• Biomolecules & Therapeutics
• /
• v.12 no.3
• /
• pp.138-144
• /
• 2004

Therapeutic effect of a Kampo medicine, Choto-san, in patients with vascular dementia was demonstrated by a double-blind and placebo-controlled clinical trial. To clarify the therapeutic efficacy of Choto-san, anti-ischemic effect in mice, hypotensive effect in spontaneously hypertensive rats (SHR), anti-oxidative effects in vitro, and N-methyl-D-aspartate (NMDA) receptor-blocking activity using Xenopus oocytes were studied. (1) Pretreatment with Choto-san (0.75-6.O g/kg, P.O.) or a component herb Chotoko (Uncaria genus: 75 - 600 mg/kg, P.O.) prevented ischemia-induced impairment of spatial learning behaviour in mice. Indole alkaloids- and phenolic fractions extracted from Chotoko also improved significantly the learning deficit. (2) Subchronic administration of Choto-san (0.5 g/kg, p.o.) caused a significant hypotensive effects in SHR. (3) Choto-san, Chotoko, and the phenolic constituent, (-) epicatechin, significantly protected the NG108-15 cell injury induced by $H_20_2$ exposure in vitro and also inhibited lipid peroxidation in the brain homogenate. (4) Indole alkaloids, rhynchophylline and isorhynchophylline (1-100 uM), reversibly reduced NMDA-induced current in the receptor-expressed Xenopus oocytes. These results suggest that anti-vascular dementia effects of Choto-san are mainly due to the effect of Chotoko. From these results, it is possible to make a novel dietary supplement through several extraction steps from Chotoko.

• Animal cells and systems
• /
• v.15 no.2
• /
• pp.115-121
• /
• 2011

Previous studies have demonstrated that N-methyl-D-aspartate (NMDA) receptors and acetylcholine receptors are related to learning and memory in rat and mice. In this study, we examined the effects of MK-801, a non-competitive NMDA receptor antagonist, on learning and memory in zebrafish using a passive avoidance test. We further tested whether or not nicotine, a nicotinic acetylcholine receptor agonist, and physostigmine, an acetylcholinesterase inhibitor, reverse the effects of MK-801. Crossing time was increased significantly in the training and test sessions for the controls. When 20 ${\mu}M$ MK-801 was administered prior to the training session, the crossing time did not increase in either session. The MK-801-induced learning deficit was rescued by pretreatment with 20 ${\mu}M$ physostigmine, and crossing time was increased in the training and test sessions compared to the MK-801-treated zebrafish. Further, the MK-801-induced learning deficit was prevented by pretreatment with 20 ${\mu}M$ nicotine, and crossing time was increased in the training session but not in the test session. These results show that MK-801 induced a learning deficit in zebrafish that was prevented by pretreatment with nicotine and physostigmine.

• Biomedical Science Letters
• /
• v.11 no.3
• /
• pp.319-326
• /
• 2005

It is well known that oxidative stress of reactive oxygen species (ROS) may be a causative factor in the pathenogenesis of bone disorder on osteoblast or osteoclast. The purpose of this study was to evaluate the cytotoxicity of oxidative stress, protective effect of glutamate receptor antagoinst against ROS-induced osteotoxicity, secretion of tumor necrosis factor $(TNF)-\alpha$ and the expression of c-fos gene in the cultured rat osteoblasts and osteoclasts. Cell viability by MTS assay or !NT assay, activity of glutathione peroxidase (GPx), lipid peroxidation (LPO) activity, protein synthesis by sulforhodamine B (SRB) assay, alkaline phosphatase (ALP) activity, lactate dehydrogenase (LDH) activity, MTS assay for NMDA (N-methyl-D-aspartate) receptor antagonist or AMPA/kainate receptor antagonist, measurement for $TNF-\alpha$, and c-fos gene expression were performed after these cells were treated with or without various cocentrations of xanthine oxidase (XO), hypoxanthine (HX), 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), respectively. In this study, XO/HX showed decreased cell viability and glutathione peroxidase (GPx) activity, but it showed increased LPO activity, $TNF-\alpha$ secretion and c-fos expression. APV and CKA incresed protein sythesis and ALP activity. While, CNQX or DNQX did not show any protective effect in LDH activity or cell viability. From these results, XO/HX showed cytotoxic effect in cultured rat osteoblast or osteoclast, and also NMDA receptor antagonist such as APV or CKA was effective in blocking XO/HX-induced osteotoxicity in these cultures.

• Korean Journal of Medicinal Crop Science
• /
• v.24 no.5
• /
• pp.375-385
• /
• 2016

Background: The study was conducted to elucidate the extraction conditions under which white ginseng has cognition-improving efficacy. Methods and Results: Extracts from white ginseng under different solvent and temperature conditions were analyzed for ginsenoside content and inhibitory effect on N-methyl-D-aspartate (NMDA) receptor and acetylcholinesterase. The total ginsenoside contents and amounts of ginsenoside Rb1 plus ginsenoside Rg1 from the 1st extracts (prepared with EtOH/$H_2O$ as solvent) were higher than those from the 2nd extracts (extracted with $H_2O$ after the 1st EtOH/$H_2O$ extraction). The contents in the 1st and 2nd extracts produced at $80^{\circ}C$ were also higher than those obtained at $50^{\circ}C$. Samples from the 1st extraction at $80^{\circ}C$ indicated higher inhibitory activities on NMDA receptors-whose excessive activation is thought to mediate the calcium-dependent neurotoxicity associated with several neurodegenerative diseases-than those from the 2nd extraction. Among the samples prepared at varying temperatures, the extract prepared at $50^{\circ}C$ showed the highest suppression activity on NMDA receptors. Note, however, that the extracts from the 2nd extraction at $50^{\circ}C$ inhibited acetylcholinesterase-whose inhibition could be a therapeutic strategy for neurodegenerative diseases with cognitive deficits and memory malfunction-more effectively than those from the 1st extraction. Conclusions: To enhance the cognition-improving activity of white ginseng extract, it is suggested that the extracts be utilized after being combined the 1st extracts (made with EtOH/$H_2O$ solvent) and the 2nd extracts (prepared with $H_2O$) at low temperature.

• Korean Journal of Psychosomatic Medicine
• /
• v.29 no.2
• /
• pp.207-212
• /
• 2021

Anti-N-methyl-D-aspartate receptor (Anti-NMDAR) encephalitis is a neuroinflammatory disease mediated by autoantibodies to NMDAR. In the initial clinical stages of anti-NMDAR encephalitis, psychiatric symptoms like delusions, perceptual disturbances, and disorganized speech or behaviors are pronounced even without obvious neurological symptoms. Early treatments like immunotherapy and/or tumor removal are central to good clinical outcomes. Hence, it is important to diagnose early anti-NMDAR encephalitis, distinguishing it from mental disorder. In the present case study, the authors described psychiatric symptoms assessed with Positive and Negative Syndrome Scale (PANSS) of Ms. A, a 26-year-old woman, in the early phase of anti-NMDAR encephalitis. We will discuss the characteristic psychopathology of anti-NMDAR encephalitis toward prompt diagnosis and treatment. Ms. A showed a higher negative subscale score than positive one on the PANSS. Compared with mental disorder, negative symptoms and cognitive impairment would be more prominent in the early stage of anti-NMDAR encephalitis. Rituximab and teratoma removal were effective, and quetiapine showed good tolerability. It is recommended to evaluate anti-NMDAR encephalitis when negative symptoms, cognitive impairment, catatonia, changes in consciousness level, and neurological symptoms are observed, especially in young women.

• Korean Journal of Medicinal Crop Science
• /
• v.27 no.2
• /
• pp.115-125
• /
• 2019

Background: Glycyrrhiza radix (licorice root) have been used as an oriental medicine material for long time, and its protective effects on oxidative stress, inflammation and cognition deficit have been recently reported. However, the cultivation of Glycyrrhiza species as medicinal crops is associated with some problems such as low productivity and early leaf fall, etc. To resolve this problems, Glycyrrhiza cultivars have been developed by direct hybridization of each Glycyrrhiza species by Korean researchers. The present study was conducted to compare the Glycyrrhiza cultivar radix (Dagam, Sinwongam and Wongam) for their anti-oxidation, anti-inflammation, and cognition improvement effects and levels of liquiritin, isoliquiritigenin and licochalcone in order to select an excellent cultivar as a material resource. Methods and Results: For evaluating the inhibitory efficacies of the Glycyrrhiza cultivar extracts on oxidative stress and inflammation in BV2 cells, we measured their reactive oxygen species (ROS) production and nitric oxide (NO) release after treating them with lipopolysccharide. The scavenging activities on 2,2-diphenyl-1-picrylhydrazyl (DPPH) and peroxynitrite ($NOO^-$) radicals were evaluated. Cell proliferation and N-methyl-D-aspartate receptor (NMDAR) inhibition were analyzed. The total phenol, liquiritin, isoliquiritigenin and licochalcone A content in the extracts of the three culivars were quantified. Furthermore, the correlation coefficient between the activities and contents of total phenol, liquiritin, isoliquiritigenin and licochalcone A were also calculated. The results indicated that Sinwongam exhibited potent anti-oxidant, anti-inflammatory and NMDAR inhibititory activities. Sinwongam also showed higher total phenol and licochalcone A contents than the other cultivars. Among the three cultivars, Dagam exhibited a positive effects on NO release inhibition, cell proliferation and contents of liquiritin and isoliquiritigenin. Conclusions: Sinwongam is expected to be the most useful resource as a functional material for anti-oxidation/anti-inflammation and cognition improvement among the three studied licorice cultivars.

• Journal of Life Science
• /
• v.15 no.3 s.70
• /
• pp.505-512
• /
• 2005

Excitotoxicity and epileptogenesis have often been associated with glutamate receptor activation. Accumulating evidences indicates that topiramate (TPM), an antiepileptic drug with multiple mechanisms of action has neuroprotective activity. We explored the neuroprotective effect of TPM on the status epilepticus (SE)-induced hippocampal neuronal death. After development of SE by kainite injection (15 mg/Kg), rats were treated with TPM (10mg/kg) for 1 week. The neuronal death was detected by Apop tag in situ detection kit, and the expression levels of glutamate receptors were semi-quantitatively analyzed by immunoblot. Kainate-induced SE caused a significant neuronal death and cell loss in CAI and CA3 regions of hippocampus at 1 week. However, treatment of TPM for 1 week after SE markedly reduced hippocampal neuronal death. The expression of N-methyl-D-aspartate (NMDA) receptor subunit 1, was increased by SE, but was not affected by 1 week treatment of TPM. The expressions of NMDA receptor subunit 2a and 2b were not changed by either SE or TPM. As for ${\alpha}-amino-3-hydroxy-5-methyl-4-isoxazole-propionate$ (AMPA) glutamate receptors (GluR), kainate-induced SE markedly up-regulated GluR1 expression but down-regulated GluR2 expression, leading to increased formation of $Ca^{2+}$ permeable GluR2- lacking AMPA receptors. TPM administration for 1 week attenuated SE-induced expression of both the up-regulation of GluR1 and down-regulation of GluR2, reversing the ratio of GluR1/GluR2 to the control value. In conclusion, TPM protects neuronal cell death against glutamate induced excitotoxicity in kainate-induced SE model, supporting the potential of TPM as a neuroprotective agent.

• The Korean Journal of Physiology and Pharmacology
• /
• v.9 no.5
• /
• pp.255-262
• /
• 2005

Striatum is involved in the control of movement and habitual memory. It receives glutamatergic input from wide area of the cerebral cortex as well as an extensive serotonergic (5-hydroxytryptamine, 5-HT) input from the raphe nuclei. In our study, the effects of 5-HT on synaptic transmission were studied in the rat corticostriatal brain slice using in vitro whole-cell recording technique. 5-HT inhibited the amplitude as well as frequency of spontaneous excitatory postsynaptic currents (sEPSC) significantly, and neither ${\gamma}-aminobutyric$ acid (GABA)A receptor antagonist bicuculline (BIC), nor $N-methyl-_{D}-aspartate$ (NMDA) receptor antagonist, $_{DL}-2-amino-5-phosphonovaleric$ acid (AP-V) could block the effect of 5-HT. In the presence non-NMDA receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenxo[f] quinoxaline-7-sulfonamide (NBQX), the inhibitory effect of 5-HT was blocked. We also figured out that 5-HT change the channel kinetics of the sEPSC. There was a significant increase in the rise time during the 5-HT application. Our results suggest that 5-HT has an effect on both pre- and postsynaptic site with decreasing neurotransmitter release probability of glutamate and decreasing the sensitivity to glutamate by increasing the rise time of non-NMDA receptor mediated synaptic transmission in the corticostriatal synapses.

• The Journal of Internal Korean Medicine
• /
• v.44 no.6
• /
• pp.1337-1345
• /
• 2023

Objectives: This study reports on the improvement of anti-N-methyl-D-aspartate (NMDA) receptor encephalitis with ovarian teratoma after Korean medicine treatment. Methods: A patient was treated with Korean medicine treatments, such as acupuncture and herbal medications (Gami-ondam-tang and Samulanshin-tang-gamibang). The patient's improvement was evaluated using manual muscle testing (MMT), the Mini-Mental State Exam-Korea (MMSE-K), the modified Barthel index (MBI), and the Clinical Assessment Scale in Autoimmune Encephalitis (CASE). Results: After using Korean medicine treatments, the patient's MMT, MMSE-K, and MBI scores increased, and the CASE score decreased. Conclusion: This case suggests that Korean medicine can be effective in treating the symptoms of anti-NMDA receptor encephalitis.

• Proceedings of the Korean Society of Applied Pharmacology
• /
• 1996.04a
• /
• pp.19-29
• /
• 1996

The neurological manifestations of AIDS include dementia, encountered even in the absence of opportunistic superinfection or malignancy. The AIDS Dementia Complex appears to be associated with several neuropathological abnormalities, including astrogliosis and neuronal injury or loss. How can HIV-1 result in neuronal damage if neurons themselves are only rarely, if ever, infected by the vitus\ulcorner In vitro experiments from several different laboratiories have lent support to the existence of HIV- and immune-related toxins. In one recently defined pathway to neuronal injury, HIV-infected macrophages/microglia as well as macrophages activated by HIV-1 envelope protein gp120 appear to secrete excitants/neurotoxins. These substances may include arachidonic acid, platelet-activating factor, free radicals (NO - and O$_2$), glutamate, quinolinate, cysteine, cytokines (TNF-${\alpha}$, IL1-B, IL-6), and as yet unidentified factors emanating from stimulated macrophages and possibly reactive astrocytes. A final common pathway for newonal suscepubility appears to be operative, similar to that observed in stroke, trauma, epilepsy, and several neurodegenerative diseases, including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves excessive activation of N-methyl-D-aspartate (NMDA) receptor-operated channels, with resultant excessive influx of Ca$\^$2+/ leading to neuronal damage, and thus offers hope for future pharmacological intervention. This chapter reviews two clinically-tolerated NMDA antagonists, memantine and nitroglycerin; (ⅰ) Memantine is an open-channel blocker of the NMDA-associated ion channel and a close congener of the anti-viral and anti-parkinsonian drug amantadine. Memantine blocks the effects of escalating levels of excitotoxins to a greater degree than lower (piysiological) levels of these excitatory amino acids, thus sparing to some extent normal neuronal function. (ⅱ) Niuoglycerin acts at a redox modulatory site of the NMDA receptor/complex to downregulate its activity. The neuroprotective action of nitroglycerin at this site is mediated by n chemical species related to nitric oxide, but in a higher oxidation state, resulting in transfer of an NO group to a critical cysteine on the NMDA receptor. Because of the clinical safety of these drugs, they have the potential for trials in humans. As the structural basis for redox modulation is further elucidated, it may become possible to design even better redox reactive reagents of chinical value. To this end, redox modulatory sites of NMDA receptors have begun to be characterized at a molecular level using site-directed mutagenesis of recombinant subunits (NMDAR1, NMDAR2A-D). Two types of redox modulation can be distinguished. The first type gives rise to a persistent change in the functional activity of the receptor, and we have identified two cysteine residues on the NMDARI subunit (#744 and #798) that are responsible for this action. A second site, presumably also a cysteine(s) because <1 mM N-ethylmaleimide can block its effect in native neurons, underlies the other, more transient redox action. It appears to be at this, as yet unidentified, site on the NMDA receptor that the NO group acts, at least in recombinant receptors.