• Archives of Pharmacal Research
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• v.27 no.5
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• pp.524-530
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• 2004

Epilepsy or the occurrence of spontaneous recurrent epileptiform discharges (SREDs, seizures) is one of the most common neurological disorders. Shift in the balance of brain between excitatory and inhibitory functions due to different types of structural or functional alterations may cause epileptiform discharges. N-Methyl-D-aspartate (NMDA) receptor dysfunctions have been implicated in modulating seizure activities. Seizures and epilepsy are clearly dependent on elevated intracellular calcium concentration ([C $a^{2+}$]$_{i}$ ) by NMDA receptor activation and can be prevented by NMDA antagonists. This perturbed [C $a^{2+}$]$_{i}$ levels is forerunner of neuronal death. However, therapeutic tools of elevated [C $a^{2+}$]$_{i}$ level during status epilepticus (SE) and SREDs have not been discovered yet. Our previous study showed fast inhibition of ginseng total saponins and ginsenoside R $g_3$ on NMDA receptor-mediated [C $a^{2+}$]$_{i}$ in cultured hippocampal neurons. We, therefore, examined the direct modulation of ginseng on hippocampal neuronal culture model of epilepsy using fura-2-based digital $Ca^{2+}$ imaging and neuronal viability assays. We found that ginseng total saponins and ginsenoside R $g_3$ inhibited $Mg^{2+}$ free-induced increase of [C $a^{2+}$]$_{i}$ and spontaneous [C $a^{2+}$]$_{i}$ oscillations in cultured rat hippocampal neurons. These results suggest that ginseng may playa neuroprotective role in perturbed homeostasis of [C $a^{2+}$]$_{i}$ and neuronal cell death via the inhibition of NMDA receptor-induced SE or SREDs.d SE or SREDs..

• Archives of Pharmacal Research
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• v.23 no.1
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• pp.31-34
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• 2000

An efficient procedure for the preparation of 7,8-dichloro-6-nitro-1H-1,5-benzodiazepine-2,4-(3H, 5H)-dione(7) as a potential lead compound for the NMDA receptor glycine binding site antagonist, starting from readily available 4,5-dichloro-2-nitroaniline(8), is described. The key step in the synthesis involves the cyclization of malonic ester amide 10 to compound 11.

• Archives of Pharmacal Research
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• v.23 no.2
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• pp.112-115
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• 2000

A synthetic procedure for the preparation of indole-2,3-dione derivatives 6 as a potential NMDA receptor glycine site antagonist with improved pharmacological profile compared with 2-carboxyindole derivative 5, starting from readily available 3,5-dichloroaniline (7), is described.

• Archives of Pharmacal Research
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• v.24 no.6
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• pp.613-617
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• 2001

The present study examined the hypothesis that NMDA, AMPA/Kainate, and metabotropic (mGlu) glutamate receptors contribute to a behavioral stimulation induced by activation of dopamine receptors by comparing responses in apomorphine-induced cage climbing behaviors in mice. MK-801, CNQX, and MCPG were served as the NMDA receptor, AMPA/Kainate receptor, and mGlu receptor antagonist, respectively, to elucidate the glutamatergic modulation in apomorphine-induced eopaminergic activation in mice. Drugs were administered intracerebroventricularly (i.c.v.) into the mouse brain 15 min before the apomorphine treatment (2 mg/kg, s.c.). 1.c.v. injection of MK-801 inhibited the apomorphine-induced cage climbing behavior dose-dependently. However, treatments with CNQX and MCPG did not any significant change in apomorphine-induced cage climbing behavior in mice. These results suggest that stimulation of NMDA type of glutamate receptors could contribute to the dopaminergic sti mutation, but not AMPA/Kainate and mGlu type glutamate receptors.

• Biomedical Science Letters
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• v.15 no.4
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• pp.355-362
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• 2009

I evaluated the protective effect of N-methyl-D-aspartate (NMDA)/glycine receptor antagonist, 7-chlorokinurenic acid (CKA) on cultured mouse astrocytes damaged by ischemia-like condition (ILC). The protective effect of CKA was assessed by cell viability, lactate dehydrogenase (LDH) activity, superoxide dismutase (SOD)-like activity and lipid peroxidation. To examine the effect of CKA on the cell apoptosis, the expression and the activity of caspase 3 were assessed by Western blotting. CKA increased the cell viability decreased by ILC. CKA also decreased the LDH activity and antioxidative effects such as SOD-like activity and inhibitory activity of lipid peroxidation. In addition, CKA suppressed the expression of caspase 3 associated with apoptosis, and increased the cell viability by the decrease of caspase 3 activity as like the caspase 3 inhibitor, Av-DVED-MED. From these results, these results suggest that ILS induces cell cytotoxicity in cultured astrocytes and CKA, NMDA/glycine receptor antagonist, is effective on the prevention of the cytotoxicity due to ILS by the antioxidative effect and the inhibition of apoptosis.

• Korean Journal of Biological Psychiatry
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• v.22 no.4
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• pp.149-154
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• 2015

Mood disorder is a common psychiatric illness with a high lifetime prevalence in the general population. Many prescribed antidepressants modulate monoamine neurotransmitters including serotonin, norepinephrine and dopamine. There has been greater focus on the major excitatory neurotransmitter in the human brain, glutamate, in the pathophysiology and treatment of major depressive disorder (MDD). Recently, ketamine, an N-methyl-D-aspartate receptor antagonist, has received attention and has been investigated for clinical trials and neurobiological studies. In this article, we will review the clinical evidence for glutamatergic dysfunction in MDD, the progress with ketamine as a rapidly acting antidepressant, and other N-methyl-D-aspartate receptor antagonist for treatment-resistant depression.

• The Korean Journal of Physiology and Pharmacology
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• v.2 no.1
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• pp.41-48
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• 1998

The present study was undertaken to characterize homocysteic acid (HCA)-and cysteic acid (CA)-mediated formation of inositol phosphates (InsP) in primary culture of rat cerebellar granule cells. HCA and CA stimulated InsP formation in a dose-dependent manner, which was prevented by the N-methyl-D-aspartate (NMDA) receptor antagonist D,L-2-amino-5-phosphopentanoic acid (APV). CA-, but not HCA-, mediated InsP formation was in part prevented by the metabotropic glutamate receptor antagonist ?${\alpha}$-methyl-4-carboxyphenylglycine ($({\pm})$-MCPG). Both HCA- and CA-mediated increases in intracellular calcium concentration were completely blocked by APV, but were not altered by $({\pm})$-MCPG. CA-mediated InsP formation was in part prevented by removal of endogenous glutamate. In contrast, the glutamate transport blocker L-aspartic acid-${\beta}$-hydroxamate synergistically increased CA responses. These data indicate that in cerebellar granule cells HCA mediates InsP formation wholly by activating NMDA receptor. In contrast, CA stimulates InsP formation by activating both NMDA receptor and metabotropic glutamate receptor, and in part by releasing endogenous glutamate into extracellular milieu.

• Biomolecules & Therapeutics
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• v.30 no.4
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• pp.320-327
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• 2022

Neurodevelopmental disorders are complex conditions that pose difficulty in the modulation of proper motor, sensory and cognitive function due to dysregulated neuronal development. Previous studies have reported that an imbalance in the excitation/inhibition (E/I) in the brain regulated by glutamatergic and/or GABAergic neurotransmission can cause neurodevelopmental and neuropsychiatric behavioral deficits such as autism spectrum disorder (ASD). NMDA acts as an agonist at the NMDA receptor and imitates the action of the glutamate on that receptor. NMDA however, unlike glutamate, only binds to and regulates the NMDA receptor subtypes and not the other glutamate receptors. This study seeks to determine whether NMDA administration in mice i.e., over-activation of the NMDA system would result in long-lasting behavioral deficits in the adolescent mice. Both gender mice were treated with NMDA or saline at early postnatal developmental period with significant synaptogenesis and synaptic maturation. On postnatal day 28, various behavioral experiments were conducted to assess and identify behavioral characteristics. NMDA-treated mice show social deficits, and repetitive behavior in both gender mice at adolescent periods. However, only the male mice but not female mice showed increased locomotor activity. This study implies that neonatal exposure to NMDA may illicit behavioral features similar to ASD. This study also confirms the validity of the E/I imbalance theory of ASD and that NMDA injection can be used as a pharmacologic model for ASD. Future studies may explore the mechanism behind the gender difference in locomotor activity as well as the human relevance and therapeutic significance of the present findings.

• Proceedings of the PSK Conference
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• 2003.04a
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• pp.72-74
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• 2003

Excitatory amino acid (EAA) receptor, particularly NMDA receptor, are now known to be one of major transmitter receptors involved in synaptic excitation. Excessive release of EAA neurotransmitter, glutamate, is an important causative factor in the neurodegenerative processes and can cause neuronal damage and cell death. This excitotoxicity has been shown to be $Ca^{++}$ dependent. (omitted)

• The Korean Journal of Pharmacology
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• v.31 no.2
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• pp.141-144
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• 1995

Serotonergic neurons in brainstem play important roles in the endogenous descending pain inhibitory system. To illucidate the involvement of glutamate receptors in the regulation of brainstem serotonergic neurons, we studied the effects of glutamate receptor agonists on 5-hydroxytryptamine(5-HT) release from cultured neurons of rat fetal (gestational age 14th day) brainstem. Cultured cells maintained for 10 days in vitro were stimulated for 30 minutes with agonists of glutamate receptor subtypes at 10-1,000 micromolar concentration. Glutamate (10-1,000 M) increased 5-HT release in a concentration-dependent manner. N-methyl-D-aspartic acid $(NMDA)(10-1,000\;{\mu}M)$ increased 5-HT release in a concentration-dependent manner. Non-NMDA receptor agonists, kainate and $AMPA(3-1,000\;{\mu}M)$ also concentration-dependently increased 5-HT release. These results suggest that both NMDA and non-NMDA receptors regulate 5-HT release from brainstem serotonergic neurons.