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The Opioid Epidemic
Published in Sahar Swidan, Matthew Bennett, Advanced Therapeutics in Pain Medicine, 2020
Activated N-methyl-D-aspartate (NMDA) receptors play a central role in the development of hyperalgesia. The excitatory neurotransmitter glutamine blinds to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainite, and NMDA receptors. NMDAR are ionotropic glutamate receptors that, once bound by glutamate and glycine (or D-serine), open and allow cations (Ca2+) to enter the neuron. The ion channel can be blocked by Mg2+ or Zn2+. The influx of calcium activates protein kinase C (PKC)—which among other phosphorylation events lowers the threshold to release the Mg2+ block on the NMDAR.5 NMDA receptors (NMDAR) are typically considered to control plasticity and memory. Opioids may play a role in creating spinal pain memory. Hyperalgesia has been attributed to the pre-synaptic N-methyl-D-aspartate (NMDA) receptor.6
Advances in Understanding the Mechanisms Underlying Synaptic Plasticity
Published in Avital Schurr, Benjamin M. Rigor, BRAIN SLICES in BASIC and CLINICAL RESEARCH, 2020
Timothy J. Teyler, Idil Cavus, Chris Coussens, Pascal DiScenna, Lawrence Grover, Yi-Ping Lee, Zeb Little
The original descriptions of LTP were made in the hippocampus, particularly area CA1, and most mechanistic studies of LTP have been done in this region. Central to understanding the mechanisms underlying LTP is the role of the N-methyl-d-aspartate (NMDA) glutamate receptor subtype. When appropriately activated, the NMDA receptor (NMDAr) gates Ca2+ into the postsynaptic cell where Ca2+-dependent biochemical processes responsible for the expression of this enduring form of increased synaptic efficacy are activated. We shall term this form NMDA LTP. More recently, a second form of LTP was described that is independent of the NMDAr. This form of LTP gates Ca2+ into the cell through voltage-dependent calcium channels (VDCCs). We shall refer to this form as non-NMDA LTP. For both forms of LTP, the metabotropic glutamate receptor (mGLUr) may also play a role in the maintenance of the potentiated response. The most prevalent form of LTD is seen at synapses subjected to a long, low-frequency stimulus train (homosynaptic LTD). Heterosynaptic LTD is less reliably seen at inactive synapses when other synapses on the same cell are activated. Like LTP, LTD is a Ca2+-dependent phenomenon. The central question of this chapter concerns how a common second messenger, Ca2+, can initiate different physiological responses in the same cell.
Computational Neuroscience and Compartmental Modeling
Published in Bahman Zohuri, Patrick J. McDaniel, Electrical Brain Stimulation for the Treatment of Neurological Disorders, 2019
Bahman Zohuri, Patrick J. McDaniel
Note that, the N-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel protein found in nerve cells. The NMDA receptor is one of three types of ionotropic glutamate receptors, the others being the AMPA and kainate receptors. It is activated when glutamate and glycine (or D-serine) bind to it, and when activated it allows positively charged ions to flow through the cell membrane.99 The NMDA receptor is very important for controlling synaptic plasticity and memory function.100
Anti-N-methyl-D-aspartate receptor encephalitis in pregnancy associated with teratoma
Published in Baylor University Medical Center Proceedings, 2023
Mridul Bansal, Aryan Mehta, Anand Karthik Sarma, Shuo Niu, Dan Alexandru Silaghi, Ashish K. Khanna, Saraschandra Vallabhajosyula
The management of this disease includes immunosuppression and removal of the neoplasm if present.4 Administration of NMDAR antagonists, such as ketamine, a noncompetitive NMDAR antagonist, may be considered. The modulation of NMDAR is responsible for the majority of its analgesic and anesthetic effects.12 The theoretical potential for NMDAR antagonism did not work here. We speculate that this could reflect the known physiology in which the receptor itself is downregulated after sufficient stimulation. NMDAR ionotropic receptors are one of the three principal receptor targets of the excitatory neurotransmitter glutamate. They play a major role in synaptic plasticity and signaling via interaction with various ligands and neurotransmitters.13 Titulaer et al noted that 53% of patients improved during the first month and 97% showed a good outcome in 24 months with first-line immunotherapy (steroids/intravenous immunoglobulins/plasmapheresis). Lower severity of symptoms and prompt treatment with immunotherapy and tumor removal were independent predictors of good outcomes.4 Anti-NMDAR encephalitis is known for its protracted disease course, often resulting in multiple relapses. One analysis found that one-fourth of patients had a relapsing episode, with manifestations ranging from mild disease to florid pathology. Given the strong association between the absence of immunotherapy administration at the first episode and an increased risk of relapse, timely treatment is necessary to reduce the associated morbidity.14
Novel Sunifiram-carbamate hybrids as potential dual acetylcholinesterase inhibitor and NMDAR co-agonist: simulation-guided analogue design and pharmacological screening
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Khalid A. Agha, Nader E. Abo-Dya, Abdul Rashid Issahaku, Clement Agoni, Mahmoud E. S. Soliman, Eatedal H. Abdel-Aal, Zakaria K. Abdel-Samii, Tarek S. Ibrahim
N-methyl-D-aspartate receptor (NMDAR) is another approach in enhancing cognition,8 it is a glutamate receptor and ion channel protein found in nerve cells as tetrameric complex and is a promising target for cognitive enhancement since it is centrally involved in cognitive processes.9 It was shown that transient activation of NMDAR is the trigger for the induction of long-term potentiation (LTP) at synapses of neurons in the hippocampus which are likely to explain their importance for learning and memory.10 Also, it has the ability to increase acetylcholine release and its inhibition result in decrease in acetylcholine secretion.11,12 Biochemical and molecular studies of NMDA receptor showed that both mRNA and protein levels of NMDARs are reduced in AD brain and AD model, suggesting hypofunction of NMDAR with increasing AD pathologic severity.13 These observations supported by findings that blocking NMDAR by ketamine and phencyclidine can induce schizophrenic like symptoms including cognitive decline in healthy individuals and exacerbate cognitive deficit in schizophrenic individuals.14,15
New investigational agents for the treatment of major depressive disorder
Published in Expert Opinion on Investigational Drugs, 2022
Bartłomiej Pochwat, Anna Julia Krupa, Marcin Siwek, Bernadeta Szewczyk
Currently, the primary molecular target of ketamine necessary for its antidepressant activity is still under debate. The blockade of the N-methyl-D-aspartate receptor (NMDAR) is the best-studied possible explanatory hypothesis of the antidepressant effects of ketamine. The NMDAR is an ion tetramer channel composed of two obligatory GluN1 subunits and two additional GluN2 or GluN3 subunits. The full activation of the NMDAR requires the binding of two glycines, or in some cases, d-serine (co-agonists of NMDAR) molecules to the GluN1 subunits and two glutamate molecules to the GluN2 subunit (GluN2 subunits exist in three different isoforms: GluN2A, B, and C) [12]. Moreover, cell depolarization by activating the glutamate receptor α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPAR) leads to the removal of Mg2+ ion from the pore of the NMDAR and the influx of Ca2+ and Na+ ions into the neurons [13]. The influx of Ca2+ ions into the cell induces profound changes in the function and morphology of neurons. The enhanced intracellular Ca2+ level is indispensable for neurons’ proper functioning and morphological states. Under pathological conditions, the overflux of Ca2+ can lead to neuronal atrophy or even death [14].