• Archives of Pharmacal Research
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• v.24 no.1
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• pp.64-68
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• 2001

Endothelin-1 (ET-1 ), a novel and potent vasoconstrictor in blood vessel, is known to have some functions in the rat central nervous system (CNS), In order to investigate the central functions of ET-1 , ET-1 was administered to the periaqueductal gray area (PAC) of anesthetized rats to induce barrel rolling and increase the arterial blood pressure (ABP). ET-1 had a modulatory effect on central cardiovascular and behavioral control. The selective N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (3${u}m/ol/kg$, i.p.) blocked the ET-1 induced responses, and both the nitric oxide synthase (NOS) inhibitor L-NAME (N-nitro-L-arginine mIThyl-ester 1 nmol/rat) and the nitric oxide (NO) scavenger hemoglobin (15 nmol/rat) had similar effects in redtAcing the IT-1 (10 pmol/rat)-induced behavioral changes and ABP elevation. However, NO donor sodium nitroprusside (SNP 10${u}g$, 1${u}g/rat$) decreased the ET-1 induced ABP elevation, and recovered the ET-1 -induced barrel rolling effect that was reduced by MK-801. These results suggest that ET-1 might have neuromodulatory functions such as ABP elevation and barrel rolling induction in the PAG of the rats via the NMDA receptor and NO.

• The Korean Journal of Pharmacology
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• v.30 no.3
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• pp.273-289
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• 1994

Reversible brain ischemia was produced by occluding both common carotid arteries for 5 min, and the effects of aminoguanidine (AG), $DL-{\alpha}-difluoromethylornithine$ (DFMO), MK-801, and nimodipine (NM) on the ischemia induced changes of the polyamine, glutamate and acetylcholine levels in the hippocampus CA1 subfield and the specific $[^3H]\;MK-801$ binding to the hippocampus synaptosomal membranes were studied with a histological reference of the cresyl violet stained hippocampus. The basal putrescine level $(PT:\;74.4{\pm}8.8\;nM)$ showed a rapid increase (up to 1.7 fold) for 5 min of ischemia, remained significantly increased for 6 h, and then resumed the further increase to amount gradually up to about 3 fold 96 h after recirculation. However, the level of spermidine was little changed, and the spermine level showed a transient increase during ischemia followed by a sustained decrease to about 40% of the preischemic level after recirculation. The increase of PT level induced by brain ischemia was enhanced with AG or MK-801, but it was reduced by DFMO or NM. The basal glutamate level $(GT:\;0.90{\pm}0.l4\;{\mu}M)$ rapidly increased to a peak level of $8.19{\pm}1.14\;{\mu}M$ within 5 min after onset of the ischemia and then decreased to the preischemic level in about 25 min after recirculation. And NM reduced the ischemia induced increase of GT level by about 25%, but AG, DFMO and MK-801 did not affect the GT increase. The basal acetylcholine level $(ACh:\;118.0{\pm}10.5\;{\mu}M)$ did little change during/after brain ischemia and was little affected by AG or NM. But DFMO and MK-801, respectively, produced the moderate decrease of ACh level. The specific $[^3H]\;MK-801$ binding to the hippocampus synaptosomal membrane was little affected by brain ischemia for 5 min. The control value (78.9 fmole/mg protein) was moderately decreased by AG and MK-801, respectively but was little changed by DFMO or NM. The microscopic findings of the brains extirpated on day 7 after ischemia showed severe neuronal damage of the hippocampus, particularly CA1 subfield. NM and AG moderately attenuated the delayed neuronal damage, and DFMO, on the contrary, aggravated the ischemia induced damage. However, MK-801 did not protect the hippocampus from ischemic damage. These results suggest that unlike to the mode of anti-ischemic action of NM, AG might protect the hippocampus from ischemic injury as being negatively regulatory on the N-methyl-D-aspartate (NMDA) receptor function in the hippocampus.

• The Korean Journal of Physiology and Pharmacology
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• v.12 no.2
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• pp.43-49
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• 2008

Flavonoids have been shown to affect calcium signaling in neurons. However, there are no reports on the effect of apigenin on glutamate-induced calcium signaling in neurons. We investigated whether apigenin affects glutamate-induced increase of free intracellular $Ca^{2+}$ concentration ($[Ca^{2+}]_i$) in cultured rat hippocampal neurons, using fura-2-based digital calcium imaging and microfluorimetry. The hippocampal neurons were used between 10 and 13 days in culture from embryonic day 18 rats. Pretreatment of the cells with apigenin ($1{\mu}M$ to $100{\mu}M$) for 5 min inhibited glutamate ($100{\mu}M$, 1 min) induced $[Ca^{2+}]_i$ increase, concentration-dependently. Pretreatment with apigenin ($30{\mu}M$) for 5 min significantly decreased the $[Ca^{2+}]_i$ responses induced by two ionotropic glutamate receptor agonists, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA, $10{\mu}M$, 1 min) and N-methyl-D-aspartate (NMDA, $100{\mu}M$, 1 min), and significantly inhibited the AMPA-induced peak currents. Treatment with apigenin also significantly inhibited the $[Ca^{2+}]_i$ response induced by 50 mM KCl solution, decreased the $[Ca^{2+}]_i$ responses induced by the metabotropic glutamate receptor agonist, (S)-3,5-dihydroxy-phenylglycine (DHPG, 100 $[Ca^{2+}]_i$, 90 s), and inhibited the caffeine (10 mM, 2 min)-induced $[Ca^{2+}]_i$ responses. Furthermore, treatment with apigenin ($30{\mu}M$) significantly inhibited the amplitude and frequency of 0.1 mM $[Mg^{2+}]_o$-induced $[Ca^{2+}]_i$ spikes. These data together suggest that apigenin inhibits glutamate-induced calcium signaling in cultured rat hippocampal neurons.

• Korean Journal of Biological Psychiatry
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• v.8 no.1
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• pp.3-19
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• 2001

Recent basic and clinical studies demonstrate a major role for neural plasticity in the etiology and treatment of depression and stress-related illness. The neural plasticity is reflected both in the birth of new cell in the adult brain(neurogenesis) and the death of genetically healthy cells(apoptosis) in the response to the individual's interaction with the environment. The neural plasticity includes adaptations of intracellular signal transduction pathway and gene expression, as well as alterations in neuronal morphology and cell survival. At the cellular level, repeated stress causes shortening and debranching of dendrite in the CA3 region of hippocampus and suppress neurogenesis of dentate gyrus granule neurons. At the molecular level, both form of structural remodeling appear to be mediated by glucocorticoid hormone working in concert with glutamate and N-methyl-D-aspartate(NMDA) receptor, along with transmitters such as serotonin and GABA-benzodiazepine system. In addition, the decreased expression and reduced level of brain-derived neurotrophic factor(BDNF) could contribute the atrophy and decreased function of stress-vulnerable hippocampal neurons. It is also suggested that atrophy and death of neurons in the hippocampus, as well as prefrontal cortex and possibly other regions, could contribute to the pathophysiology of depression. Antidepressant treatment could oppose these adverse cellular effects, which may be regarded as a loss of neural plasticity, by blocking or reversing the atrophy of hippocampal neurons and by increasing cell survival and function via up-regulation of cyclic adenosine monophosphate response element-binding proteins(CREB) and BDNF. In this article, the molecular and cellular mechanisms that underlie stress, depression, and action of antidepressant are precisely discussed.

• The Korean Journal of Pain
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• v.13 no.1
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• pp.31-37
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• 2000

Background: Recent studies suggested that a preoperative block of N-methyl-D-aspartate (NMDA) receptors with NMDA antagonists may reduce postoperative pain. In this double-blind study, magnesium sulfate, a natural NMDA receptor antagonist, was administered preoperatively to investigate the effects of magnesium sulfate on postoperative pain and pulmonary function. Methods: Seventy patients who were to undergo gastrectomy under general anesthesia were randomly assigned to one of three groups. Groups 2 and 3 received intravenous magnesium, preoperatively (Group 2: 50 mg/kg bolus, 7.5 mg/kg/hr for 20 hr, Group 3: 50 mg/kg bolus, 15 mg/kg/hr for 20 hr). Group 1 received normal saline as the control group. Visual analog scale (VAS) for postoperative pain and mood, cumulative analgesic consumption, recovery of pulmonary function and side effects were evaluated at 6, 24, 48 and 72 hours after the operation. Results: In Groups 2 and 3, plasma concentration of magnesium were significantly higher than in Group 1 at 6 and 20 hours after infusion (P<0.05). There were no significant differences in the analgesic consumption, and recovery of pulmonary function and the incidence of side effects at 6, 24, 48 and 72 hours after the operation among the three groups. In Group 3, pain scores at rest measured 24 and 48 hours after operation were lower than the control group, and pain scores when deep breathing were significantly lower than the control group at postoperative 6, 24, 48, and 72 hours. Conclusions: We conclude that intravenous infusion of greater amount of magnesium has little effectiveness in reducing postoperative pain. However, further studies are needed to characterize the clinical significance of these effects on postoperative pain.

• The Korean Journal of Pain
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• v.18 no.2
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• pp.138-141
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• 2005

Background: There have been many attempts to alleviate pain after surgery, but there is no common approach to the control of postoperative pain. The use of epidural opioids, with local anesthetics, has been a widely employed formula to date. Ketamine, an N-methyl-d-aspartate receptor antagonist, has an excellent analgesic effect. Although there have been many reports on the dose and route of administrating analgesics, there have been few concerning the continuous epidural infusion of ketamine with fentanyl. We designed this study to find the effects of ketamine compared to those of epidurally injected bupivacaine and fentanyl, and used this trial to study any potential side effects. Methods: In a double blind trial, 55 patients received either fentanyl, $0.3{\mu}g/kg/h$ (Group F), or fentanyl, $0.3{\mu}g/kg/h$, and ketamine, 0.1 mg/kg/h (Group FK), added to 0.125% bupivacaine, at rates as high as 2 ml/h, for patient controlled epidural analgesia (PCEA) following a transabdominal hysterectomy. Ten minutes before the operation, patients received 10 ml of 0.125% bupivacaine, with either 0.5 mg/kg ketamine or the same amount of normal saline with $50{\mu}g$ fentanyl added. The pain scores and the side effects were recorded at 1, 3, 6 and 24 hour post operation. Results: There were no differences in the pain scores or side effects between the two groups. Conclusions: We failed to find any effect of the addition of epidural ketamine compared to the that of the bupivacaine and fentanyl formula. However, it is suggested that further investigations will be required on the dose and route of administration.

• The Korean Journal of Physiology and Pharmacology
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• v.16 no.4
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• pp.231-236
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• 2012

We studied the effects of acetylcholinesterase inhibitors, donepezil and galantamine, and an N-methyl-D-aspartate (NMDA) receptor blocker, memantine, on sleep-wake architecture in rats. Screw electrodes were chronically implanted into the frontal and parietal cortex for the electroencephalography (EEG). EEG was recorded with a bio-potential amplifier for 8 h from 09:30 to 17:30. Vibration was recorded to monitor animal activity with a vibration measuring device. Sleep-wake states such as wake (W), slow-wave sleep (S) and paradoxical or rapid eye movement sleep (P), were scored every 10 sec by an experimenter. We measured mean episode duration and number of episode to determine which factor sleep disturbance was attributed to. Donepezil and memantine showed a significant increase in total W duration and decreases in total S and P duration and delta activity. Memantine showed increases in sleep latency and motor activity. Changes of S and P duration in memantine were attributed from changes of mean episode duration. Galantamine had little effect on sleep architecture. From these results, it is showed that galantamine may be an anti-dementia drug that does not cause sleep disturbances and memantine may be a drug that causes severe sleep disturbance.

• The Korean Journal of Pain
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• v.23 no.2
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• pp.99-108
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• 2010

Chronic pain is a multifactorial condition with both physical and psychological symptoms, and it affects around 20% of the population in the developed world. In spite of outstanding advances in pain management over the past decades, chronic pain remains a significant problem. This article provides a mechanism- and evidence-based approach to improve the outcome for pharmacologic management of chronic pain. The usual approach to treat mild to moderate pain is to start with a nonopioid analgesic. If this is inadequate, and if there is an element of sleep deprivation, then it is reasonable to add an antidepressant with analgesic qualities. If there is a component of neuropathic pain or fibromyalgia, then a trial with one of the gabapentinoids is appropriate. If these steps are inadequate, then an opioid analgesic may be added. For moderate to severe pain, one would initiate an earlier trial of a long term opioid. Skeletal muscle relaxants and topicals may also be appropriate as single agents or in combination. Meanwhile, the steps of pharmacologic treatments for neuropathic pain include (1) certain antidepressants (tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors), calcium channel ${\alpha}2-{\delta}$ ligands (gabapentin and pregabalin) and topical lidocaine, (2) opioid analgesics and tramadol (for first-line use in selected clinical circumstances) and (3) certain other antidepressant and antiepileptic medications (topical capsaicin, mexiletine, and N-methyl-d-aspartate receptor antagonists). It is essential to have a thorough understanding about the different pain mechanisms of chronic pain and evidence-based multi-mechanistic treatment. It is also essential to increase the individualization of treatment.

• The Korean Journal of Pain
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• v.26 no.3
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• pp.270-276
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• 2013

Background: Ketamine, an N-methyl-D-aspartate receptor antagonist, might play a role in postoperative analgesia, but its effect on postoperative pain after caesarean section varies with study design. We investigated whether the preemptive administration of low-dose intravenous ketamine decreases postoperative opioid requirement and postoperative pain in parturients receiving intravenous fentanyl with patient-controlled analgesia (PCA) following caesarean section. Methods: Spinal anesthesia was performed in 40 parturients scheduled for elective caesarean section. Patients in the ketamine group received a 0.5 mg/kg ketamine bolus intravenously followed by 0.25 mg/kg/h continuous infusion during the operation. The control group received the same volume of normal saline. Immediately after surgery, the patients were connected to a PCA device set to deliver 25-${\mu}g$ fentanyl as an intravenous bolus with a 15-min lockout interval and no continuous dose. Postoperative pain was assessed using the cumulative dose of fentanyl and visual analog scale (VAS) scores at 2, 6, 24, and 48 h postoperatively. Results: Significantly less fentanyl was used in the ketamine group 2 h after surgery (P = 0.033), but the difference was not significant at 6, 12, and 24 h postoperatively. No significant differences were observed between the VAS scores of the two groups at 2, 6, 12, and 24 h postoperatively. Conclusions: Intraoperative low-dose ketamine did not have a preemptive analgesic effect and was not effective as an adjuvant to decrease opioid requirement or postoperative pain score in parturients receiving intravenous PCA with fentanyl after caesarean section.

• BMB Reports
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• v.46 no.2
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• pp.103-106
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• 2013

Phosphoinositide 3-kinases (PI3Ks) play key roles in synaptic plasticity and cognitive functions in the brain. We recently found that genetic deletion of $PI3K{\gamma}$, the only known member of class IB PI3Ks, results in impaired N-methyl-D-aspartate receptor-dependent long-term depression (NMDAR-LTD) in the hippocampus. The activity of RalA, a small GTP-binding protein, increases following NMDAR-LTD inducing stimuli, and this increase in RalA activity is essential for inducing NMDAR-LTD. We found that RalA activity increased significantly in $PI3K{\gamma}$ knockout mice. Furthermore, NMDAR-LTD-inducing stimuli did not increase RalA activity in $PI3K{\gamma}$ knockout mice. These results suggest that constitutively increased RalA activity occludes further increases in RalA activity during induction of LTD, causing impaired NMDAR-LTD. We propose that $PI3K{\gamma}$ regulates the activity of RalA, which is one of the molecular mechanisms inducing NMDAR-dependent LTD.