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nmdar inhibitors

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...
March 12, 2018: Brain: a Journal of Neurology
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
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
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...
February 20, 2018: Journal of Cellular and Molecular Medicine
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
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 due to 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
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
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
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 H2O2 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 H2O2 at 200μM concentration which did not cause any significant toxicity to cells itself in our experiments...
September 12, 2017: Oncotarget
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
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
MingJie Wang, ZiQiang Luo, Yinyan Yue, YanRui Wang, Shu Wu, ChuanDing Cao, ZhengChang Liao, XiaoHe Yu, ShaoJie Yue
Studies have suggested that endogenous glutamate and N-methyl-d-aspartate (NMDA) receptor have an excitotoxity role during acute lung injury. Fibroblasts play a critical role in lung development and chronic lung disease after acute lung injury. This study aims to explore the immediate role of NMDAR activation in human lung fibroblasts. The expression of NMDAR 1 subtype (NR1) and four individual NMDAR 2 (NR2) subtypes (NR 2 A to D) was measured in human fetal lung fibroblasts (HFL-1 and MRC-5). Five NMDARs expression were all detectable in two cell lines...
October 5, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
Xue Zhang, Shaorui Chen, Hong Chen, Huilin Pan, Yilin Zhao
Our previous study has proposed that increased presynaptic NMDARs activities play pivotal roles in the development of opioid tolerance and hyperalgesia, and blocking spinal NMDARs attenuates chronic morphine-induced synaptic plasticity and behavior. However, the cellular signaling mechanisms remain to be investigated. The aim of this research was to address the role of β-ARK1 in opioid analgesia. Opioid tolerance and hyperalgesia was induced by daily systemic morphine injections in rats for eight consecutive days...
October 3, 2017: Molecular Neurobiology
De-Pei Li, Jing-Jing Zhou, Jixiang Zhang, Hui-Lin Pan
NMDAR activity in the hypothalamic paraventricular nucleus (PVN) is increased and critically involved in heightened sympathetic vasomotor tone in hypertension. Calcium/calmodulin-dependent protein kinase II (CaMKII) binds to and modulates NMDAR activity. In this study, we determined the role of CaMKII in regulating NMDAR activity of PVN presympathetic neurons in male spontaneously hypertensive rats (SHRs). NMDAR-mediated EPSCs and puff NMDA-elicited currents were recorded in spinally projecting PVN neurons in SHRs and male Wistar-Kyoto (WKY) rats...
November 1, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Baosheng Huang, Panhong Chen, Lei Huang, Shuai Li, Ronglan Zhu, Tao Sheng, Wan Yu, Zheng Chen, Tianlu Wang
BACKGROUND/AIMS: Calcium-permeable ionotropic NMDAR-mediated hyperactivity is regarded as the critical factor in modulating the development of ischaemic stroke. Recently, there has been increasing interest in preventing post-stroke neuronal death by focusing on intervening in the function of subpopulations of NMDARs and their downstream signalling. Geniposide, an iridoid glycoside, has been found to have cytoprotective functions in various conditions. However, it is still unclear whether and how geniposide affects neuronal insult under experimental stroke...
2017: Cellular Physiology and Biochemistry
Tao Chen, Jie Zhu, Li-Kun Yang, Yi Feng, Wei Lin, Yu-Hai Wang
Arc/Arg3.1 is a unique immediate early gene whose expression is highly dynamic and correlated with various forms of synaptic plasticity. Many previous reports highlight the complexity of mechanisms that regulate Arc/Arg3.1 expression in neurons. In the present study, the expression and regulation of Arc/Arg3.1 after glutamate treatment in primary cultured cortical neurons were investigated. We found that both Arc/Arg3.1 mRNA and Arc/Arg3.1 protein dynamically increased within 24h after glutamate treatment. The results of immunostaining showed that abundant amounts of Arc/Arg3...
November 20, 2017: Neuroscience Letters
Sarah E Robinson, Vikaas S Sohal
Dopaminergic modulation of prefrontal cortex (PFC) is thought to play key roles in many cognitive functions and to be disrupted in pathological conditions, such as schizophrenia. We have previously described a phenomenon whereby dopamine D2 receptor (D2R) activation elicits afterdepolarizations (ADPs) in subcortically projecting (SC) pyramidal neurons within L5 of the PFC. These D2R-induced ADPs only occur following synaptic input, which activates NMDARs, even when the delay between the synaptic input and ADPs is relatively long (e...
October 18, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Olafur Sveinsson, Mathias Granqvist, Yngve Forslin, Kaj Blennow, Henrik Zetterberg, Fredrik Piehl
We describe an extremely severe case of therapy refractory NMDA receptor encephalitis (NMDAe) in a 26-year-old woman. After rituximab, bilateral oophorectomy, repeated cycles of high dose methylprednisolone and plasma exchange, she received repeated cyclophosphamide, tocilizumab (interleukin-6 inhibitor) and finally bortezomib (plasma cell depleting drug) leading to remission after 204days in intensive care. Two years after disease onset her cognitive functions are still affected, but slowly improving and the cerebral atrophy has been partly reversed...
November 15, 2017: Journal of Neuroimmunology
Kelly E Bosse, Max F Oginsky, Laura L Susick, Sailesh Ramalingam, Carrie R Ferrario, Alana C Conti
Neuroadaptive responses to chronic ethanol, such as behavioral sensitization, are associated with N-methyl-D-aspartate receptor (NMDAR) recruitment. Ethanol enhances GluN2B-containing NMDAR function and phosphorylation (Tyr-1472) of the GluN2B-NMDAR subunit in the dorsal medial striatum (DMS) through a protein kinase A (PKA)-dependent pathway. Ethanol-induced phosphorylation of PKA substrates is partially mediated by calcium-stimulated adenylyl cyclase 1 (AC1), which is enriched in the dorsal striatum. As such, AC1 is poised as an upstream modulator of ethanol-induced DMS neuroadaptations that promote drug responding, and thus represents a therapeutic target...
November 2017: Journal of Pharmacology and Experimental Therapeutics
Francisco Zafra, Ignacio Ibáñez, David Bartolomé-Martín, Dolores Piniella, Marina Arribas-Blázquez, Cecilio Giménez
Glycine plays two roles in neurotransmission. In caudal areas like the spinal cord and the brainstem, it acts as an inhibitory neurotransmitter, but in all regions of the CNS, it also works as a co-agonist with L-glutamate at N-methyl-D-aspartate receptors (NMDARs). The glycine fluxes in the CNS are regulated by two specific transporters for glycine, GlyT1 and GlyT2, perhaps with the cooperation of diverse neutral amino acid transporters like Asc-1 or SNAT5/SN2. While GlyT2 and Asc-1 are neuronal proteins, GlyT1 and SNAT5 are mainly astrocytic, although neuronal forms of GlyT1 also exist...
2017: Advances in Neurobiology
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