Structure, Function, and Pharmacology of NMDA Receptor Channels

Vyklický, Vojtěch; Kořı́nek, Miloslav; Smejkalová, Tereza; Balík, Aleš; Krausová, Barbora; Kaniakova, Martina; Lichnerová, Katarína; Černý, Jiří; Krůšek, Jan; Dittert, Ivan; Hořák, Martin; Vyklický, Ladislav

doi:10.33549/physiolres.932678

Cited by 236 publications

(130 citation statements)

References 95 publications

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“…NMDAR is an ionic glutamate receptor involved in learning and memory, synaptic plasticity, excitotoxicity, and so on, and it is closely related to depression. 49,50 NMDARs are heterooligomeric complexes that consist of essential NR1 subunit and regulatory NR2 (NR2A-D) subunits, 51 NR2A-and NR2B-containing NMDARs are considered the major isoforms of functional NMDARs in neurons. 52 NR2B-containing NMDARs mainly reside at extrasynaptic sites and are involved in cell death.…”

Section: Dovepressmentioning

confidence: 99%

<p>Electroacupuncture Relieves LPS-Induced Depression-Like Behaviour in Rats Through IDO-Mediated Tryptophan-Degrading Pathway</p>

Zhang¹,

Liu²,

Gao³

et al. 2020

NDT

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Background: Neuroinflammation is an important pathological mechanism of depression that leads to an increase in indoleamine-2,3-dioxygenase (IDO) activity and NMDAR activation. This study aimed to observe the effects of electroacupuncture on depressionlike behaviour in lipopolysaccharide (LPS)-treated rats and the underlying mechanism. Methods: Wistar rats were intraperitoneally administered LPS (0.5 mg/kg) for 7 consecutive days to establish a depression model. Electroacupuncture treatment was administered 1 hour after daily LPS injection. The open field test (OFT), forced swimming test (FST), and sucrose preference test (SPT) were used to evaluate the depressive-like behaviours. IL-1β, IL-6, and TNF-α levels were determined by enzyme-linked immunosorbent assay (ELISA); Trp, 5-hydroxytryptamine (5-HT), kynurenine (Kyn) and quinolinic acid (Quin) were detected by ultra-high-performance liquid chromatography-tandem mass spectrometry; and N-methyl-D-aspartate receptor (NMDAR) protein and mRNA were assessed by Western blot and real-time qPCR. Results: The results showed that electroacupuncture treatment successfully corrected LPSinduced depressive-like behaviour, reduced the inflammatory factor (IL-1β, IL-6 and TNF-α) levels in the blood and hippocampus, prevented IDO over-activation and recovered NR2B expression after challenge by LPS. Conclusion: Electroacupuncture treatment provided protection against LPS-induced depressive-like behaviour, and the associated mechanisms may be related to inhibiting the inflammatory response, regulating the IDO-mediated tryptophan-degrading pathway, and inhibiting NR2B activation.

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Section: Dovepressmentioning

confidence: 99%

<p>Electroacupuncture Relieves LPS-Induced Depression-Like Behaviour in Rats Through IDO-Mediated Tryptophan-Degrading Pathway</p>

Zhang¹,

Liu²,

Gao³

et al. 2020

NDT

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“…Unlike during physiological responses, ischemia induces massive glutamate release (especially within the ischemic core), which results in over-activation of NMDAR, leading to excessive influx of Ca 2þ into the ischemia-affected neurons. This Ca 2þ overload dysregulates Ca 2þ -dependent processes and leads to neuronal injury, referred to as excitotoxicity, [35][36][37] and results in necrotic or apoptotic neuronal death. 38,39 While various sources of intracellular Ca 2þ may result in activation of a distinct subset of Ca 2þ -dependent enzymes, one enzyme that is activated in neurons in response to Ca 2þ entry through NMDAR activation is the Ca 2þ /calmodulin-dependent serine/threonine protein phosphatase, CN.…”

Section: Discussionmentioning

confidence: 99%

Excitatory pathway engaging glutamate, calcineurin, and NFAT upregulates IL-4 in ischemic neurons to polarize microglia

Ting

Zhao

Zheng

et al. 2019

J Cereb Blood Flow Metab

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Excitotoxicity and microglia/macrophage over-activation are the important pathogenic steps in brain damage caused by ischemic stroke. Recent studies from our group suggest that the neurons in ischemic penumbra generate an anti-inflammatory cytokine, interleukin-4 (IL-4). This neuron-produced IL-4 could subsequently convert surrounding microglia/macrophages to a reparative (M2)-phenotype. The present study was designed to establish the mechanisms by which neurons under transient ischemic condition produce/secrete IL-4. We employed primary rat cortical neurons and a validated in vitro ischemic injury model involving transient oxygen–glucose deprivation (OGD). We discovered that only sublethal OGD induces IL-4 production/secretion by neurons. We then showed that excitotoxic stimulus (an integral component of OGD-mediated damage) involving N-methyl-D-aspartate (NMDA), and not kainate receptor, triggers neuronal IL-4 production/release. Of note, oxidative stress or pro-apoptotic stimuli did not induce IL-4 production by neurons. Next, using the calcineurin inhibitor FK506, we implicated this phosphatase in activation of the nuclear factor of activated T-cells (NFAT; a transcription factor activated through calcineurin-mediated dephosphorylation) and propose that this pathway is involved in transcriptional upregulation of the IL-4 synthesis in NMDA-treated neurons. Finally, using a transfer of culture medium from NMDA-conditioned neuron to microglia, we showed that the neuronal IL-4 can polarize microglia toward a restorative, phagocytic phenotype.

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“…In recent years, there has been increased interest in noble gases as novel treatments for ischemic and traumatic brain injury (127)(128)(129). Excessive activation of N-methyl-D-aspartate (NMDA)-type glutamate receptors is, in general, a key mechanism of excitotoxicity after brain injury (130,131). During excitotoxicity, excessive glutamate release results in the activation of NMDA receptors, leading to calcium overload inside the neurons and the different types of neuroglia.…”

Section: Xenonmentioning

confidence: 99%

Inhaled Gases as Therapies for Post–Cardiac Arrest Syndrome: A Narrative Review of Recent Developments

et al. 2021

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Despite recent advances in the management of post–cardiac arrest syndrome (PCAS), the survival rate, without neurologic sequelae after resuscitation, remains very low. Whole-body ischemia, followed by reperfusion after cardiac arrest (CA), contributes to PCAS, for which established pharmaceutical interventions are still lacking. It has been shown that a number of different processes can ultimately lead to neuronal injury and cell death in the pathology of PCAS, including vasoconstriction, protein modification, impaired mitochondrial respiration, cell death signaling, inflammation, and excessive oxidative stress. Recently, the pathophysiological effects of inhaled gases including nitric oxide (NO), molecular hydrogen (H2), and xenon (Xe) have attracted much attention. Herein, we summarize recent literature on the application of NO, H2, and Xe for treating PCAS. Recent basic and clinical research has shown that these gases have cytoprotective effects against PCAS. Nevertheless, there are likely differences in the mechanisms by which these gases modulate reperfusion injury after CA. Further preclinical and clinical studies examining the combinations of standard post-CA care and inhaled gas treatment to prevent ischemia–reperfusion injury are warranted to improve outcomes in patients who are being failed by our current therapies.

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Structure, Function, and Pharmacology of NMDA Receptor Channels

Cited by 236 publications

References 95 publications

<p>Electroacupuncture Relieves LPS-Induced Depression-Like Behaviour in Rats Through IDO-Mediated Tryptophan-Degrading Pathway</p>

<p>Electroacupuncture Relieves LPS-Induced Depression-Like Behaviour in Rats Through IDO-Mediated Tryptophan-Degrading Pathway</p>

Excitatory pathway engaging glutamate, calcineurin, and NFAT upregulates IL-4 in ischemic neurons to polarize microglia

Inhaled Gases as Therapies for Post–Cardiac Arrest Syndrome: A Narrative Review of Recent Developments

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