• 생명과학회지
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• 제19권4호
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• pp.532-537
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• 2009

알코올 의존과 N-methyl-D-aspartate (NMDA) 수용체와 밀접한 관계가 있을 수 있다는 연구들이 있는데, 즉 NMDA 수용체가 알코올의 금단, 내성의 발생과 관련이 있다는 연구 결과들이다. 그러나 NMDA 수용체 길항제가 알코올 의존의 재발 예방에 효과가 있을 것이라는 것에 대해서는 아직 논란이 되고 있다. 본 연구는 유전적으로 알코올을 선호하는 C57BL/6형 생쥐를 이용하여 유한접근법으로 NMDA 수용체 길항제인 memantine을 5, 25, 50 mg/kg으로 각각 투여하였을 때 알코올 섭취량에 미치는 영향을 알아보고자 하였다. 알코올 의존화된 C57BL/6형 수컷 생쥐를 5군으로 나눈 뒤, 12일간 각 군에 vehicle, naltrexone 1.0 mg/kg, memantine 5, 25, 50 mg/kg으로 각각 투여하면서 알코올의 섭취량, 물 섭취량, 사료 섭취량 및 체중을 조사하였다. 본 연구의 결과, 2시간 알코올 섭취량의 12일간 변화에 대해 vehicle 투여군과 naltrexone, memantine 5, 25, 50 mg/kg 투여군 각각의 군을 repeated measure ANOVA를 이용하여 비교하였을 때, naltrexone (df=4, F=11.827, p<0.01), memantine 5 mg/kg (df=4, F=7.999, p<0.01), memantine 25 mg/kg (df=4, F=6.199, p<0.05) 및 memantine 50 mg/kg (df=4, F=10.522, p<0.01) 투여군에서 각각 유의한 군과 일수의 상호작용을 보였다. 그러나 22시간 물 섭취량, 24시간 사료섭취량 및 체중의 12일간 변화에 대해서는 vehicle 투여군과 memantine 투여군 3군 각각에서 유의한 상호작용이 없었다. 한편, vehicle 투여군과 naltrexone 투여군 간에는 체중의 변화에서 유의한 군과 일수의 상호작용을 보였고, 22시간 물 섭취량 및 24시간 사료 섭취량에서는 유의한 상호 작용이 없었다. 이상의 결과는 NMDA 수용체 길항제인 memantine을 생쥐에게 투여하였을 때 알코올 섭취량에 영향을 줄 수 있다는 것을 의미한다. 이는 앞으로 부작용은 적으면서 치료 효과는 우수한 알코올 의존 재발 예방 치료제 개발의 가능성을 제안하고 있다.

• Journal of Korean Neurosurgical Society
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• 제60권2호
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• pp.130-137
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• 2017

Objective : Autophagy is one of the key responses of cells to programmed cell death. Memantine, an approved anti-dementia drug, has an antiproliferative effect on cancer cells but the mechanism is poorly understood. The aim of the present study was to test the possibility of induction of autophagic cell death by memantine in glioma cell lines. Methods : Glioma cell lines (T-98 G and U-251 MG) were used for this study. Results : The antiproliferative effect of memantine was shown on T-98 G cells, which expressed N-methyl-D-aspartate 1 receptor (NMDAR1). Memantine increased the autophagic-related proteins as the conversion ratio of light chain protein 3-II (LC3-II)-/LC3-I and the expression of beclin-1. Memantine also increased formation of autophagic vacuoles observed under a transmission electron microscope. Transfection of small interfering RNA (siRNA) to knock down NMDAR1 in the glioma cells induced resistance to memantine and decreased the LC3-II/LC3-I ratio in T-98 G cells. Conclusion : Our study demonstrates that in glioma cells, memantine inhibits proliferation and induces autophagy mediated by NMDAR1.

• The Korean Journal of Physiology and Pharmacology
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• 제27권5호
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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.

• 분석과학
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• 제6권4호
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• pp.405-409
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• 1993

Memantine HCl을 자외부 유도화제인 MPCN과 반응시켜 흡광광도법으로 정량하였다. 유도화반응은 pH 5, $50^{\circ}C$에서 MPCN을 1:20배 몰비로 사용하여 30분간 반응시켰으며 dichloromethane으로 추출한 후 324.5nm에서 흡광도를 측정하였다. 그 결과 memantine HCl의 최종 농도로써 $5.0{\times}10^{-6}{\sim}6.5{\times}10^{-5}M$ 사이에서 직선성을 나타냈으며 detection limit는 $0.43{\mu}g/ml$이었다. 본 분석법을 제제에 적용하였을 때 주사제는 $100.08{\pm}0.72%$였고 정제는 $99.75{\pm}0.77%$로, 부형제에 의한 영향 없이 간편하고 신속하게 재현성 있는 결과를 나타내므로 의약품의 품질관리에 효과적으로 응용될 수 있으리라 사료된다.

• The Korean Journal of Pain
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• 제23권3호
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• pp.179-185
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• 2010

Background: Vincristine-induced peripheral neuropathy is a major dose limiting side effect and thus effective therapeutic strategy is required. In this study, we investigated the antinociceptive effect of memantine and morphine on a vincristine-induced peripheral neuropathy model in rats. Methods: Male Sprague-Dawley rats weighing 220-240 g were used in all experiments. Rats subsequently received daily intraperitoneal injections of either vincristine sulfate (0.1 ml/kg/day) or saline (0.1 ml/kg/day) over 12 days, immediately following behavioral testing. For assessment of mechanical allodynia, mechanical stimuli using von Frey filament was applied to the paw to measure withdrawal threshold. The effects of N-methyl-D-aspartate receptors antagonist (memantine; 2.5, 5, 10 mg/kg intraperitoneal), opioid agonist (morphine; 2.5, 5, 10 mg/kg intraperitoneal) and vehicle (saline) on vicristine-induced neuropathy were evaluated. Results: Mechanical allodynia developed over the course of ten daily injections of vincristine relative to groups receiving saline at the same time. Morphine abolished the reduction in paw withdrawal threshold compared to vehicle and produced dose-responsiveness. Only the highest dose of memantine (10 mg/kg) was able to increase paw withdrawal threshold compared to vehicle. Conclusions: Systemic morphine and memantine have an antinociceptive effect on the vincristine-induced peripheral neuropathy model in rats. These results suggest morphine and memantine may be an alternative approach for the treatment of vincristine-induced peripheral neuropathic pain.

• The Korean Journal of Physiology and Pharmacology
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• 제16권4호
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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.

• 대한예방한의학회지
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• 제15권3호
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• pp.39-49
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• 2011

Objectives : Vascular dementia is the second common cause of dementia after Alzheimer's disease. It assumed that the ratio of prescription drugs on vascular dementia are quite different from each hospital in Western medicine or Oriental medicine, respectively. The aim of this research is to collect and analyze the ratio of prescription drugs on vascular dementia in Western medicine or Oriental medicine in university hospitals. Methods : We collected and analyzed the data related to prescriptions on vascular dementia in the department of neurology in three university hospitals(A, B, C) and in the department of internal medicine in two Oriental medicine hospitals(Daegu Haany Oriental Hospital, Dong Eui Oriental Hospital). Results : In the department of neurology in A university hospital, donepezil(69.1%), memantine(14.0%), rivastigmine(12.3%), galantamine(4.5%) were prescribed in order. In B university hospital, galantamine(57.8%) donepezil(33.3%), rivastigmine(6.7%), donepezil with memantine(4.4%) were prescribed. In C university hospital, donepezil(62.0%), rivastigmine(25.0%), galantamine(7.0%) memantine(6.0%) were prescribed. The average frequencies of prescribed medication in the department of neurology in A, B, C university hospitals were donepezil(54.8%), galantamine(23.1%), rivastigmine(14.7%), memantine(7.4%). In Oriental medicine hospitals, various prescriptions have been used for vascular dementia. Among them, Ansincheongnoetang (安神淸腦湯) and Gamijihangeumja(加味地黃飮子) were often prescribed in Daegu Haany Oriental Hospital, and Bojungikgitang(補中益氣湯) in Dong Eui Oriental Hospital, too. Conclusions : Cholinesterase inhibitors such as donepezil, galantamine, rivastigmine and NMDA receptor inhibitor like memantine have been used as a drug of choice for vascular dementia in all surveyed university hospitals. In oriental hospitals, various prescriptions have been used for vascular dementia.

• The Korean Journal of Pain
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• 제22권3호
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• pp.210-215
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• 2009

Background: Several studies have indicated that a nerve injury enhances the expression of the voltage-gated calcium channel ${\alpha}2{\delta}1$ subunit (Cav ${\alpha}2{\delta}1$) in sensory neurons and the dorsal spinal cord. This study examined whether NMDA receptor activation is essential for Cav ${\alpha}2{\delta}1$-mediated tactile allodynia in Cav ${\alpha}2{\delta}1$ overexpressing transgenic mice and L5/6 spinal nerve ligated rats (SNL). These two models show similar Cav ${\alpha}2{\delta}1$ upregulation and behavioral hypersensitivity, without and with the presence of other injury factors, respectively. Methods: The transgenic (TG) mice were generated as described elsewhere (Feng et al., 2000). The left L5/6 spinal nerves in the Harlan Sprague Dawley rats were ligated tightly (SNL) to induce neuropathic pain, as described by Kim et al. (1992). Memantine 2 mg/kg (10 ul) was injected directly into the L5/6 spinal region followed by $10{\mu}l$ saline. Tactile allodynia was tested for any mechanical hypersensitivity. Results: The tactile allodynia in the SNL rats could be reversed by an intrathecal injection of memantine 2 mg/kg at 1.5 hours. The tactile allodynia in the Cav ${\alpha}2{\delta}1$ over-expressing TG mice could be reversed by an intrathecal injection of memantine 2 mg/kg at 1.5, 2.0 and 2.5 hours. Conclusions: The behavioral hypersensitivity was similar in the TG mice and nerve injury pain model, supporting the hypothesis that elevated Cav ${\alpha}2{\delta}1$ mediates similar pathways that underlie the pain states in both models. The selective activation of spinal NMDA receptors plays a key role in mediating the pain states in both the nerve-injury rats and TG mice.

• 대한의사협회지
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• 제61권12호
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• pp.758-764
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• 2018

Dementia is a clinical syndrome characterized by a cluster of symptoms and signs that manifest as difficulties in cognitive functions such as memory, psychological and psychiatric changes, and impairments in activities of daily living. As a result of worldwide trends of population aging, dementia has had a huge impact on public health in almost all countries. Disease modification therapies for dementia have not yet been developed. However, pharmacotherapy is essential in patients with dementia to combat delays in their cognitive and functional decline. In this article, we review the current pharmacotherapy for dementia. Three acetylcholinesterase inhibitors-donepezil, rivastigmine, galantamine-and memantine are the only medications that have been approved for the treatment of dementia. We present the indications, dose recommendations, side effects, and criteria for National Health Insurance coverage in Korea of these medications for dementia treatment. Although the Ministry of Food and Drug Safety in Korea has not approved any medications for managing the behavioral and psychological symptoms of dementia, some antipsychotics and antidepressants have been studied and used clinically for those purposes. Clinicians may consider vitamin E, Ginkgo biloba extract, choline alfoscerate, or omega-3 fatty acids as additional treatment options. Non-steroid anti-inflammatory drugs, estrogen hormone therapy, and statins are not generally recommended for dementia treatment. We believe that our findings will aid clinicians in the treatment of patients with cognitive decline.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1996년도 춘계학술대회
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• pp.19-29
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• 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.