• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1993년도 제2회 신약개발 연구발표회 초록집
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• pp.161-161
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• 1993

중추 Cholinergic성 신경계 작용약의 유발한 치매동물 모델의 타당성 여부를 확인하기 위해 흰쥐에 Scopolamine, Physostigmine 및 생약을 반복 투여하였을 때의 active avoidance에 미치는 영향을 단회 투여하여 가역적인 작용을 가질때의 영향과 비교하고 이때 대뇌피질에서의 Cholinergic성 신경계의 활성 변화를 측정하여 중추 Cholinergic성 신경계의 학습, 기억 과정에서의 역할 및 나아가 치매의 발생 원인 및 발병 져로 규명에 접근하고자 하였다. 6 주된 Wistar계 웅성 래트에 Cholinergic성 신경계 작용약인 Scopolamine(1 mg/kg), Posostigmine (0.1mg/kg)과 생약인 Ginseng Total Saponine(100 mg/kg), 오미자 추출물 (150 mg/kg)등을 단독 혹은 병용으로 피하와 복강내로 7 일간 반복 투여하면서 Shuttle Box를 이용하여 Active Avoidance 의 습득율을 측정하고 이후 실험동물을 단두치사하여 대뇌피질 영역에서의 Acetylcholine 농도와 Acetylcholinesterase 활성 변화를 Chemi luminosence 법을 이용하여 측정하였다.

• The Korean Journal of Physiology and Pharmacology
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• 제17권4호
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• pp.331-338
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• 2013

AMP-activated protein kinase (AMPK), an important regulator of energy metabolism, is activated in response to cellular stress when intracellular levels of AMP increase. We investigated the neuroprotective effects of AMPK against scopolamine-induced memory impairment in vivo and glutamate-induced cytotoxicity in vitro. An adenovirus expressing AMPK wild type alpha subunit (WT) or a dominant negative form (DN) was injected into the hippocampus of rats using a stereotaxic apparatus. The AMPK WT-injected rats showed significant reversal of the scopolamine induced cognitive deficit as evaluated by escape latency in the Morris water maze. In addition, they showed enhanced acetylcholinesterase (AChE)-reactive neurons in the hippocampus, implying increased cholinergic activity in response to AMPK. We also studied the cellular mechanism by which AMPK protects against glutamate-induced cell death in primary cultured rat hippocampal neurons. We further demonstrated that AMPK WT-infected cells increased cell viability and reduced Annexin V positive hippocampal neurons. Western blot analysis indicated that AMPK WT-infected cells reduced the expression of Bax and had no effects on Bcl-2, which resulted in a decreased Bax/Bcl-2 ratio. These data suggest that AMPK is a useful cognitive impairment treatment target, and that its beneficial effects are mediated via the protective capacity of hippocampal neurons.

• The Korean Journal of Physiology and Pharmacology
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• 제21권1호
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• pp.55-64
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• 2017

Progressive memory impairment such as that associated with depression, stroke, and Alzheimer's disease (AD) can interfere with daily life. In particular, AD, which is a progressive neurodegenerative disorder, prominently features a memory and learning impairment that is related to changes in acetylcholine and abnormal ${\beta}$-amyloid ($A{\beta}$) deposition in the brain. In the present study, we investigated the effects of dehydroevodiamine HCl (DHED) on cognitive improvement and the related mechanism in memory-impaired rat models, namely, a scopolamine-induced amnesia model and a $A{\beta}_{1-42}$-infused model. The cognitive effects of DHED were measured using a water maze test and a passive avoidance test in the memory-impaired rat models. The results demonstrate that DHED (10 mg/kg, p.o.) and Donepezil (1 mg/kg, p.o.) ameliorated the spatial memory impairment in the scopolamine-induced amnestic rats. Moreover, DHED significantly improved learning and memory in the $A{\beta}_{1-42}$-infused rat model. Furthermore, the mechanism of these behavioral effects of DHED was investigated using a cell viability assay, reactive oxygen species (ROS) measurement, and intracellular calcium measurement in primary cortical neurons. DHED reduced neurotoxicity and the production of $A{\beta}$-induced ROS in primary cortical neurons. In addition, similar to the effect of MK801, DHED decreased intracellular calcium levels in primary cortical neurons. Our results suggest that DHED has strong protective effects against cognitive impairments through its antioxidant activity and inhibition of neurotoxicity and intracellular calcium. Thus, DHED may be an important therapeutic agent for memory-impaired symptoms.

• Biomolecules & Therapeutics
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• 제21권5호
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• pp.405-410
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• 2013

Codonopsis lanceolata (Campanulaceae) traditionally have been used as a tonic and to treat patients with lung abscesses. Recently, it was proposed that the extract and some compounds isolated from C. lanceolata reversed scopolamine-induced memory and learning deficits. The purpose of this study was to evaluate the improvement of cognitive enhancing effect of C. lanceolata by steam and fermentation process in scopolamine-induced memory impairment mice models by passive avoidance test and Morris water maze test. The extract of C. lanceolata or the extract of steamed and fermented C. lanceolata (SFCE) was orally administered to male mice at the doses of 100 and 300 mg/kg body weight. As a result, mice treated with steamed and fermented C. lanceolata extract (SFCE) (300 mg/kg body weight, p.o.) showed shorter escape latencies than those with C. lanceolata extract or the scopolamine-administered group in Morris water maze test. Also, it exerted longer step-through latency time than scopolamine treated group in passive avoidance test. Furthermore, neuroprotective effect of SFCE on glutamate-induced cytotoxicity was assessed in HT22 cells. Only SFCE-treated cells showed significant protection at 500 ${\mu}g/ml$. Interestingly, steamed C. lanceolata with fermentation contained more phenolic acid including gallic acid and vanillic acid than original C. lanceolata. Collectively, these results suggest that steam and fermentation process of C. lanceolata increased cognitive enhancing activity related to the memory processes and neuroprotective effect than original C. lanceolata.

• 대한본초학회지
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• 제35권5호
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• pp.33-39
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• 2020

Objectives : Increasing evidence supports the biological and pharmacological activities of essential oils on the central nervous system such as pain, anxiety, attention, arousal, relaxation, sedation and learning and memory. The purpose of present work is to investigate the protective effect and molecular mechanism of cypress essential oil (CEO) against scopolamine (SCO)-induced cognitive impairments in C57BL/6 mice. Methods : A series of behavior tests such as Morris water maze, passive avoidance, and fear conditioning tests were conducted to monitor learning and memory functions. Immunoblotting and RT-PCR were also performed in the hippocampal tissue to determine the underlying mechanism of CEO. Results : SCO induced cognitive impairments as assessed by decreased step-through latency in passive avoidance test, relatively low freezing time in fear conditioning test, and increased time spent to find the hidden platform in Morris water maze test. Conversely, CEO inhalation significantly reversed the SCO-induced cognitive impairments in C57BL/6 mice comparable to control levels. To elucidate the molecular mechanisms of memory enhancing effect of CEO we have examined the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. CEO effectively elevated the protein as well as mRNA expression of BDNF via activation of cAMP response element binding protein (CREB). Conclusions : Our findings suggest that CEO inhalation effectively restored the SCO-impaired cognitive functions in C56BL/6 mice. This learning and memory enhancing effect of CEO was partly mediated by up-regulation of BDNF via activation of CREB.

• Advances in Traditional Medicine
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• 제7권2호
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• pp.182-190
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• 2007

Alzheimer's disease is a neurodegenerative disorder associated with a decline in cognitive abilities. Dementia is one of the aged related mental problems and a characteristic symptom of Alzheimer's disease. Nootropic agents like piracetam and cholinesterase inhibitors like $Donepezil^{\circledR}$ are used in situations where there is organic disorder in learning abilities, but the resulting side-effects associated with these agents have limited their utility. Foeniculum (F.) vulgare Linn. is widely used in Indian traditional systems of medicines and also as a house remedy for nervous debility. The present work was undertaken to assess the potential of F. vulgare as a nootropic and anti-cholinesterase agent in mice. Exteroceptive behavioral models such as Elevated plus maze and Passive avoidance paradigm were employed to assess short term and long term memory in mice. To delineate the possible mechanism through which F. vulgare elicits the anti-amnesic effects, its influence on central cholinergic activity was studied by estimating the whole brain acetylcholinesterase activity. Pretreatment of methanolic extract of fruits of F. vulgare Linn. for 8 successive days, ameliorated the amnesic effect of scopolamine (0.4 mg/kg) and aging induced memory deficits in mice. F. vulgare extract significantly decreased transfer latencies of young mice and aged mice, increased step down latency and exhibited significant anti-acetyl cholinesterase effects, when compared to piracetam, scopolamine and control groups of mice. F. vulgare might prove to be a useful memory restorative agent in the treatment of dementia seen in the elderly.

• 동의생리병리학회지
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• 제35권3호
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• pp.97-103
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• 2021

Perilla frutescens (P. frutescens) is an important herb used for many purposes such as medicinal, aromatic, and functional food in Asian countries and has beneficial effects such as antioxidant activity, anti-inflammation activity, anti-depression activity, and anxiolytic activity. However, there have been no studies on the protective effect of P. frutescens extract (PFE) on amnesia in vivo. The present study aimed to investigate whether PFE protects memory deficit using a scopolamine-induced mice model and elucidate the underlying mechanisms involved. The protective effect of PFE against scopolamine-induced memory deficits was investigated using Y-maze, passive avoidance, and Morris water maze tests. Furthermore, the potential mechanisms of PFE in improving memory capabilities related to the cholinergic system and antioxidant activity were examined. PFE significantly increased spontaneous alternation in the Y-maze test, step-through latency in the passive avoidance test, and swimming time in the target quadrant in the probe test when compared to the scopolamine-treated group. Likewise, PFE significantly decreased escapes latency in the Morris water maze test. PFE could not regulate cholinergic function in acetylcholine level and acetylcholine esterase activity. However, PFE increased DPPH radical scavenging activity dose-dependently and total polyphenol content was 127.7±1.2 ㎍ GAE/mg. The results showed that the PFE could be a preventive and/or therapeutic candidate for memory and cognitive dysfunction in Alzheimer's disease.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1992년도 제1회 신약개발 연구발표회 초록집
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• pp.43-43
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• 1992

최근 수년 전부터 학습(learning), 기억(memory)의 분자약리학적 기전과 치매(dementia)의 신경생리학적 원인 규명에 대한 연구가 사회적 요구에 부응하여 증가하고 있다. 이에 본 연구에서는 횐쥐를 이용하여 실험실적 건망모델을 설정하여 항치매 물질의 효력 screening을 시도하였다. 실험실적 건망모델은 다음 두 가지 방법으로 설정하였다. 첫째, Acetylcholine 길항제인 Scopolamine을 사용하여 중추신경계중 기억, 학습기전과 관련된 것으로 알려진 cholinergic신경계률 차단하여 유발한 실험적 건망모델과, 둘째, 단백질합성 저해제인 cycloheximide를 사용하여 기억, 학습경로에 관여하는 수종의 중추 단백질듈을 비선택적으로 저해하여 유발한 실험적 건망모델을 이용하여 인삼, 오미자등의 항치매 효과를 검색하고자 수동적 회피학습능, 능동적 회피학습능, 자발운동량을 측정하여 기억, 학습, 행동의 상관 관계를 고찰하였다.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1994년도 춘계학술대회 and 제3회 신약개발 연구발표회
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• pp.233-233
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• 1994

인삼 성분이 학습 및 기억력 중진에 미치는 효과를 연구하기 위하여, 학습 및 기억력 저하를 유발하는 약물들에 대한 아답타겐 (상품명) 과 인삼 수 엑기스산의 효과를 관찰하였다. Ethylcholine aziridium ion(AF64A), scopolamine 및 morphine을 쥐 및 생쥐의 해마와 복강에 각 각 주입하여 학습 및 기억력 저하를 유발한 후 아답타겐을 경구 투여하여 학습 및 기억력에 미치는 효과를 수로시험을 통하여 측정하였다. 또한 인삼 수 엑기스산을 일주일 동안 복강 주사하여 각 효과를 수로시험을 통하여 측정하였다. 또한 인삼 수 엑기스산을 일주일동안 복강 주사하여 각종 신경계에 미치는 변화를 효소 활성도, 신경전달물질의 농도, 수용체 결합을 지표로 하여 살펴보았다. AF64A 투여군 중 플랫폼을 전혀 인지치 못한 군에 아답타겐을 투여시에는 투여 횟수에 따라 플랫폼을 인지하는 비율이 증가했다. 연습 후 일주일간 물을 투여한 대조군의 도달 시간에 큰 변화가 없음에 반해, 아답타겐을 투여시에는 3일 투여 후 최대 시간이 걸리고, 투여횟수가 증가할수록 점차 도달 시간이 단축되었다. 인공 뇌척수액 및 AF64A의 투여군에서 아답타겐을 5일간 투여한 경우 대조군보다 각각 3배 빠른 속도로 플랫폼을 기억하였다. 한편 scopola mine 투여시에는 아답타겐을 투여한 군이 투여하지 않은 군보다 약 3배 빨리 플랫폼에 도달하였으나 각 투여군의 매일의 도달 시간 차이에는 변화를 나타내지 않았다. 또한 4일 전에 아답타겐을 투여시에는 saline 및 merphine 투여시 약 1.4배 빨리 플랫폼을 인지하였다. 인삼 추출물을 7일 투여 했을 경우 선조체에서 도파민 합성 효소인 tyrosine hydroxylase 활성이 유의성 있게 증가했으며, 대사체인 DOPAC의 농도도 증가를 나타냈다. 그러나, 도파민, HVA및 대사율인 DOPAC/DA와 HVA/DA에는 변화를 보이지 않았다. 또한 선조체의 GABA농도는 약 66%로 낮아졌지만 AChE의 활성도는 변화가 없었다. 인삼 수 추출물을 2주일 투여시 선조체의 도파민 수용체의 특성변화는, D1 수용체의 친화력에는 변화가 없는 반면, 최대 결합 수용체 수는 약간 낮아졌고, D2 수용체의 경우 최대 결합 수용체수는 변화가 없었으나 친화력은 감소하였다. 또한 피질의 benzodiazipine수용체 결합 친화력에는 변화가 없는 반면 최대 결합 수용체 수는 약 15%의 증가를 나타내었고 연수의 benzodiazepine 및 피질의 GABA 수용체의 특성에는 에는 변화를 나타내지 않았다. 이상의 결과, AF64A, 아급성 scopolamine 및 급성 morphine꽈 투여로 학습능이 저하되고 아답타겐을 경구 투여시엔 저하된 학습능력 빛 기억력의 증가를 보였다. 또한 본 결과는 인삼성분 중에는 도파민 및 GABA신경계에 영향을 주는 성분이 있음을 제시하였다.

• Biomolecules & Therapeutics
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• 제21권4호
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• pp.299-306
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• 2013

In the present study, we investigated the effect of ethanolic extract of the seed of Zizyphus jujuba var. spinosa (EEZS) on cholinergic blockade-induced memory impairment in mice. Male ICR mice were treated with EEZS. The behavioral tests were conducted using the passive avoidance, the Y-maze, and the Morris water maze tasks. EEZS (100 or 200 mg/kg, p.o.) significantly ameliorated the scopolamine-induced cognitive impairment in our present behavioral tasks without changes of locomotor activity. The ameliorating effect of EEZS on scopolamine-induced memory impairment was significantly reversed by a sub-effective dose of MK-801 (0.0125 mg/kg, s.c.). In addition, single administration of EEZS in normal naive mouse enhanced latency time in the passive avoidance task. Western blot analysis was employed to confirm the mechanism of memory-ameliorating effect of EEZS. Administration of EEZS (200 mg/kg) increased the level of memory-related signaling molecules, including phosphorylation of extracellular signal-regulated kinase or cAMP response element-binding protein in the hippocampal region. Also, the time-dependent expression level of brain-derived neurotrophic factor by the administration of EEZS was markedly increased from 3 to 9 h. These results suggest that EEZS has memory-ameliorating effect on scopolamine-induced cognitive impairment, which is mediated by the enhancement of the cholinergic neurotransmitter system, in part, via NMDA receptor signaling, and that EEZS would be useful agent against cognitive dysfunction such as Alzheimer's disease.