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https://www.readbyqxmd.com/read/29772491/calpain-inhibition-reduces-nmda-receptor-rundown-in-rat-substantia-nigra-dopamine-neurons
#1
Jerry Zhao, Michel Baudry, Susan Jones
Repeated activation of N-Methyl-d-aspartate receptors (NMDARs) causes a Ca2+ -dependent reduction in NMDAR-mediated current in dopamine (DA) neurons of the substantia nigra pars compacta (SNc) in one week old rats; however, a Ca2+ -dependent regulatory protein has not been identified. The role of the Ca2+ -dependent cysteine protease, calpain, in mediating NMDAR current rundown was investigated. In brain slices from rats aged postnatal day 7-9 ('P7'), bath application of either of the membrane permeable calpain inhibitors, N-Acetyl-L-leucyl-L-leucyl-L-norleucinal (ALLN, 20 μM) or MDL-28170 (30 μM) significantly reduced whole-cell NMDAR current rundown...
May 4, 2018: Neuropharmacology
https://www.readbyqxmd.com/read/29760409/histone-deacetylase-inhibitor-ms-275-restores-social-and-synaptic-function-in-a-shank3-deficient-mouse-model-of-autism
#2
Kaijie Ma, Luye Qin, Emmanuel Matas, Lara J Duffney, Aiyi Liu, Zhen Yan
Autism is a neurodevelopmental disorder characterized by social deficits and repetitive behaviors. Genetic screening has identified synaptic, transcriptional, and chromatin genes disrupted in autistic patients. Haploinsufficiency of Shank3, which encodes a scaffold protein at glutamatergic synapses, is causally linked to autism. Using a Shank3-deficient mouse model that exhibits prominent autism-like phenotypes, we have found that histone acetylation in the prefrontal cortex (PFC) is abnormally low, which can be reversed by MS-275 (also known as Entinostat, SNDX-275), a class I histone deacetylase (HDAC) inhibitor that is selectively potent in PFC...
April 19, 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/29736613/inhibition-of-acid-sensing-ion-channel-3-aggravates-seizures-by-regulating-nmdar-function
#3
Qian Cao, Zhe-Man Xiao, Xi Wang, Chao Weng, Man Ding, Fan Zhu, Zu-Neng Lu
The existing data about whether acid sensing ion channels (ASICs) are proconvulsant or anticonvulsant are controversial. Particularly, acid sensing ion channel 3 (ASIC3) is the most sensitive to extracellular pH and has the characteristic ability to generate a biphasic current, but few studies have focused on the role of ASIC3 in seizure. Here we found ASIC3 expression was increased in the hippocampus of pilocarpine induced seizure rats, as well as in hippocampal neuronal cultures undergoing epileptiform discharge elicited by Mg2+ -free media...
May 7, 2018: Neurochemical Research
https://www.readbyqxmd.com/read/29732929/drug-development-for-alzheimer-s-disease-review
#4
Kejing Lao, Naichun Ji, Xiaohua Zhang, Wenwei Qiao, Zhishu Tang, Xingchun Gou
Alzheimer's disease (AD) is a chronic neurodegenerative disease, which is considered one of the most intractable medical problems with heavy social and economic costs. The current drugs for AD, including acetylcholinesterase inhibitors (AChEIs) and memantine, a NMDA receptor antagonist, only temporarily ameliorate cognitive decline, but are unable to stop or reverse the progression of dementia. This paper reviewed the recent advance in AD drug development. The drug discovery programs under clinical trials targeting cholinergic system, α7 nicotinic acetylcholine receptors (nAChRs), N-methyl-D-aspartate receptor (NMDAR), β-secretase, γ-secretase modulators, tau, inflammatory mediators and glucagon-like peptide-1 (GLP-1) were discussed...
May 7, 2018: Journal of Drug Targeting
https://www.readbyqxmd.com/read/29670547/medications-used-for-cognitive-enhancement-in-patients-with-schizophrenia-bipolar-disorder-alzheimer-s-disease-and-parkinson-s-disease
#5
REVIEW
Wen-Yu Hsu, Hsien-Yuan Lane, Chieh-Hsin Lin
Background/aims: Cognitive impairment, which frequently occurs in patients with schizophrenia, bipolar disorder, Alzheimer's disease, and Parkinson's disease, has a significant impact on the daily lives of both patients and their family. Furthermore, since the medications used for cognitive enhancement have limited efficacy, the issue of cognitive enhancement still remains a clinically unsolved challenge. Sampling and methods: We reviewed the clinical studies (published between 2007 and 2017) that focused on the efficacy of medications used for enhancing cognition in patients with schizophrenia, bipolar disorder, Alzheimer's disease, and Parkinson's disease...
2018: Frontiers in Psychiatry
https://www.readbyqxmd.com/read/29648983/enhancement-of-brain-d-serine-mediates-recovery-of-cognitive-function-after-tbi
#6
Sigal Liraz-Zaltsman, Barbara Slusher, Dana Atrakchi-Baranes, Kinneret Rosenblatt, Yael Friedman Levi, Efrat Leah Kesner, Alcino J Silva, Anat Biegon, Esther Shohami
Cognitive deficits, especially memory loss, are common and devastating neuropsychiatric sequelae of traumatic brain injury (TBI). The deficits may persist for a long time and may be accompanied by increased risk of developing early onset dementia. Past attempts to reverse the neuropsychological effects of brain injury with glutamate-N-methyl-D-aspartate (NMDA) antagonists failed to show any benefits or worsened the outcome, suggesting activation, rather than blockage, of the NMDA receptor (NMDAR) may be useful in the sub-acute period after TBI and stroke...
March 14, 2018: Journal of Neurotrauma
https://www.readbyqxmd.com/read/29614089/hippocampal-protein-kinase-d1-is-necessary-for-dhpg-induced-learning-and-memory-impairments-in-rats
#7
Wei Wang, Florian Duclot, Bradley R Groveman, Nicole Carrier, Haifa Qiao, Xiao-Qian Fang, Hui Wang, Wenkuan Xin, Xing-Hong Jiang, Michael W Salter, Xin-Sheng Ding, Mohamed Kabbaj, Xian-Min Yu
BACKGROUND: Understanding molecular mechanisms underlying the induction of learning and memory impairments remains a challenge. Recent investigations have shown that the activation of group I mGluRs (mGluR1 and mGluR5) in cultured hippocampal neurons by application of (S)-3,5-Dihydroxyphenylglycine (DHPG) causes the regulated internalization of N-methyl-D-aspartate receptors (NMDARs), which subsequently activates protein kinase D1 (PKD1). Through phosphorylating the C-terminals of the NMDAR GluN2 subunits, PKD1 down-regulates the activity of remaining (non-internalized) surface NMDARs...
2018: PloS One
https://www.readbyqxmd.com/read/29606348/gkap-acts-as-a-genetic-modulator-of-nmdar-signaling-to-govern-invasive-tumor-growth
#8
Leanne Li, Qiqun Zeng, Arjun Bhutkar, José A Galván, Eva Karamitopoulou, Daan Noordermeer, Mei-Wen Peng, Alessandra Piersigilli, Aurel Perren, Inti Zlobec, Hugh Robinson, M Luisa Iruela-Arispe, Douglas Hanahan
Genetic linkage analysis previously suggested that GKAP, a scaffold protein of the N-methyl-D-aspartate receptor (NMDAR), was a potential modifier of invasion in a mouse model of pancreatic neuroendocrine tumor (PanNET). Here, we establish that GKAP governs invasive growth and treatment response to NMDAR inhibitors of PanNET via its pivotal role in regulating NMDAR pathway activity. Combining genetic knockdown of GKAP and pharmacological inhibition of NMDAR, we implicate as downstream effectors FMRP and HSF1, which along with GKAP demonstrably support invasiveness of PanNET and pancreatic ductal adenocarcinoma cancer cells...
March 9, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29578035/ras-inhibitor-s-trans-trans-farnesylthiosalicylic-acid-enhances-spatial-memory-and-hippocampal-long-term-potentiation-via-up-regulation-of-nmda-receptor
#9
Ya Wang, Tingting Chen, Zihao Yuan, Yajie Zhang, Baofeng Zhang, Liandong Zhao, Ling Chen
Statins by reducing farnesyl-pyrophosphate or farnesyl transferase inhibitors have been demonstrated to enhance spatial memory and long-term potentiation (LTP). The objective of this study was to investigate effects of the synthetic Ras inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS) on spatial cognitive function in adult mice, synaptic plasticity in hippocampal CA1 regions, and NMDA receptor (NMDAr) activity of pyramidal cells. Here, we show that administering FTS (5 mg/kg, i.p.) enhanced spatial cognitive performance, as assessed via Morris water maze and Y-maze tests...
March 22, 2018: Neuropharmacology
https://www.readbyqxmd.com/read/29538620/camkii-dependent-endoplasmic-reticulum-fission-by-whisker-stimulation-and-during-cortical-spreading-depolarization
#10
Krzysztof Kucharz, Martin Lauritzen
Cortical spreading depolarization waves, the cause underlying migraine aura, are also the markers and mechanism of pathology in the acutely injured human brain. Propagation of spreading depolarization wave uniquely depends on the interaction between presynaptic and postsynaptic glutamate N-methyl-d-aspartate receptors (NMDARs). In the normally perfused brain, even a single wave causes a massive depolarization of neurons and glia, which results in transient loss of neuronal function and depression of the ongoing electrocorticographic activity...
April 1, 2018: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29534733/targeting-nmda-receptors-in-stroke-new-hope-in-neuroprotection
#11
REVIEW
Qiu Jing Wu, Michael Tymianski
NMDA (N-methyl-d-aspartate) receptors (NMDARs) play a central role in excitotoxic neuronal death caused by ischemic stroke, but NMDAR channel blockers have failed to be translated into clinical stroke treatments. However, recent research on NMDAR-associated signaling complexes has identified important death-signaling pathways linked to NMDARs. This led to the generation of inhibitors that inhibit these pathways downstream from the receptor without necessarily blocking NMDARs. This therapeutic approach may have fewer side effects and/or provide a wider therapeutic window for stroke as compared to the receptor antagonists...
March 13, 2018: Molecular Brain
https://www.readbyqxmd.com/read/29495345/mesenchymal-stem-cell-protection-of-neurons-against-glutamate-excitotoxicity-involves-reduction-of-nmda-triggered-calcium-responses-and-surface-glur1-and-is-partly-mediated-by-tnf
#12
Irini Papazian, Vasiliki Kyrargyri, Maria Evangelidou, Anda Voulgari-Kokota, Lesley Probert
Mesenchymal stem cells (MSC) provide therapeutic effects in experimental CNS disease models and show promise as cell-based therapies for humans, but their modes of action are not well understood. We previously show that MSC protect rodent neurons against glutamate excitotoxicity in vitro, and in vivo in an epilepsy model. Neuroprotection is associated with reduced NMDA glutamate receptor (NMDAR) subunit expression and neuronal glutamate-induced calcium (Ca2+ ) responses, and increased expression of stem cell-associated genes...
February 25, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29461008/propofol-exposure-during-early-gestation-impairs-learning-and-memory-in-rat-offspring-by-inhibiting-the-acetylation-of-histone
#13
Jiamei Lin, Shengqiang Wang, Yunlin Feng, Weihong Zhao, Weilu Zhao, Foquan Luo, Namin Feng
Propofol is widely used in clinical practice, including non-obstetric surgery in pregnant women. Previously, we found that propofol anaesthesia in maternal rats during the third trimester (E18) caused learning and memory impairment to the offspring rats, but how about the exposure during early pregnancy and the underlying mechanisms? Histone acetylation plays an important role in synaptic plasticity. In this study, propofol was administered to the pregnant rats in the early pregnancy (E7). The learning and memory function of the offspring were tested by Morris water maze (MWM) test on post-natal day 30...
May 2018: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/29459050/n-methyl-d-aspartate-type-glutamate-receptor-modulators-and-related-medications-for-the-enhancement-of-auditory-system-plasticity-in-schizophrenia
#14
Joshua T Kantrowitz
Deficits in N-methyl-d-aspartate-type (NMDAR) function contribute to cognitive deficits in schizophrenia, particularly dysfunction in neuroplasticity, defined as reduced learning during training on exercises that place implicit, increasing demands on early sensory (auditory and visual) information processing. Auditory mismatch negativity (MMN) can be both a target engagement biomarker for the NMDAR and a proxy measure of neurophysiological plasticity. This review covers the evidence for using NMDAR modulator and related compounds for enhancement of cognition, with a particular focus on early auditory processing/plasticity...
February 17, 2018: Schizophrenia Research
https://www.readbyqxmd.com/read/29319606/disruption-of-nnos-nos1ap-protein-protein-interactions-suppresses-neuropathic-pain-in-mice
#15
Wan-Hung Lee, Li-Li Li, Aarti Chawla, Andy Hudmon, Yvonne Y Lai, Michael J Courtney, Andrea G Hohmann
Elevated N-methyl-D-aspartate receptor (NMDAR) activity is linked to central sensitization and chronic pain. However, NMDAR antagonists display limited therapeutic potential because of their adverse side effects. Novel approaches targeting the NR2B-PSD95-nNOS complex to disrupt signaling pathways downstream of NMDARs show efficacy in preclinical pain models. Here, we evaluated the involvement of interactions between neuronal nitric oxide synthase (nNOS) and the nitric oxide synthase 1 adaptor protein (NOS1AP) in pronociceptive signaling and neuropathic pain...
January 9, 2018: Pain
https://www.readbyqxmd.com/read/29138698/soluble-epoxide-hydrolase-inhibitor-and-14-15-epoxyeicosatrienoic-acid-facilitated-long-term-potentiation-through-camp-and-camkii-in-the-hippocampus
#16
Han-Fang Wu, Yi-Ju Chen, Su-Zhen Wu, Chi-Wei Lee, I-Tuan Chen, Yi-Chao Lee, Chi-Chen Huang, Chung-Hsi Hsing, Chih-Wei Tang, Hui-Ching Lin
Epoxyeicosatrienoic acids (EETs) are derived from arachidonic acid and metabolized by soluble epoxide hydrolase (sEH). The role of EETs in synaptic function in the central nervous system is still largely unknown. We found that pharmacological inhibition of sEH to stabilize endogenous EETs and exogenous 14,15-EET significantly increased the field excitatory postsynaptic potential (fEPSP) response in the CA1 area of the hippocampus, while additionally enhancing high-frequency stimulation- (HFS-) induced long-term potentiation (LTP) and forskolin- (FSK-) induced LTP...
2017: Neural Plasticity
https://www.readbyqxmd.com/read/29029785/a-single-dose-of-cocaine-potentiates-glutamatergic-synaptic-transmission-onto-locus-coeruleus-neurons
#17
Feipeng Zhu, Qihui Wu, Jie Li, Katarzyna Grycel, Bing Liu, Xiaoxuan Sun, Li Zhou, Ruiyin Jiao, Rui Song, Younus M Khan, Qinglong Wang, Lun Wang, Yongxin Xu, Jin Li, Bo Zhang, Zhuan Zhou
The brainstem locus coeruleus (LC), the primary norepinephrinergic (NE) nucleus in the brain, has been implicated in the abuse of drugs such as opioids. However, whether and how the LC-NE system is involved in cocaine addiction remains elusive. Here, we demonstrated cocaine-evoked synaptic plasticity of glutamatergic transmission onto LC neurons as one of the earliest traces occurring after a single injection of cocaine. Twenty-four hours after mice were injected intraperitoneally with cocaine, the evoked α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) mediated synaptic transmission onto LC neurons were strongly potentiated without major effect on N-methyl-d-aspartate receptor (NMDAR) mediated synaptic transmission...
November 2017: Cell Calcium
https://www.readbyqxmd.com/read/29029433/h-2-o-2-attenuates-igf-1r-tyrosine-phosphorylation-and-its-survival-signaling-properties-in-neuronal-cells-via-nr2b-containing-nmda-receptor
#18
Zhiwen Zeng, Dejun Wang, Uma Gaur, Liao Rifang, Haitao Wang, Wenhua Zheng
Impairment of insulin-like growth factor I (IGF-I) signaling plays an important role in the development of neurodegeneration. In the present study, we investigated the effect of H2 O2 on the survival signaling of IGF-1 and its underlying mechanisms in human neuronal cells SH-SY5Y. Our results showed that IGF-1 promoted cell survival and stimulated phosphorylation of IGF-1R as well as its downstream targets like AKT and ERK1/2 in these cells. Meanwhile, these effects of IGF-1 were abolished by H2 O2 at 200μM concentration which did not cause any significant toxicity to cells itself in our experiments...
September 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/28993142/ghrelin-upregulates-the-phosphorylation-of-the-glun2b-subunit-of-the-nmda-receptor-by-activating-ghsr1a-and-fyn-in-the-rat-hippocampus
#19
Liza Berrout, Masako Isokawa
Ghrelin and its receptor GHSR1a have been shown to exert numerous physiological functions in the brain, in addition to the well-established orexigenic role in the hypothalamus. Earlier work indicated that ghrelin stimulated the phosphorylation of the GluN1 subunit of the NMDA receptor (NMDAR) and enhanced synaptic transmission in the hippocampus. In the present study, we report that the exogenous application of ghrelin increased GluN2B phosphorylation. This increase was independent of GluN2B subunit activity or NMDAR channel activity...
January 1, 2018: Brain Research
https://www.readbyqxmd.com/read/28992110/nfat3-c4-mediated-excitotoxicity-in-hippocampal-apoptosis-during-radiation-induced-brain-injury
#20
Meiling Xu, Qiuhong Fan, Junjun Zhang, Yanfang Chen, Ruizhe Xu, Liesong Chen, Peifeng Zhao, Ye Tian
Whole brain irradiation (WBI) has become an indispensible tool in the treatment of head and neck cancer, and it has greatly improved patient survival rate and total survival time. In addition, prophylactic cranial irradiation (PCI) has dramatically decreased the incidence of brain metastatic carcinoma. However, WBI may induce temporary functional deficits or even progressive, irreversible cognitive dysfunction that compromises the quality of life for survivors. Unfortunately, the exact molecular mechanisms for cognitive damage remain elusive, and no treatment or preventative measures are available for use in the clinic...
November 1, 2017: Journal of Radiation Research
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