• Journal of Periodontal and Implant Science
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• v.41 no.1
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• pp.17-22
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• 2011

Purpose: Nitric oxide (NO) has been known as an important regulator of osteoblasts and periodontal ligament cell activity. This study was performed to investigate the relationship between NO-mediated cell death of human periodontal ligament fibroblasts (PDLFs) and N-methyl-D-aspartic acid (NMDA) receptor antagonist (+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine hydrogen maleate (MK801). Methods: Human PDLFs were treated with various concentrations (0 to 4 mM) of sodium nitroprusside (SNP) with or without $200\;{\mu}M$ MK801 in culture media for 16 hours and the cell medium was then removed and replaced by fresh medium containing MTS reagent for cell proliferation assay. Western blot analysis was performed to investigate the effects of SNP on the expression of Bax, cytochrome c, and caspase-3 proteins. The differences for each value among the sample groups were compared using analysis of variance with 95% confidence intervals. Results: In the case of SNP treatment, as a NO donor, cell viability was significantly decreased in a concentration-dependent manner. In addition, a synergistic effect was shown when both SNP and NMDA receptor antagonist was added to the medium. SNP treated PDLFs exhibited a round shape in culture conditions and were dramatically reduced in cell number. SNP treatment also increased levels of apoptotic marker protein, such as Bax and cytochrome c, and reduced caspase-3 in PDLFs. Mitogen-activated protein kinase signaling was activated by treatment of SNP and NMDA receptor antagonist. Conclusions: These results suggest that excessive production of NO may induce apoptosis and that NMDA receptor may modulate NO-induced apoptosis in PDLFs.

• The Korean Journal of Physiology and Pharmacology
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• v.27 no.5
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• pp.449-456
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• 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.

• Natural Product Sciences
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• v.22 no.4
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• pp.246-251
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• 2016

This study investigated the effects of (-)-sesamin on memory deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse model of Parkinson's disease (PD). MPTP lesion (30 mg/kg/day, 5 days) in mice showed memory deficits including habit learning memory and spatial memory. However, treatment with (-)-sesamin (25 and 50 mg/kg) for 21 days ameliorated memory deficits in MPTP-lesioned mouse model of PD: (-)-sesamin at both doses improved decreases in the retention latency time of the passive avoidance test and the levels of dopamine, norepinephrine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid, improved the decreased transfer latency time of the elevated plus-maze test, reduced the increased expression of N-methyl-D-aspartate (NMDA) receptor, and increased the reduced phosphorylation of extracellular signal-regulated kinase (ERK1/2) and cyclic AMP-response element binding protein (CREB). These results suggest that (-)-sesamin has protective effects on both habit learning memory and spatial memory deficits via the dopaminergic neurons and NMDA receptor-ERK1/2-CREB system in MPTP-lesioned mouse model of PD, respectively. Therefore, (-)-sesamin may serve as an adjuvant phytonutrient for memory deficits in PD patients.

• BMB Reports
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• v.55 no.5
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• pp.238-243
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• 2022

Autism or autism spectrum disorder (ASD) is a behavioral syndrome characterized by persistent deficits in social interaction, and repetitive patterns of behavior, interests, or activities. The gene encoding Methyl-CpG binding protein 2 (MeCP2) is one of a few exceptional genes of established causal effect in ASD. Although genetically engineered mice studies may shed light on how MeCP2 loss affects synaptic activity patterns across the whole brain, such studies are not considered practical in ASD patients due to the overall level of impairment, and are technically challenging in mice. For the first time, we show that hippocampal MeCP2 knockdown produces behavioral abnormalities associated with autism-like traits in rats, providing a new strategy to investigate the efficacy of therapeutics in ASD. Ketamine, an N-Methyl-D-aspartate (NMDA) blocker, has been proposed as a possible treatment for autism. Using the MeCP2 knockdown rats in conjunction with a rat model of valproic acid (VPA)-induced ASD, we examined gene expression and ASD behaviors upon ketamine treatment. We report that the core symptoms of autism in MeCP2 knockdown rats with social impairment recovered dramatically following a single treatment with ketamine.

• Biomolecules & Therapeutics
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• v.6 no.1
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• pp.25-30
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• 1998

The roles of dopamine(DA) and N-methyl-D-aspartate(NMDA) system in the development and expression of morphine dependence were investigated by monitoring the concentrations of extracellular DA and its metabolites by in vivo microdialysis and simultaneous observation of behavioral changes in morphine dependent rats. Extracellular DA level in caudate putamen of morphine-dependent rat was decreased and the concentrations of its metabolites, dihydroxy phenylacetic acid(DOPAC) and homovanillic acid(HVA), were increased during naloxone-precipitated withdrawal. DA contents were recovered to normal levels by pretreatment of MK-801, a noncompetitive NMDA receptor antagonist, which may explain the mechanism of diminishing effect of MK-801 on withdrawal symptoms in morphine-dependent rats. MK-801(0.3 mg/tg, i.p.) induced the untoward hamful neurological signs such as ataxia and severe rotations, which may be produced by hyperactivation of dopaminergic system. These results suggest that MK-801 may inhibit the expression of mophine dependence by altering the dopamine release.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1996.04a
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• pp.247-247
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• 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.

• 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.

• Archives of Pharmacal Research
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• v.25 no.3
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• pp.349-356
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• 2002

The present study was performed to examine the effect of fangchinoline, a bis- benzylisoquinoline alkaloid, which exhibits the characteristics of a $Ca^{2+}$ channel blocker, on cyanide-induced neurotoxicity using cultured rat cerebellar granule neurons. NaCN produced a concentration-dependent reduction of cell viability, which was blocked by MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist, verapamil, L-type$Ca^{2+}$channel blocker, and L-NAME, a nitric oxide synthase inhibitor. Pretreatment with fangchinoline over a concentration range of 0.1 to 10 $\mu$M significantly decreased the NaCN-induced neuronal cell death, glutamate release into medium, and elevation of $[Ca^{2+}]_i$ and oxidants generation. These results suggest that fangchinoline may mitigate the harmful effects of cyanide-induced neuronal cell death by interfering with $[Ca^{2+}]_i$influx, due to its function as a $Ca^{2+}$ channel blocker, and then by inhibiting glutamate release and oxidants generation.

• Proceedings of the Korean Society of Applied Pharmacology
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• 1995.10a
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• pp.125-132
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• 1995

In neurons, nitric oxide(NO) is produced by neuronal nitric oxide synthase following stimulation of N-methyl-D-aspartate(NMDA) receptors and the subsequent influx of Ca$\^$2+/. NO, induced in this manner, reportedly plays critical roles in neuronal plasticity, including neurite outgrowth, synaptic transmission, and long-term potentiation(LTP) (1-7). However, excessive activation of NMDA receptors has also been shown to be associated with various neurological disorders, including focal ischemia, epilepsy, trauma, neuropathic pain and chronic neurodegenerative maladies, such as Parkinson's disease, Hungtington's disease and amyotrophic lateral sclerosis(8). The paradox that nitric oxide(NO) has both neuroprotective and neurodestructive effects may be explained, at least in part, by the finding that NO effects on neurons are dependent on the redox state. This claim may be supported by the recent finding that tissue concentrations of cysteine approach 700 ${\mu}$M in settings of cerebral ischemia (9), levels of thiol that is expected to influence both the redox state of the system and the NO group itself(10).

• Clinical and Experimental Pediatrics
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• v.57 no.1
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• pp.1-18
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• 2014

Channelopathies are a heterogeneous group of disorders resulting from the dysfunction of ion channels located in the membranes of all cells and many cellular organelles. These include diseases of the nervous system (e.g., generalized epilepsy with febrile seizures plus, familial hemiplegic migraine, episodic ataxia, and hyperkalemic and hypokalemic periodic paralysis), the cardiovascular system (e.g., long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia), the respiratory system (e.g., cystic fibrosis), the endocrine system (e.g., neonatal diabetes mellitus, familial hyperinsulinemic hypoglycemia, thyrotoxic hypokalemic periodic paralysis, and familial hyperaldosteronism), the urinary system (e.g., Bartter syndrome, nephrogenic diabetes insipidus, autosomal-dominant polycystic kidney disease, and hypomagnesemia with secondary hypocalcemia), and the immune system (e.g., myasthenia gravis, neuromyelitis optica, Isaac syndrome, and anti-NMDA [N-methyl-D-aspartate] receptor encephalitis). The field of channelopathies is expanding rapidly, as is the utility of molecular-genetic and electrophysiological studies. This review provides a brief overview and update of channelopathies, with a focus on recent advances in the pathophysiological mechanisms that may help clinicians better understand, diagnose, and develop treatments for these diseases.