROUND: Bestrophin-1 (Best1) is a calcium-activated anion channel (CAAC) that is expressed broadly in mammalian tissues including the brain. We have previously reported that Best1 is expressed in hippocampal astrocytes at the distal peri-synaptic regions, called microdomains, right next to synaptic junctions, and that it disappears from the microdomains in Alzheimer's disease mouse model. Although Best1 appears to be dynamically regulated, the mechanism of its regulation and modulation is poorly understood...
November 9, 2017: Molecular Brain
https://www.readbyqxmd.com/read/29116427/cart-neurons-in-the-lateral-hypothalamus-communicate-with-the-nucleus-accumbens-shell-via-glutamatergic-neurons-in-paraventricular-thalamic-nucleus-to-modulate-reward-behavior
#12
Amit G Choudhary, Amita R Somalwar, Sneha Sagarkar, Abhishek Rale, Amul Sakharkar, Nishikant K Subhedar, Dadasaheb M Kokare
Paraventricular thalamic nucleus (PVT) serves as a transit node processing food and drug-associated reward information, but its afferents and efferents have not been fully defined. We test the hypothesis that the CART neurons in the lateral hypothalamus (LH) project to the PVT neurons, which in turn communicate via the glutamatergic fibers with the nucleus accumbens shell (AcbSh), the canonical site for reward. Rats conditioned to self-stimulate via an electrode in the right LH-medial forebrain bundle were used...
November 7, 2017: Brain Structure & Function
https://www.readbyqxmd.com/read/29106899/vinpocetine-protects-inner-retinal-neurons-with-functional-nmda-glutamate-receptors-against-retinal-ischemia
#13
Lisa Nivison-Smith, Pauline Khoo, Monica L Acosta, Michael Kalloniatis
Retinal ischemia is involved in the pathogenesis of many major vision threatening diseases. Vinpocetine is a natural drug, which has a range of neuroprotective actions against retinal ischemia including modulating cation flow, improving metabolic activity and preventing apoptosis. The exact mechanism behind these actions remains unknown but may involve glutamate receptors, major components of the ischemic cascade. This study examined the effects of vinpocetine in association with specific ionotropic glutamate receptor agonists: N-methyl-D-aspartate (NMDA) and kainate...
November 4, 2017: Experimental Eye Research
https://www.readbyqxmd.com/read/29103920/influence-of-the-anteromedial-thalamus-on-social-defeat-associated-contextual-fear-memory
#14
Miguel J Rangel, Marcus Vinicius C Baldo, Newton Sabino Canteras
The ventral part of the anteromedial thalamic nucleus (AMv) is heavily targeted by the dorsal premammillary nucleus (PMd), which is the main hypothalamic site that is responsive to both predator and conspecific aggressor threats. This PMd-AMv pathway is likely involved in modulating memory processing, and previous findings from our group have shown that cytotoxic lesions or pharmacological inactivation of the AMv drastically reduced contextual fear responses to predator-associated environments. In the present study, we investigated the role of the AMv in both unconditioned (i...
November 2, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/29102760/partial-inhibition-of-catecholamine-activity-and-enhanced-responsiveness-to-nmda-after-sustained-administration-of-vortioxetine
#15
Mohammad Ebrahimzadeh, Mostafa El Mansari, Pierre Blier
Vortioxetine is a multimodal drug that blocks serotonin (5-HT) reuptake and directly modulates 5-HT receptors. The effects of subacute and long-term administration of vortioxetine on various aspects of catecholamine and glutamate systems were investigated using single-unit extracellular recordings and microiontophoresis in the rat brain. The firing rate of dopamine (DA) neurons was significantly decreased (26%) after 14, but not 4 days of vortioxetine administration (vortioxetine-containing chow, 1.8 g/kg vortioxetine)...
November 13, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/29101377/a-high-throughput-model-for-investigating-neuronal-function-and-synaptic-transmission-in-cultured-neuronal-networks
#16
Jasmeet K Virdee, Gabriella Saro, Antoine Fouillet, Jeremy Findlay, Filipa Ferreira, Sarah Eversden, Michael J O'Neill, Joanna Wolak, Daniel Ursu
Loss of synapses or alteration of synaptic activity is associated with cognitive impairment observed in a number of psychiatric and neurological disorders, such as schizophrenia and Alzheimer's disease. Therefore successful development of in vitro methods that can investigate synaptic function in a high-throughput format could be highly impactful for neuroscience drug discovery. We present here the development, characterisation and validation of a novel high-throughput in vitro model for assessing neuronal function and synaptic transmission in primary rodent neurons...
November 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29099938/nyx-2925-is-a-novel-nmda-receptor-specific-spirocyclic-%C3%AE-lactam-that-modulates-synaptic-plasticity-processes-associated-with-learning-and-memory
#17
M Amin Khan, David R Houck, Amanda L Gross, Xiao-Lei Zhang, Cassia Cearley, Torsten M Madsen, Roger A Kroes, Patric K Stanton, Jeffrey Burgdorf, Joseph R Moskal
Background: N-methyl-D-aspartate receptors (NMDAR) are one member of a family of ionotropic glutamate receptors that play a pivotal role in synaptic plasticity processes associated with learning and have become attractive therapeutic targets for diseases such as depression, anxiety, schizophrenia, and neuropathic pain. NYX-2925 ((2S, 3R)-3-hydroxy-2-((R)-5-isobutyryl-1-oxo-2,5-diazaspiro[3.4]octan-2-yl)butanamide) is one member of a spiro--lactam-based chemical platform that mimics some of the dipyrrolidine structural features of rapastinel (formerly GLYX-13: threonine-proline-proline-threonine) and is distinct from known NMDAR agonists or antagonists such as D-cycloserine, ketamine, MK-801, kynurenic acid or ifenprodil...
November 1, 2017: International Journal of Neuropsychopharmacology
https://www.readbyqxmd.com/read/29096588/non-nmda-receptor-mediated-vibrotactile-responses-of-neurons-from-the-hindpaw-representation-in-the-rat-si-cortex
#18
Bige Vardar, Burak Güçlü
Non-NMDA receptor-mediated vibrotactile responses of neurons from the hindpaw representation were investigated in the rat SI cortex. We recorded single-unit spikes evoked by sinusoidal (duration: 500 ms; frequency: 5, 40, and 250 Hz; amplitude: 100 μm peak-to-peak) stimulation of the glabrous skin. The responses were obtained with microinjection of aCSF (sham), bicuculline, and AMPA near the isolated neurons in anaesthetized rats. Blocking most of the NMDA receptors by ketamine revealed local dynamics differentially modulated by each drug...
September 2017: Somatosensory & Motor Research
https://www.readbyqxmd.com/read/29093636/agmatine-modulates-the-phenotype-of-macrophage-acute-phase-after-spinal-cord-injury-in-rats
#19
Jae Hwan Kim, Jae Young Kim, Chin Hee Mun, Minah Suh, Jong Eun Lee
Agmatine is a decarboxylated arginine by arginine decarboxylase. Agmatine is known to be a neuroprotective agent. It has been reported that agmatine works as a NMDA receptor blocker or a competitive nitric oxide synthase inhibitor in CNS injuries. In spinal cord injury, agmatine showed reduction of neuropathic pain, improvement of locomotor function, and neuroprotection. Macrophage is a key cellular component in neuroinflammation, a major cause of impairment after spinal cord injury. Macrophage has subtypes, M1 and M2 macrophages...
October 2017: Experimental Neurobiology
https://www.readbyqxmd.com/read/29070712/l-serine-enhances-light-induced-circadian-phase-resetting-in-mice-and-humans
#20
Shinobu Yasuo, Ayaka Iwamoto, Sang-Il Lee, Shotaro Ochiai, Rina Hitachi, Satomi Shibata, Nobuo Uotsu, Chie Tarumizu, Sayuri Matsuoka, Mitsuhiro Furuse, Shigekazu Higuchi
Background: The circadian clock is modulated by the timing of ingestion or food composition, but the effects of specific nutrients are poorly understood.Objective: We aimed to identify the amino acids that modulate the circadian clock and reset the light-induced circadian phase in mice and humans.Methods: Male CBA/N mice were orally administered 1 of 20 l-amino acids, and the circadian and light-induced phase shifts of wheel-running activity were analyzed. Antagonists of several neurotransmitter pathways were injected before l-serine administration, and light-induced phase shifts were analyzed...
October 25, 2017: Journal of Nutrition
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