• Archives of Pharmacal Research
• /
• 제22권2호
• /
• pp.113-118
• /
• 1999

Previous work in our laboratory has shown that the N-methyl-D-aspartate (NMDA) receptor antagonists, AP-5, CPP, MK-801, ketamine, dextrorphan and dextromethorphan cause a pronounced enhancement of 5-hydroxytryptamine (5-HT)-induced head-twitch response (HTR) in intact mice, suggesting the involvement of NMDA receptors in the glutamatergic modulation of serotonergic function at the postsynaptic $5-HT_{2}$ receptors. The purpose of this study was to extend our previous work on the behavioral interaction between glutamatergic and serotonergic receptors. In the present study, both competitive (AP-5 and CPP) and noncompeti-tive (MI-801, ketamine, dextrorphan and dextromethorphan) NMDA receptor antagonists markedly enhanced 5-HT-induced selective serotonergic behavior, HTR, in p-chlorophenylalanine (PCPA)-treated mice which were devoid of any involvement of indirect serotonergic function, to establish the involvement of the NMDA receptor in 5-HT-induced HTR at the postsyaptic $5-HT_{2}$receptors. In addition, the enhancement of 5-HT-induced HTR was inhibited by a dopamine agonist, apomorphine, NMDA receptor antagonist, NMDA and a serotonin $5-HT_{2}$receptor antagonist, cyproheptadine, in PCPA-treated mice. Therefore, the present results support our previous conclusion that the NMDA receptors play an important role in the glutamatergic modulation of serotonergic function at the poststynaptic $5-HT_{2}$ receptors.

• 한국응용약물학회:학술대회논문집
• /
• 한국응용약물학회 1996년도 춘계학술대회
• /
• pp.247-247
• /
• 1996

Previous work in our laboratory has shown that noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists, MK-801, ketamine, dextrorphan and dextromethorphan cause a pronounced inhibition of apomorphine-induced cage climbing behavior in intact mice, suggesting the involvement of NMDA receptors in the glutamatergic modulation of dopaminergic function at the postsynaptic dopamine (DA) receptors: Therefore, in order to definitively establish the involvement of NMDA receptor in the apomorphine-induced dopaminergic response at the postsynaptic DA receptor, it is necessary to investigate whether or not the noncompetitive NMDA receptor antagonists would inhibit these phenomena not only in intact mice but also in the mice that are devoid of any involvement of indirect dopaminergic function. To minimize the risk of any indirect involvement of NMDA antagonists with DA neurons, vesicular DA stores were first depleted with reserpine.

• Archives of Pharmacal Research
• /
• 제18권6호
• /
• pp.391-395
• /
• 1995

Several lines of evidence indicate that physiological activity of N-methyl-D-aspartate (NMDA) receptor was blocked by physiological concentration of $Mg^{2+}$ (1.2 mM). However, the activity of NMDA receptor may not be blocked totally with this concentration of $Mg^{2+}$ under elevated membrane potential by kainate. Here, we described the effect of $Mg^{2+}$ on NMDA receptor and how much of NMDA receptor functions could be activated by kainate. Effects of NMDA receptor antagonist on kainate-induced elevation of intracellualr $Ca^{2+}$ levels $([Ca^{2+}]_i)$ and extracellular glutamate level were examined in cultured rat cerebellar granule neurons. kainate-induced elevation of $([Ca^{2+}]_i)$ was not affected by physiological concentration of $Mg^{2+}$. Kainate-induced NMDA-induced elevation was blocked by the same concentration of $MG^{2+}$Kainate-induced elevation of [$([Ca^{2+}]_i)$ was decreased by 32% in the presence of NMDA antagonists, MK-801 and CPP (3-[2-carboxypiperazine-4-yl]propyl-1-phosphonic acid), in $Mg^{2+}$ free buffer. Kainate receptor-activated gluamate release was also decreased (30%) by MK-801 or CPP. These resuts show that certain extent of elevations of intracellular $Ca^{2+}$ and extracellular glutamate by kainate is due to coativation of NMDA receptors.

• The Korean Journal of Physiology and Pharmacology
• /
• 제27권5호
• /
• pp.449-456
• /
• 2023

N-methyl-D-aspartate (NMDA) receptors are ionic glutamine receptors involved in brain development and functions such as learning and memory formation. NMDA receptor inhibition is associated with autophagy activation. In this study, we investigated whether the NMDA receptor antagonists, memantine and ifenprodil, induce autophagy in human retinal pigment epithelial cells (ARPE-19) to remove N-retinylidene-N-retinylethanolamine (A2E), an intracellular lipofuscin component. Fluorometric analysis using labeled A2E (A2E-BDP) and confocal microscopic examination revealed that low concentrations of NMDA receptor antagonists, which did not induce cytotoxicity, significantly reduced A2E accumulation in ARPE-19 cells. In addition, memantine and ifenprodil activated autophagy in ARPE-19 cells as measured by microtubule-associated protein 1A/1B-light chain3-II formation and phosphorylated p62 protein levels. Further, to understand the correlation between memantine- and ifenprodil-mediated A2E degradation and autophagy, autophagy-related 5 (ATG5) was depleted using RNA interference. Memantine and ifenprodil failed to degrade A2E in ARPE-19 cells lacking ATG5. Taken together, our study indicates that the NMDA receptor antagonists, memantine and ifenprodil, can remove A2E accumulated in cells via autophagy activation in ARPE-19 cells.

• 한국응용약물학회:학술대회논문집
• /
• 한국응용약물학회 1997년도 춘계학술대회
• /
• pp.102-102
• /
• 1997

The purpose of this study was to determine the behavioral interaction between glutamatergic and serotonergic receptors. In the present study, both the competitive (AP-5 and D-CPP) and the noncompetitive (MK-801, ketamine, dextrorphan and dextromethorphan) N-methyl-D-aspartate (NMDA) receptor antagonists markedly enhanced 5-HT(5-hydroxytryptamine)-induced selective serotonergic behavior, head-twitch response (HTR), in mice. These results suggest that the glutamatergic neurotransmission may modulate serotonergic function at the 5-HT receptor. The precise relationship between glutamatergic and serotonergic system is as yet undefined. However, these are the first data available regarding glutamatergic modulation of serotonergic function at the 5-HT receptor in intact mice, and the present results support the notion that the NMDA receptors may play important roles in the glutamatergic modulation of serotonergic function at the 5-HT receptor.

• 대한약학회:학술대회논문집
• /
• 대한약학회 2003년도 Proceedings of the Convention of the Pharmaceutical Society of Korea Vol.1
• /
• pp.72-74
• /
• 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)

• 동의생리병리학회지
• /
• 제17권4호
• /
• pp.996-1001
• /
• 2003

It is well known that oxidative stress of reactive oxygen species(ROS) may be a causative factor in the pathogenesis of bone disorder. The purpose of this study was to evaluate the cytotoxicity of oxidative stress. Cell viability by MTS assay or INT assay, activity of glutathione peroxidase(GPx), lipid peroxidation(LPO) activity and cell viablity. And also protctive effect of glutamate receptors against ROS-induced osteotoxicity was examined by protein synthesis, alkaline phosphatase (ALP) activity and lactate dehydrogenase (LDH) activity in cultured rat osteoblasts and osteoclasts. XO/HX decreased cell viability and GPx activity, protein synthesis and ALP activity, but increased LPO activity and LDH activity. In the protective effect, N-methyl-D-aspartate (NMDA) receptor antagonists or AMPA/kainate receptor antagonists such as D-2-amino-5-phosphonovaleric acid (APV), 7-chlorokynurenic acid (CKA), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 6,7-dinitroquinoxaline-2,3-dione (DNQX), NMDA receptor antagonists but AMPA/kainate receptor antagonists showed protective effect on xanthine oxidase (XO) and hypoxanthine (HX) in these cultures by the increse of protein synthesis, ALP activity.

• Archives of Pharmacal Research
• /
• 제20권4호
• /
• pp.351-357
• /
• 1997

A series of 4-substituted-kynurenic acid derivatives possessing several different substituents at C4-position which are consisted of both a flexible propyloxy chain and an adjunct several type of carbonyl groups has been synthesized and evaluated for their in vitro antagonist activity at the glycine site on the NMDA receptor. Of them, N-benzoylthiourea 15c and N-phenylthiourea 15a were found to have the best in vitro binding affinity with $IC_{50}$ of 3.95 and $6.04{\mu}M$, respectively. On the other hand, in compounds 12a-c and 13 the displacement of a thiourea group to an amide or a carbamate caused a significant decrease of the in vitro binding affinity. In the SAR study of the 4-substituted kynurenic acid derivatives, it was realized that the terminal substitution pattern on a flexible C4-propyloxy chain of kynurenic acid nucleus significantly influences on the binding affinity for glycine site; the binding affinity to the NMDA receptor might be increased by the introduction of a suitable electron rich substituent at C4 of kynurenic acid nucleus.

• Applied Microscopy
• /
• 제28권4호
• /
• pp.591-601
• /
• 1998

The neurotoxic effects of radiation have been studied in NSC-34 hybrid cells derived from embryonic mouse spinal cord cells. NSC-34 cells irradiated at 25Gy were decreased the cell viability in a time and dose dependent manner. The decrease in cell viability induced by the irradiation was blocked by catalase. Antagonists of the N-methyl-D-aspartate (NMDA) receptor, including D-2-amino-5-phosphonovaleric acid (APV) and chlorokynurenic acid (CKA), similarly blocked radiational induced in cell viability. We performed morphological analysis of light and electron microscope. NSC-34 cells irradiated at 25Gy were decreased the cell density and increased lysosomes and vacuoles in the cytoplasm. Especially chromatin modification was observed. These results indicated that radiation was involved in the oxidant-initiated neurotoxicity and the compounds catalase, APV and CKA were shown to be neuroprotective against radiation.

• 생물정신의학
• /
• 제22권4호
• /
• pp.149-154
• /
• 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.