• The Korean Journal of Physiology and Pharmacology
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• 제4권3호
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• pp.177-183
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• 2000

We examined the neurotoxic effects of 3 glutathione (GSH) depletors, buthionine sulfoximine (BSO), diethyl maleate (DEM) and phorone, under the presence of trolox, cycloheximide (CHX), pyrrolidine dithiocarbamate (PDTC) or MK-801 in primary mouse cortical cell cultures. All three depletors induced neuronal death in dose and exposure time dependent manner, and decreased total cellular GSH contents. The patterns of the neuronal death and the GSH decrements were dependent on the individual agents. DEM $(200\;{\mu}M)$ induced rapid and irreversible decrement of the GSH. BSO (1 mM) also decreased the GSH irreversibly but the rate of decrement was more progressive than that of DEM. Phorone (1 mM) reduced the GSH content to 40% by 4 hr exposure, that is comparable to the decrement of BSO, but the GSH recovered and reached over the control value by 36 hr exposure. BSO showed a minimal neurotoxicity $(0{\sim}10%)$ at the end of 24 hr exposure, but marked neuronal cell death at the end of 48 hr exposure. The BSO (1 mM)-induced neurotoxicity was markedly inhibited by trolox or CHX and partially attenuated by MK-801. DEM induced dose-dependent cytotoxicity at the end of 24 hr exposure. Over the doses of $400\;{\mu}M,$ glial toxicity also appeared. DEM $(200\;{\mu}M)-induced$ neurotoxicity was markedly inhibited by trolox or PDTC. Phorone (1 mM) induced moderate neurotoxicity (40%) at the end of 48 hr exposure. Only CHX showed significant inhibitory effect on the phorone-induced neurotoxicity. These results suggest that the GSH depletors induce neuronal injury via different mechanisms and that GSH depletors should be carefully employed in the researches of neuronal oxidative injuries.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1996년도 춘계학술대회
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• pp.212-212
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• 1996

Effects of ginseng total saponin(GTS) on changes in the glutamatergic nervous system induced by AF64A were studied in rats. Rats were pretreated with the infusion of AF64A (3mM) into lateral ventricle and were posttreated with GTS (50mg/kg, j.p) for 1 week. Twenty four hrs after the last administration, rats were sacrified and each brain resions was dissected ; striatum, hippocampus and frontal cortex. At each brain regions, total glutamate and other amino acids levels, [$^3$H]MK801 binding sites and glutamine synthetase activity were measured using HPLC-ECD, ligand binding assay and enzyme activity assay, respectively. The AF64-induced increase in the levels of total glutamate in hippocampus were significantly decreased by the administration of GTS. Furthermore, that compared with saline and GTS was decreased in striatum. The levels of total GABA compared with saline and GTS were declined in frontal cortex. Moreover, the AF64A-induced decrease in the levels of total taurine were significantly increased by the administration of GTS to extents of normal states. The numbers of [$^3$H]MK801 binding sites were differently affected in brain resiojns ; the decrease in hippocampus and no change in both striatum and frontal cortex, Glutamine synthetase activity was significantly increased in hippocampus. In comparision with saline and GTS, that was significantly decreased in striatum These results suggest that GTS may adjust the levels of glutamate, GABA and taurine constantly and may induce increase of glutamine synthetase activity declined.

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

• Korean Journal of Radiology
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• 제20권5호
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• pp.801-811
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• 2019

Objective: To determine whether diffusion kurtosis imaging (DKI) is effective in monitoring tumor response to neoadjuvant chemotherapy in patients with osteosarcoma. Materials and Methods: Twenty-nine osteosarcoma patients (20 men and 9 women; mean age, 17.6 ± 7.8 years) who had undergone magnetic resonance imaging (MRI) and DKI before and after neoadjuvant chemotherapy were included. Tumor volume, apparent diffusion coefficient (ADC), mean diffusivity (MD), mean kurtosis (MK), and change ratio (ΔX) between pre-and post-treatment were calculated. Based on histologic response, the patients were divided into those with good response (≥ 90% necrosis, n = 12) and those with poor response (< 90% necrosis, n = 17). Several MRI parameters between the groups were compared using Student's t test. The correlation between image indexes and tumor necrosis was determined using Pearson's correlation, and diagnostic performance was compared using receiver operating characteristic curves. Results: In good responders, MD_post, ADC_post, and MK_post values were significantly higher than in poor responders (p < 0.001, p < 0.001, and p = 0.042, respectively). The ΔMD and ΔADC were also significantly higher in good responders than in poor responders (p < 0.001 and p = 0.01, respectively). However, no significant difference was observed in ΔMK (p = 0.092). MD_post and ΔMD showed high correlations with tumor necrosis rate (r = 0.669 and r = 0.622, respectively), and MD_post had higher diagnostic performance than ADC_post (p = 0.037) and MK_post (p = 0.011). Similarly, ΔMD also showed higher diagnostic performance than ΔADC (p = 0.033) and ΔMK (p = 0.037). Conclusion: MD is a promising biomarker for monitoring tumor response to preoperative chemotherapy in patients with osteosarcoma.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1996년도 춘계학술대회
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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.

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

• 고려인삼학회:학술대회논문집
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• 고려인삼학회 2004년도 추계 학술대회 및 정기총회
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• pp.7-11
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• 2004

We previously reported that ginseng inhibited NMDA receptors in cultured hippocampal neurons. Here, we further examined the detailed mechanism of ginseng-mediated inhibition using its main active ingredient, ginsenoside Rg$_3$. Co-application of ginsenoside Rg$_3$ with increasing concentrations of NMDA did not change the EC$_{50}$ of NMDA to the receptor, suggesting ginsenoside Rg$_3$ inhibits NMDA receptors without competing with the NMDA-binding site. Ginsenoside Rg$_3$-mediated inhibition also occurred in a distinctive manner from the well-characterized NMDA receptor open channel blocker, MK-801, However, ginsenoside Rg$_3$ produced its effect in a glycine concentration-dependent manner and shifted the glycine concentration-response curve to the right without changing the maximal response, suggesting the role of ginsenoside Rg$_3$ as a competitive NMDA receptor antagonist. We also demonstrated that ginsenoside Rg$_3$ significantly protected neurons against NMDA insults. Therefore, these results suggest that ginsenoside Rg$_3$ protects NMDA-induced neuronal death via a competitive interaction with the glycine-binding site of NMDA receptors in cultured hippocampal neurons.

• Toxicological Research
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• 제11권2호
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• pp.187-192
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• 1995

The cytotoxic effects of hydrogen peroxide and neuroprotective effects of a variety of agents were investigated in newborn mouse forebrain tissue culture. In our experiments, oxygen radical was generated enzymatically by glucose oxidase and the values were expressed as a percentage of number of living cells by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Cytotoxicity of oxygen radicals was prevented by catalase and (N, N, N', N', -tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), but N-tetra-ot-butyl-phenylnitrone (PBN), and deferoxamine (DFX), failed to show protective effects against oxygen radicals. Antagonists of the N-methyl-D-aspartate (NMDA) receptor, D-2-amino-5-phosphonovaleric acid (APV), 7-chlorokynurenic acid (CKA), and MK801 (a non-competitive NMDA antagonist) were also not effective in blocking neurotoxicity induced by glucose oxidase generated oxygen radicals.

• Archives of Pharmacal Research
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• 제25권3호
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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.

• The Korean Journal of Physiology and Pharmacology
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• 제5권6호
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• pp.479-485
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• 2001

The existence of opioid receptors in mammalian cerebellum except human, has not been clearly understood. In the present study, we found that NPY was inducible by morphine in the mouse cerebellar granular and Purkinje cell layers. We performed in situ RT-PCR and immunohistochemistry to characterize the NPY expression. The increase of NPY gene expression by morphine (30 mg/kg, i.p.) was inhibited by pretreatment with not only naloxone (100 mg/kg, i.p.) but also a noncompetitive NMDA antagonist, MK-801 (0.3 mg/kg, i.p.). The competitive NMDA antagonist, AP-5 (0.9 mg/kg, i.p.) slightly attenuated the increased NPY expression by morphine. Also, the finding similar to morphine was shown by NMDA (70 mg/kg, i.p.) treatment. Our results indicate that NPY was inducible by morphine and this might reflect activation of NMDA receptors in granule cells that relay mossy fiber inputs to Purkinje cells via parallel fibers.