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NMDA receptor

Meysam Amidfar, Gislaine Z Réus, Joao Quevedo, Yong-Ku Kim
A developing body of evidence indicates that disturbed glutamate neurotransmission especially through N-methyl-d-aspartate (NMDA) is central to the pathophysiology of major depressive disorder (MDD) and NMDA receptor antagonists have shown therapeutic potential in the MDD treatment. Memantine is an uncompetitive NMDA receptor antagonist, approved for treatment of Alzheimer's disease (AD) that in contrast to other NMDA receptor antagonists at therapeutic doses does not induce highly undesirable side effects...
March 15, 2018: European Journal of Pharmacology
Leila Dehestani, Nematollah Ahangar, Seyedeh Mahdieh Hashemi, Hamid Irannejad, Patrick Honarchian Masihi, Aidin Shakiba, Saeed Emami
A series of phenacyl triazole hydrazones 3 have been designed based on the hybridization of (arylalkly)triazole and aroyl hydrazone scaffolds as new anticonvulsant agents. The target compounds 3 were easily synthesized from appropriate phenacyl triazoles and aryl acid hydrazides and characterized by IR, NMR and Mass spectroscopy. The in vivo anticonvulsant evaluation of synthesized compounds by using MES and PTZ tests revealed that they are more effective in MES model respect to PTZ test. All compounds showed 33-100% protection against MES-induced seizures at the dose of 100 mg/kg...
March 7, 2018: Bioorganic Chemistry
Luan Castro Tonelli, Markus Wöhr, Rainer Schwarting, Liana Melo-Thomas
Paradoxical kinesia is a sudden transient ability of akinetic patients to perform motor tasks they are otherwise unable to perform. This phenomenon is known to depend on the patient's emotional state and external stimuli. Paradoxical kinesia can be induced by appetitive 50-kHz ultrasonic vocalizations (USV) in rats displaying catalepsy following systemic haloperidol. We investigated the role of the inferior colliculus (IC) in paradoxical kinesia induced by 50-kHz USV, since the IC modulates haloperidol-induced catalepsy...
March 14, 2018: Neuropharmacology
Jayashri Kulkarni, Natalie Thomas, Abdul-Rahman Hudaib, Emorfia Gavrilidis, Jasmin Grigg, Raelene Tan, Jacinta Cheng, Amelia Arnold, Caroline Gurvich
BACKGROUND: Borderline personality disorder (BPD) is a complex, severe and highly stigmatised psychiatric illness. Several lines of evidence highlight the causal link between chronic stress, glucocorticoid response to stress and glutamatergic overactivity as a key event in the pathophysiology of BPD. Therefore, molecular mechanisms capable of regulating glutamate excitotoxicity represent novel and potentially promising treatment targets. Memantine-HCl is a voltage-dependent N-methyl-D-aspartate (NMDA) receptor 'channel blocker' that selectively blocks pathological glutamate overactivity...
March 16, 2018: CNS Drugs
Makoto Hara, Eugenia Martinez-Hernandez, Helena Ariño, Thais Armangué, Marianna Spatola, Mar Petit-Pedrol, Albert Saiz, Myrna R Rosenfeld, Francesc Graus, Josep Dalmau
OBJECTIVE: To determine the frequency and clinical relevance of immunoglobulin (Ig)G, IgA, and IgM N -methyl-d-aspartate receptor (NMDAR) antibodies in several diseases, and whether the IgG antibodies occur in disorders other than anti-NMDAR encephalitis. METHODS: Evaluation of IgG, IgA, and IgM NMDAR antibodies in serum of 300 patients with anti-NMDAR encephalitis, stroke, dementia, schizophrenia, or seronegative autoimmune encephalitis. Antibodies and their effect on cultured neurons were examined with cell-based assays and brain and live neuronal immunostaining...
March 16, 2018: Neurology
Stephany M Biello, David R Bonsall, Lynsey A Atkinson, Penny C Molyneux, Mary E Harrington, Gurprit S Lall
Robust physiological circadian rhythms form an integral part of well-being. The aging process has been found to negatively impact systems that drive circadian physiology, typically manifesting as symptoms associated with abnormal/disrupted sleeping patterns. Here, we investigated the age-related decline in light-driven circadian entrainment in male C57BL/6J mice. We compared light-driven resetting of circadian behavioral activity in young (1-2 months) and old (14-18 months) mice and explored alterations in the glutamatergic pathway at the level of the circadian pacemaker, the suprachiasmatic nucleus (SCN)...
February 20, 2018: Neurobiology of Aging
Alessio Travaglia, Adam B Steinmetz, Janelle M Miranda, Cristina M Alberini
Episodic memories in early childhood are rapidly forgotten, a phenomenon that is associated with "infantile amnesia," the inability of adults to remember early-life experiences. We recently showed that early aversive contextual memory in infant rats, which is in fact rapidly forgotten, is actually not lost, as reminders presented later in life reinstate a long-lasting and context-specific memory. We also showed that the formation of this infantile memory recruits in the hippocampus mechanisms typical of developmental critical periods...
April 2018: Learning & Memory
Madelyne A Bisby, Kathryn D Baker, Rick Richardson
NMDA receptors (NMDARs) are considered critical for the consolidation of extinction but recent work challenges this assumption. Namely, NMDARs are not required for extinction retention in infant rats as well as when extinction training occurs for a second time (i.e., reextinction) in adult rats. In this study, a possible third instance of NMDAR-independent extinction was tested. Although adolescents typically exhibit impaired extinction retention, rats that are conditioned as juveniles and then given extinction training as adolescents (JuvCond-AdolesExt) have good extinction retention...
April 2018: Learning & Memory
Guang-Zhe Huang, Mutsuo Taniguchi, Ye-Bo Zhou, Jing-Ji Zhang, Fumino Okutani, Yoshihiro Murata, Masahiro Yamaguchi, Hideto Kaba
The formation of mate recognition memory in mice is associated with neural changes at the reciprocal dendrodendritic synapses between glutamatergic mitral cell (MC) projection neurons and GABAergic granule cell (GC) interneurons in the accessory olfactory bulb (AOB). Although noradrenaline (NA) plays a critical role in the formation of the memory, the mechanism by which it exerts this effect remains unclear. Here we used extracellular field potential and whole-cell patch-clamp recordings to assess the actions of bath-applied NA (10 µM) on the glutamatergic transmission and its plasticity at the MC-to-GC synapse in the AOB...
April 2018: Learning & Memory
Kamila Cagliari Zenki, Eduardo Kalinine, Eduardo R Zimmer, Thainá Garbino Dos Santos, Ben Hur Marins Mussulini, Luis Valmor Cruz Portela, Diogo Lösch de Oliveira
Several works have demonstrated that status epilepticus (SE) induced-neurodegeneration appears to involve an overactivation of N-methyl-D-aspartate receptors and treatment with high-affinity NMDAR antagonists is neuroprotective against this brain damage. However, these compounds display undesirable side effects for patients since they block physiological NMDA receptor dependent-activity. In this context, memantine (MN), a well tolerable low-affinity NMDAR channel blocker, will be a promising alternative, since it does not compromise the physiological role of NMDA receptors on synaptic transmission...
March 12, 2018: Neurotoxicology
Kyeongjun Lee, Chowee Park, Yeonsoo Oh, Heesoon Lee, Jungsook Cho
Excitotoxicity and oxidative stress play vital roles in the development of neurodegenerative disorders including Alzheimer's disease (AD). In the present study, we investigated the effect of N -((3,4-dihydro-2H-benzo[h]chromen-2-yl)methyl)-4-methoxyaniline (BL-M) on excitotoxic neuronal cell damage in primary cultured rat cortical cells, and compared to that of memantine, a non-competitive N -methyl-d-aspartate (NMDA) receptor antagonist clinically used to treat AD. We found that BL-M inhibited glutamate- or N -methyl-d-aspartate (NMDA)-induced excitotoxic cell damage...
March 15, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Amy Chia-Ching Kao, Sonia Spitzer, Daniel C Anthony, Belinda Lennox, Philip W J Burnet
Olanzapine is an effective antipsychotic drug but since it causes significant weight gain, it is not well tolerated by psychosis patients. The prebiotic, B-GOS® , attenuates metabolic dysfunction in obese subjects, and in rodents, alters central NMDA receptors and may affect serotonin receptors that are relevant in psychosis. We have determined whether B-GOS® influenced olanzapine-associated weight gain and central NMDA and serotonin receptors. Circulating acetate, IL-1β, IL-8 and TNFα, liver acetyl-CoA carboxylase (ACC), white adipose tissue (WAT) acetate receptor GPR43, and specific faecal bacteria genera were also measured to provide mechanistic information...
March 15, 2018: Translational Psychiatry
Caroline Morel, Tessi Sherrin, Norman J Kennedy, Kelly H Forest, Seda Avcioglu Barutcu, Michael Robles, Ezekiel Carpenter-Hyland, Naghum Alfulaij, Claire L Standen, Robert A Nichols, Morris Benveniste, Roger J Davis, Cedomir Todorovic
The c-Jun N-terminal kinase (JNK) signal transduction pathway is implicated in learning and memory. Here, we examined the role of JNK activation mediated by the JIP1 scaffold protein. We compared male wild-type mice with a mouse model harboring a point mutation in the Jip1 gene that selectively blocks JIP1-mediated JNK activation. These male mutant mice exhibited increased NMDA receptor currents, increased NMDA receptor-mediated gene expression, and a lower threshold for induction of hippocampal long-term potentiation...
March 14, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
C G Bien
The paraneoplastic and autoimmune encephalitides are now well-established entities. Detection of neural autoantibodies enables specific diagnoses, provides information on the underlying disease pathophysiology, immunological treatability and the likelihood of a tumor being the underlying cause. This is true for the "high ranking" neural antibodies that have been established in the context of circumscribed clinical images and in consideration of large control groups, have been found in the same way by other laboratories and they respond to immunotherapy...
March 13, 2018: Der Nervenarzt
Kenneth J O'Riordan, Neng-Wei Hu, Michael J Rowan
Synaptic long-term depression (LTD) is believed to underlie critical mnemonic processes in the adult hippocampus. The roles of the metabotropic and ionotropic actions of glutamate in the induction of synaptic LTD by electrical low-frequency stimulation (LFS) in the living adult animal is poorly understood. Here we examined the requirement for metabotropic glutamate (mGlu) and NMDA receptors in LTD induction in anaesthetized adult rats. LTD induction was primarily dependent on NMDA receptors and required the involvement of both the ion channel function and GluN2B subunit of the receptor...
March 13, 2018: Scientific Reports
Nellihela Leel, Hemanshoo S Thakkar, David Drake, Nordeen Bouhadiba
Anti-N-methyl D-aspartate receptor (NMDAR) encephalitis is a paraneoplastic, immune-mediated encephalopathy with a known association with ovarian teratomas. We present the first case in the UK of a 7-year-old patient presenting with this condition. Having been previously fit and healthy, the patient presented with an acute onset of cognitive disturbances. The initial suspicion was that of an infective encephalopathy; however, the lumbar puncture results were negative. Electroencephalography reported diffuse background slowing, supporting a diagnosis of encephalopathy...
March 13, 2018: BMJ Case Reports
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
Peter Hertelendy, Jozsef Toldi, Ferenc Fulop, Laszlo Vecsei
Ischemic stroke is one of the leading causes of mortality and permanent disability in developed countries. Stroke induces massive glutamate release, which in turn causes N-Methyl-D-aspartate (NMDA) receptor over-excitation and thus calcium overload in neurons leading to cell death via apoptotic cascades. The kynurenine pathway is a complex enzymatic cascade of tryptophan catabolism, generating various neuroactive metabolites. One metabolite, kynurenic acid (KYNA), is a potent endogenous NMDA glutamate receptor antagonist, making it a possible therapeutic tool to decrease excitotoxicity and neuroinflammation...
March 12, 2018: Current Medicinal Chemistry
Luye Qin, Kaijie Ma, Zi-Jun Wang, Zihua Hu, Emmanuel Matas, Jing Wei, Zhen Yan
Haploinsufficiency of the SHANK3 gene is causally linked to autism spectrum disorder (ASD), and ASD-associated genes are also enriched for chromatin remodelers. Here we found that brief treatment with romidepsin, a highly potent class I histone deacetylase (HDAC) inhibitor, alleviated social deficits in Shank3-deficient mice, which persisted for ~3 weeks. HDAC2 transcription was upregulated in these mice, and knockdown of HDAC2 in prefrontal cortex also rescued their social deficits. Nuclear localization of β-catenin, a Shank3-binding protein that regulates cell adhesion and transcription, was increased in Shank3-deficient mice, which induced HDAC2 upregulation and social deficits...
March 12, 2018: Nature Neuroscience
Sean Doyle, Daniel Bloch Hansen, Jasmine Vella, Peter Bond, Glenn Harper, Christian Zammit, Mario Valentino, Robert Fern
The axon myelin sheath is prone to injury associated with N-methyl-D-aspartate (NMDA)-type glutamate receptor activation but the source of glutamate in this context is unknown. Myelin damage results in permanent action potential loss and severe functional deficit in the white matter of the CNS, for example in ischemic stroke. Here, we show that in rats and mice, ischemic conditions trigger activation of myelinic NMDA receptors incorporating GluN2C/D subunits following release of axonal vesicular glutamate into the peri-axonal space under the myelin sheath...
March 12, 2018: Nature Communications
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