• 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.

• The Korean Journal of Pain
• /
• 제23권2호
• /
• pp.109-115
• /
• 2010

Background: The pathophysiological and neurochemical changes following spinal injury are not yet elucidated. This study was designed to evaluate the morphological changes of the dorsal horn of the spinal cord and profiles of pain behaviors following intraspinal injection of NMDA in rats. Methods: Rats were randomized into three groups: a sham-operated control group and groups where the rats received 10 mM or 100 mM N-methyl-D-aspatate (NMDA) injected into their spinal dorsal horn. Following injection, hypersensitivity to cold and mechanical stimuli and excessive grooming behaviors were assessed serially for four weeks. Morphological changes of the spinal cord were evaluated four weeks after intraspinal injection. Results: Few animals in the NMDA groups developed hypersensitivity to cold and mechanical stimuli. The number of groomers and the severity of excessive grooming were significantly higher in the 100 mM NMDA group than those values of the control and 10 mM NMDA groups. The size of the neck region (lamina III-IV) was significantly smaller in the 100 mM NMDA group than in the control and 10 mM NMDA groups. Conclusions: In conclusion, intraspinal injection of NMDA in rats leads to the pathological sequela in the spinal cord and to excessive grooming behavior. These results support the use of NMDA and excessive grooming behavior after excitotoxic SCI as a model to study chronic pain after SCI.

• Korean Journal of Veterinary Research
• /
• 제39권2호
• /
• pp.287-293
• /
• 1999

Isoeugenol, one of the phenylpropanoid derivatives has been known to inhibit the lipid peroxidation via scavenging effect on hydroxyl or superoxide radical production. We examined whether isoeugenol has a inhibitory effect against N-methyl-D-aspartate(NMDA)-, oxygen/glucose deprivation- and xanthine/xanthine oxidase(X/XO)-induced neurotoxicity or NMDA-induced $^{45}Ca^{+2}$ uptake elevation in primary mouse vertical cultures. We also evaluated whether isoeugenol exhibits inhibitory action on NMDA-induced convulsion in mice. Isoeugenol ($30{\sim}300{\mu}M$) attenuated NMDA- and X/XO-induced neurotoxicity by 11~85% and 83~92%, respectively. In the oxyge/glucose deprivation(60 min)-induced neurotoxicity, isoeugenol significantly(p<0.05) reduced by 32% at the maximal concentration. However, it failed to ameliorate NMDA-induced $^{45}Ca^{+2}$ uptake elevation. Isoeugenol(0.5g/kg, i.p.) delayed 6.5 times on the onset time of convulsion evoked by NMDA($0.1{\mu}g$) compared to that of control. These results suggest that the neuroprotective action of isoeugenol may be ascribed to the modulation of massive generation of reactive oxygen species(ROS) occurred during the ischemic or excitotoxic damage, not by directly affecting the NMDA receptor.

• The Korean Journal of Physiology and Pharmacology
• /
• 제13권3호
• /
• pp.209-214
• /
• 2009

The striatum receives glutamatergic afferents from the cortex and thalamus, and these synaptic transmissions are mediated by ${\alpha}$-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl D-aspartate (NMDA) receptors. The purpose of this study was to characterize glutamate receptors by analyzing NMDA/AMPA ratio and rectification of AMPA and NMDA excitatory postsynaptic currents (EPSCs) using a whole-cell voltage-clamp method in the dorsal striatum. Receptor antagonists were used to isolate receptor or subunit specific EPSC, such as (DL)-2-amino-5-phosphonovaleric acid (APV), an NMDA receptor antagonist, ifenprodil, an NR2B antagonist, CNQX, an AMPA receptor antagonist and IEM-1460, a GluR2-lacking AMPA receptor blocker. AMPA and NMDA EPSCs were recorded at - 70 and + 40 mV, respectively. Rectification index was calculated by current ratio of EPSCs between + 50 and - 50 mV. NMDA/AMPA ratio was 0.20${\pm}$0.05, AMPA receptor ratio of GluR2-lacking/GluR2-containing subunit was 0.26${\pm}$0.05 and NMDA receptor ratio of NR2B/NR2A subunit was 0.32${\pm}$0.03. The rectification index (control 2.39${\pm}$0.27) was decreased in the presence of both APV and combination of APV and IEM-1460 (1.02${\pm}$0.11 and 0.93${\pm}$0.09, respectively). These results suggest that the major components of the striatal glutamate receptors are GluR2-containing AMPA receptors and NR2A-containing NMDA receptors. Our results may provide useful information for corticostriatal synaptic transmission and plasticity studies.

• The Korea Journal of Herbology
• /
• 제20권2호
• /
• pp.115-125
• /
• 2005

Objectives : Polygalae Radix (PR) from Polygalae tenuifolia (Polygalaceae) has been clinically used as a sedative, anti-inflammatory, and anti-bacterial agent. To extend pharmacological effects of PR in the central nervous system (CNS) on the basis of its CNS protective effect, the present study was conducted to identify the effect of PR, whether it shows the neuroprotective action against excitatory neurotoxicity. Methods : To identify the protective effect of PR to excitatory neuro-toxic agent, the present study was focused on the PR effect on cell death, that was caused by applying NMDA to nerve cell, elevation of $(Ca^{2+})_i$, releasement of glutamate, and ROS generation. Result : 1. PR methanol extract, at the concentration range of 0.05 to 5 g/ml, significantly inhibited NMDA (1 mM)-induced neuronal cell death as well as MK-801 (non competitive NMDA antagonist). 2. PR methanol extract $(0.5\;{\mu}g/ml)$ inhibited NMDA (1 mM)-induced elevation of cytosolic calcium concentration $[Ca^{2+}]_i$. NMDA application in the presence of MK-801 $(10\;{\mu}M)$ failed to produce the increase of $[Ca^{2+}]_i$ through all the measurement time. 3. PR methanol extract $(0.5\;{\mu}g/ml)$ inhibited the NMDA-induced elevation of glutamate release. Also, MK-801 showed similar protective effects. 4. PR methanol extract $(0.5\;{\mu}g/ml)$ inhibited the NMDA-induced elevation of ROS generation. Also, MK-801 showed similar protective effects. Conclusion : The present study provides the availability of PR to exert its protective effect on the neuronal cell death in various neurodegenerative pathophysiological conditions.

• Archives of Pharmacal Research
• /
• 제22권1호
• /
• pp.48-54
• /
• 1999

These studies were designed to examine the differential effect of nitric oxide (NO) and cGMP on glutamate neurotransmission. In primary cultures of rat cerebellar granule cells, the glutamate receptor agonist N-methyl-D-aspartate (NMDA) stimulates the elevation of intracellular calcium concentration ($[Ca^{2+}]_i$), the release of glutamate, the synthesis of NO and an increase of cGMP. Although NO has been shown to stimulate guanylyl cyclase, it is unclear yet whether NO alters the NMDA-induced glutamate release and ${[Ca^{2+}]}_i$ elevation. We showed that the NO synthase inhibitor, NG-monomethyl-L-arginine (NMMA), partially prevented the NMDA-induced release of glutamate and elevation of ${[Ca^{2+}]}_i$ and completely blocked the elevation of cGMP. These effects of NO on glutamate release and [Ca2+]i elevation were unlikely to be secondary to cGMP as the cGMP analogue, dibutyryl cGMP (dBcGMP), did not suppress the effects of NMDA. Rather, dBcGMP slightly augmented the NMDA-induced elevation of ${[Ca^{2+}]}_i$ with no change in the basal level of glutamate or ${[Ca^{2+}]}_i$. The extracellular NO scavenger hydroxocobalamine prevented the NMDA-induced release of glutamate providing indirect evidence that the effect of NO may act on the NMDA receptor. These results suggest that low concentration of NO has a role in maintaining the NMDA receptor activation in a cGMP-independent manner.

• Archives of Pharmacal Research
• /
• 제18권3호
• /
• pp.153-158
• /
• 1995

The levels of extracellualr glutamate, intracellular $Ca^{2+}\;([Ca2+]_i)$ and cGMP were determined for 1 h with the excitatory amino acids, N-methyl-D-aspartate (NMDA) or kainate in cultured cerebellar granule cells. Both NMDA and kainate produced a time-dependent release of glutamate, and kainate was more potent than NMDA in glutamate elevation. The elevation of extracellular glutamate was not purely governed by intracellular $Ca^{2+}$ concentration. However, in opposite to the time-dependent elevation of glutamate, the elevation of cGMP by NMDA and kainate were at maximum level in short-time (1 min) incubation then remarkably decreased with longer incubation times. Post-applications (30 min after agonist) of EAA antagonist did not block EAAs-induced glutamate elevation. However, NMDA antagonist, phencyclidine (PCP), blocked NMDA-induced cGMP elevation at pre- or post-application, but kainate antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX), paradoxically augmented kainate-induced cGMP elevation for 1 h incubation. These results show that NMDA or kainate induces time-dependent elevations of extracellular glutamate, while the elevations of cGMP by these EAAs are remarkably decreased with longer incubation times. However, NMDA- arid kainate-indcued glutamate release was blocked by pre-application of each receptor antagonist but not by post-application while EAA-induced $[Ca^{2+}]_i$ was blocked by post-application of antagonist. These observations suggest that EAA-induced elevation of $[Ca^{2+}]_i$ is not parallel with elevation of glutamate release or cGMP.

• Proceedings of the Korean Society of Applied Pharmacology
• /
• 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.

• Korean Journal of Veterinary Research
• /
• 제38권2호
• /
• pp.290-296
• /
• 1998

Histological changes was investigated in the 4 weeks old rat brain using NMDA (N-methyl-D-asparate) which is capable of mediating excitotoxic events. The changes were occured when the injected NMDA solved in PBS was over $1.0{\mu}g/g$(about 90nM). The necrosis of Purkinje cells in cerebellum and the increasement of coloidal plexus cell number were prevalent. The Purkinje cell number of necrosis were increased according to increasement of amount of injected NMDA. In spite of increasement of degenerated Purkinje cell number, differentiation of new Purkinje cell was not identified because total number of Purkinje cell was not changed. The change of cell number was observed in coloidal plexus cell rather than degeneration of cell. About 5 time increasement was occured. This change may cause increasement of cerebrospinal fluid and the makes mophorogy of brain more round than nomal.

• The Korean Journal of Physiology and Pharmacology
• /
• 제5권5호
• /
• pp.389-396
• /
• 2001

Neuroprotective properties of lithium were investigated by using in vivo NMDA excitotoxicity model. The appearance of TUNEL positive cells was prominent within 24 h of NMDA (70 mg/kg, i.p.) injection in the regions of the cortex, hippocampal formation, and thalamus of mouse cerebrum. NMDA treatment resulted in the extensive enhancement of Bax immunoreactivity in the cortical and hippocampal regions. NMDA also increased the immunoreactivity of caspase 8 in the similar regions of the mouse cerebrum. However, the increased immunoreactivity of Bax and caspase 8 were dramatically attenuated by chronic lithium pretreatment (lithium chloride, 300 mg/kg/d, i.p. for $7{\sim}10$ days). At the same time, lithium ion blocked the appearance of TUNEL positive cells, and the morphological assessment indicated an effective neuroprotection by lithium against NMDA excitotoxicity. Although the exact action mechanism of lithium is not straightforward at this time, we propose that the inhibition of Bax and caspase cascade is involved in the neuroprotective action of lithium.