scholarly journals GRIN2A-Related Severe Epileptic Encephalopathy Treated with Memantine: An Example of Precision Medicine

2019 ◽  
Vol 09 (04) ◽  
pp. 252-257 ◽  
Author(s):  
Ali Mir ◽  
Mohammed Qahtani ◽  
Shahid Bashir
Keyword(s):  
Nmda Receptor ◽  
Precision Medicine ◽  
Treatment Approach ◽  
Case Reports ◽  
Nmda Receptor Antagonist ◽  
Epileptic Encephalopathy ◽  
Drug Resistant ◽  
A Subunit ◽  
Generation Sequencing

AbstractEpileptic spasm (ES) is one of the seizure types which is difficult to treat. Next-generation sequencing has facilitated rapid gene discovery that is linked to ES and GRIN2A being one of them. Genotype-driven precision medicine is on the horizon and is a targeted treatment approach toward the precise molecular cause of the disease. GRIN2A gene encodes for a subunit of N-methyl-D-aspartate (NMDA) receptor and it has been suggested from in vitro studies and few case reports that memantine, a NMDA receptor antagonist, was shown to reduce seizures in patients with GRIN2A mutations. Here, we describe a patient with a novel GRIN2A mutation and severe drug-resistant ES who became seizure free with memantine.

scholarly journals Mechanistic Distinctions between Excitotoxic and Acidotic Hippocampal Damage in an in vitro Model of Ischemia

1990 ◽  
Vol 10 (4) ◽  
pp. 527-535 ◽  
Author(s):  
Geoffrey C. Tombaugh ◽  
Robert M. Sapolsky
Keyword(s):  
Nmda Receptor ◽  
Cell Injury ◽  
Neuronal Damage ◽  
Nmda Receptor Antagonist ◽  
Hippocampal Damage ◽  
Neuron Death ◽  
Vitro Model ◽  
Posthypoxic Period ◽  
Ph Range

Excitotoxicity is believed to underlie the selective loss of vulnerable neurons after transient ischemia, while lactic acidosis seems to be the principal feature and probable cause of tissue infarcts. Primary hippocampal cultures containing both neurons and astrocytes derived from fetal rats were used to examine the relative contributions of and interactions between excitotoxic and acidotic cell injury. Hypoxia-induced damage was energy dependent and involved the N-methyl-D-aspartate (NMDA) receptor. Glucose above 1 m M could completely protect against hypoxia-induced injury in a pH range of 7.4–6.5, while the NMDA receptor antagonist D,L-2-amino-5-phosphonovaleric acid (500 μ M) during the posthypoxic period provided only partial protection in the absence of glucose. Astrocyte cultures were undamaged by ischemic-like treatment in this pH range, suggesting that hypoxia-induced cell death in mixed cultures was restricted to neurons. Lowering the extracellular pH to 7.0 and 6.5 caused no neuronal damage in normoxic controls, but in each case provided significant protection against hypoxic neuronal injury. In contrast, a second type of neurotoxicity was observed after a 6-h exposure to pH 6.0, while exposure to pH 5.5 was required to kill astrocytes. This acidotic damage appeared to be energy independent and did not involve the NMDA receptor. These results suggest that excitotoxic neuron death has an energetic component and that acidosis may produce both protective and damaging effects in the hippocampus during ischemic insults.

Characterization of 3-carboxy-5-phosphono-1,2,3,4-tetrahydroisoquinoline (SC-48981), a potent competitive (NMDA) receptor antagonist, in vitro and in vivo

1992 ◽  
Vol 135 (2) ◽  
pp. 149-152 ◽  
Author(s):  
Michael L. Vazquez ◽  
Danny J. Garland ◽  
Eric T. Sun ◽  
Julie A. Cler ◽  
Steve J. Mick ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Receptor Antagonist ◽  
Nmda Receptor Antagonist

Role of excitatory amino acids in mediating burst discharge of red nucleus neurons in the in vitro turtle brain stem-cerebellum

1991 ◽  
Vol 65 (3) ◽  
pp. 454-467 ◽  
Author(s):  
J. Keifer ◽  
J. C. Houk
Keyword(s):  
Spinal Cord ◽  
Amino Acid ◽  
Nmda Receptor ◽  
Excitatory Amino Acid ◽  
Red Nucleus ◽  
Nmda Receptor Antagonist ◽  
Excitatory Amino Acid Receptor ◽  
Bath Application

1. Bursts of discharge have been recorded in the red nucleus in several species and are thought to represent the expression of motor commands. A cerebellorubral circuit comprised of recurrent connections among the cerebellum, red nucleus, and reticular formation was postulated to function as a positive feedback loop that generates these motor commands and transmits them to the spinal cord via the rubrospinal pathway. We have used an in vitro preparation from the turtle that leaves the circuitry connecting the cerebellum, brain stem, and spinal cord intact to study the role of excitatory amino acid neurotransmitters and recurrent excitation in mediating the generation of burst discharges in the red nucleus. 2. Burst discharges were recorded extracellularly from single cells in the red nucleus in response to single pulse or brief train stimulation of the contralateral spinal cord or brief train stimuli applied to the ipsilateral cerebellar cortex. The firing characteristics and pharmacologic sensitivities of the bursts were independent of the type of stimulus used. The bursts had long durations ranging from 2 to 17 s and showed spike frequency adaptation. 3. Transection of the cerebellar peduncle, which eliminates inhibition impinging onto the cerebellorubral circuit, greatly enhanced the spontaneous activity and burst discharges recorded in the contralateral red nucleus. Furthermore, bath application of a solution containing elevated levels of calcium and magnesium blocked the expression of burst discharges even though synaptic activation of the neurons was not blocked. 4. The possibility that excitatory amino acid receptors mediate burst responses in the red nucleus was investigated in light of the antagonistic effects of elevated magnesium ions on bursting. Bath application of 100 microns DL-2-amino-5-phosphonovaleric acid (APV), a specific N-methyl-D-aspartate (NMDA) receptor antagonist; [10 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)], a specific non-NMDA receptor antagonist; or 100 microM, DL-2-amino-4-phosphonobutyric acid (AP4), an agonist of a fourth class of excitatory amino acid receptor, blocked burst activity in the red nucleus. With a multibarreled pipette for simultaneous ejection of drug and recording, iontophoresis of APV or CNQX into the red nucleus blocked bursting whereas AP4 failed to show a significant effect. These data suggest that red nucleus neurons have both NMDA and non-NMDA receptors. The site of action of the AP4-sensitive receptor appears to be elsewhere in the cerebellorubral circuit. 5. Iontophoretic application of excitatory amino acid receptor agonists NMDA and quisqualate (Q) induced excitation of red nucleus neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Ketamine Increases Proliferation of Human iPSC-Derived Neuronal Progenitor Cells via Insulin-Like Growth Factor 2 and Independent of the NMDA Receptor

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1139 ◽  
Author(s):  
Alessandra Grossert ◽  
Narges Zare Mehrjardi ◽  
Sarah J. Bailey ◽  
Mark A. Lindsay ◽  
Jürgen Hescheler ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Growth Factor ◽  
Progenitor Cells ◽  
Neural Progenitor Cells ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Nmda Receptor Antagonist ◽  
Insulin Like Growth Factor

The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine offers promising perspectives for the treatment of major depressive disorder. Although ketamine demonstrates rapid and long-lasting effects, even in treatment-resistant patients, to date, the underlying mode of action remains elusive. Thus, the aim of our study was to investigate the molecular mechanism of ketamine at clinically relevant concentrations by establishing an in vitro model based on human induced pluripotent stem cells (iPSCs)-derived neural progenitor cells (NPCs). Notably, ketamine increased the proliferation of NPCs independent of the NMDA receptor, while transcriptome analysis revealed significant upregulation of insulin-like growth factor 2 (IGF2) and p11, a member of the S100 EF-hand protein family, which are both implicated in the pathophysiology of depression, 24 h after ketamine treatment. Ketamine (1 µM) was able to increase cyclic adenosine monophosphate (cAMP) signaling in NPCs within 15 min and cell proliferation, while ketamine-induced IGF2 expression was reduced after PKA inhibition with cAMPS-Rp. Furthermore, 24 h post-administration of ketamine (15 mg/kg) in vivo confirmed phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in the subgranular zone (SGZ) of the hippocampus in C57BL/6 mice. In conclusion, ketamine promotes the proliferation of NPCs presumably by involving cAMP-IGF2 signaling.

Effect of Three NR3C1 mutations in Pathogenesis of Pituitary ACTH Adenoma

Endocrinology ◽  
2021 ◽  
Author(s):  
Hui Miao ◽  
Yang Liu ◽  
Lin Lu ◽  
Fengying Gong ◽  
Linjie Wang ◽  
...  
Keyword(s):  
Protein Expression ◽  
Nuclear Translocation ◽  
Treatment Approach ◽  
Wild Type ◽  
Acth Secretion ◽  
Novel Treatment ◽  
Generation Sequencing ◽  
Nuclear Receptor Subfamily ◽  
Corticotropic Adenoma

Abstract Objective Glucocorticoids act through the glucocorticoid receptor (GR) encoded by the Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1) gene. This study aimed to examine the function of NR3C1 variants and their possible pathogenic role in Cushing’s disease (CD). Methods Next Generation Sequencing was conducted in 49 CD patients. Corticotroph tumor GR protein expression was examined by immunohistochemistry (IHC). Constructs harboring the three NR3C1-mutants and wild-type (WT) GR were transfected into the murine corticotropic adenoma cell line (AtT-20) and GR protein expression was quantified by western blot. Translocation activity was assessed by immunofluorescence and effects of the GR mutants on corticotroph tumor proliferation, pro-opiomelanocortin (POMC) transcription and ACTH secretion were tested. Results Clinical features were similar in patients harboring the NR3C1 mutations and WT GR. Recurrent adenomas showed higher GR IHC score than non-recurrent tumors. In vitro studies demonstrated that the p.R469X mutant generated a truncated GR protein, and the p.D590G and p.Y693D GR mutants resulted in lower GR expression. Dexamethasone (DEX) treatment of AtT-20 cells demonstrated decreased DEX-induced nuclear translocation, increased cell proliferation and attenuated suppression of POMC transcription of 3 GR mutants. Interestingly, the p.R469X GR mutant resulted in increased murine corticotroph tumor ACTH secretion compared to WT GR. Conclusion Our findings identify 3/49 (6.1%) consecutive human corticotroph tumors harboring GR mutations. Further findings demonstrate the role NR3C1 plays in CD pathogenesis and offer insights into a novel treatment approach in this patient subset.

Mechanisms underlying induction of long-term potentiation in rat medial and lateral perforant paths in vitro

1993 ◽  
Vol 69 (4) ◽  
pp. 1150-1159 ◽  
Author(s):  
A. Colino ◽  
R. C. Malenka
Keyword(s):  
Nmda Receptor ◽  
Receptor Antagonist ◽  
Intracellular Calcium ◽  
Granule Cells ◽  
Long Term Potentiation ◽  
Nmda Receptor Antagonist ◽  
Perforant Path ◽  
Term Potentiation

1. The mechanisms underlying the induction of long-term potentiation (LTP) in the medial and lateral perforant paths were studied by recording excitatory postsynaptic potentials (EPSPs) from rat dentate granule cells in vitro using extracellular and whole-cell recording techniques. 2. Paired stimuli (interstimulus interval, 50-1,000 ms) resulted in facilitation of the lateral and depression of the medial perforant path-evoked EPSPs, respectively. This physiological difference was used to isolate responses evoked by stimulation of a single path. 3. Tetanic stimulation induced LTP in both pathways, although the magnitude of LTP in the lateral perforant path was significantly less than that in the medial perforant path. Both forms of LTP were blocked by the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphonovaleric acid (D-APV). 4. Buffering intracellular calcium by loading granule cells with the calcium chelator bis (O-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid prevented LTP in both pathways. 5. Pairing of low-frequency (0.25 Hz) afferent stimulation with postsynaptic depolarization induced LTP in the medial but not the lateral perforant path. However, pairing of higher-frequency stimulation (1-4 Hz) with postsynaptic depolarization did potentiate the lateral perforant path-evoked EPSP in some cells. 6. Both the medial and lateral perforant path-evoked EPSPs had two components; a fast component blocked by the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione and a slower, voltage-dependent component blocked by D-APV. 7. The results indicate that the induction of LTP in both the medial and lateral perforant paths requires activation of postsynaptic NMDA receptors and a rise in intracellular calcium.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Synthesis and Cytotoxic Activity Evaluation of New Cu(I) Complexes of Bis(pyrazol-1-yl) Acetate Ligands Functionalized with an NMDA Receptor Antagonist

2020 ◽  
Vol 21 (7) ◽  
pp. 2616 ◽  
Author(s):  
Maura Pellei ◽  
Luca Bagnarelli ◽  
Lorenzo Luciani ◽  
Fabio Del Bello ◽  
Gianfabio Giorgioni ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Carboxylic Acid ◽  
Receptor Antagonist ◽  
Three Dimensional ◽  
Human Tumor ◽  
Nmda Antagonist ◽  
Nmda Receptor Antagonist ◽  
Ic50 Values ◽  
Drug Resistant Phenotype

In the present article, copper(I) complexes of bis(pyrazol-1-yl) carboxylic acid (LH), bis(3,5-dimethylpyrazol-1-yl) carboxylic acid (L2H), and bis(pyrazol-1-yl) acetates conjugated with an N-methyl-d-aspartate (NMDA) receptor antagonist (LNMDA or L2NMDA) and phosphane ligands (triphenylphosphine or 1,3,5-triaza-7-phosphaadamantane) were synthesized. The selection of an NMDA antagonist for the coupling with LH and L2H was suggested by the observation that NMDA receptors are expressed and play a role in different types of cancer models. All the new complexes showed a significant antitumor activity on a panel of human tumor cell lines of different histology, with cisplatin-sensitive, cisplatin-resistant, or multi-drug-resistant phenotype. Their half maximal inhibitory concentration (IC50) values were in the low- and sub-micromolar range and, in general, significantly lower than that of cisplatin. Interestingly, the fact that all the complexes proved to be significantly more active than cisplatin even in three-dimensional (3D) spheroids of H157 and BxPC3 cancer cells increased the relevance of the in vitro results. Finally, morphological analysis revealed that the most representative complex 8 induced a massive swelling of the endoplasmic reticulum (ER) membrane, which is a clear sign of ER stress.

Two types of network oscillations in neocortex mediated by distinct glutamate receptor subtypes and neuronal populations

1996 ◽  
Vol 75 (2) ◽  
pp. 951-957 ◽  
Author(s):  
A. C. Flint ◽  
B. W. Connors
Keyword(s):  
Nmda Receptor ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptors ◽  
Field Potential ◽  
Nmda Receptor Antagonist ◽  
Receptor Subtypes ◽  
Synchronous Oscillation ◽  
Population Activity ◽  
Dominant Frequencies

1. Two distinct forms of spontaneous synchronous oscillations were investigated with field potential recordings in slices of rat somatosensory cortex in vitro. 2. The first type of synchronous oscillation was activated by low extracellular [Mg2+] and had dominant frequencies of 8-12 Hz. It was abolished reversibly by the N-methyl-D-aspartate (NMDA) receptor antagonists D-2-amino-5-phosphonovaleric acid and was relatively unaffected by the non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX). The duration of oscillatory events was increased by blocking gamma-aminobuturic acid-A receptors with bicuculline or by activating metabotropic glutamate receptors with trans-1-aminocyclopentane-1,3-dicarboxylic acid. 3. A second form of synchronous oscillation was activated by acute application of kainic acid (10 microM), had dominant frequencies of 1-5 Hz, and was abolished reversibly by DNQX. Low concentrations of domoic acid mimicked the effects of kainate, but alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid or quisqualic acid did not, suggesting a role for the GluR5-7 and KA1-2 glutamate receptor subunits. 4. Surgical isolation of cortical layers showed that spontaneous NMDA receptor-dependent oscillations originated within layer 5 exclusively, but kainate receptor-dependent oscillations were uniquely generated by neurons in layers 2/3. 5. Our results suggest that neocortical neurons in layers 2/3 and layer 5 can independently generate two distinct forms of rhythmic population activity, each dependent upon activation of a different subtype of glutamate receptor.

Functional in vitro characterization of CR 3394: A novel voltage dependent N-methyl-d-aspartate (NMDA) receptor antagonist

2006 ◽  
Vol 50 (3) ◽  
pp. 277-285 ◽  
Author(s):  
Gabriele Losi ◽  
Marco Lanza ◽  
Francesco Makovec ◽  
Roberto Artusi ◽  
Gianfranco Caselli ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Receptor Antagonist ◽  
Nmda Receptor Antagonist ◽  
In Vitro Characterization ◽  
Voltage Dependent

scholarly journals Nicotinic and Muscarinic Reduction of Unitary Excitatory Postsynaptic Potentials in Sensory Cortex; Dual Intracellular Recording In Vitro

2006 ◽  
Vol 95 (4) ◽  
pp. 2155-2166 ◽  
Author(s):  
Robert B. Levy ◽  
Alex D. Reyes ◽  
Chiye Aoki
Keyword(s):  
Nmda Receptor ◽  
Receptor Antagonist ◽  
Pyramidal Neurons ◽  
Glutamate Release ◽  
Receptor Activation ◽  
Nmda Receptor Antagonist ◽  
Excitatory Postsynaptic Potentials ◽  
Postsynaptic Potentials ◽  
Sensory Activity

We studied the cholinergic modulation of glutamatergic transmission between neighboring layer 5 regular-spiking pyramidal neurons in somatosensory cortical slices from young rats (P10-P26). Brief bath application of 5–10 μM carbachol, a nonspecific cholinergic agonist, decreased the amplitude of evoked unitary excitatory postsynaptic potentials (EPSPs). This effect was blocked by 1 μM atropine, a muscarinic receptor antagonist. Nicotine (10 μM), in contrast to carbachol, reduced EPSPs in nominally magnesium-free solution but not in the presence of 1 mM Mg+2, indicating the involvement of NMDA receptors. Likewise, when the postsynaptic cell was depolarized under voltage clamp to allow NMDA receptor activation in the presence of 1 mM Mg+2, synaptic currents were reduced by nicotine. Nicotinic EPSP reduction was prevented by the NMDA receptor antagonist d-AP5 (50 μM) and by the nicotinic receptor antagonist mecamylamine (10 μM). Both carbachol and nicotine reduced short-term depression of EPSPs evoked by 10 Hz stimulation, indicating that EPSP reduction happens via reduction of presynaptic glutamate release. In the case of nicotine, several possible mechanisms for NMDAR-dependent EPSP reduction are discussed. As a result of NMDA receptor dependence, nicotinic EPSP reduction may serve to reduce the local spread of cortical excitation during heightened sensory activity.

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