• 한국식품과학회지
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• 제51권2호
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• pp.160-168
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• 2019

AD는 뇌의 신경세포 사멸뿐만 아니라 학습 및 기억능 소실을 초래하는 퇴행성 뇌 질환이며, 기억과 관련된 주요 뇌 구역인 해마(hippocampus)는 콜린성 조절(cholinergic modulation)에 의해 영향을 받는다(Konishi 등, 2015). AD 병인에 대한 다양한 해석과 설명이 있으나 크게는 amyloid cascade hypothesis과 함께 cholinergic hypothesis가 주류를 이루고 있다. 몇몇의 연구에서 ChAT 합성, ACh 분비, nicotin 및 muscarinic 수용체 감소가 AD 뇌의 대뇌피질과 해마에서 관찰되어(Tata 등, 2014) 퇴행성 뇌질환에서의 중요성이 제시되었고, 이를 배경으로 한 acetylcholinesterase inhibitors (AChEI)가 AD 증상 완화의 목적으로 미국 FDA로부터 승인되어 시판되고 있다. 본 연구에서는 인삼의 활성 성분인 진세노사이드가 다량 함유된 PGBC가 $A{\beta}42$로 유도된 치매 모델에서 뇌세포 보호, ACh 분비 증가, 학습력/기억력 증가, ChAT 발현 증가를 확인하여 인삼열매 추출물의 치매 적용 여부를 확인하고자 하였다. 결과에서 언급한 바와 같이 PGBC는 익기 직전의 4년근 인삼 열매에 추출 및 발효 단계를 추가하여 확보된 물질로서, $A{\beta}42$ 섭취, 제거 및 ACh 분비 촉진 활성이 있는 Re, Rd, Rg3 함량이 증가되어(Kim 등, 2014; Jang 등, 2015), PGBC 자체로서 치매 인자에 대한 조절 효능이 예측되었다. 특히, 7증 7포 및 발효과정을 거친 이중가공 인삼 열매 추출물이 비 발효 증포 추출물에 비해 Rg3가 현저히 증가하는 사전 연구결과와 Rg3가 $A{\beta}42$ 제거 활성을 가지는 것으로 확인된 결과를 종합할 때 PGBC 투여가 AD 증상 완화의 조절자 역할을 할 것으로 생각된다(Kim 등, 2013; Jang 등 2015). 본 연구에 따르면, 마우스 치매 모델에 PGBC 처리 시 PAT 및 Morris water-maze test를 통해 대조군 대비 유의한 수준의 인지능력 개선, ACh 합성을 유도하는 ChAT 유전자 발현 증가, ACh 분비량 증가 등이 확인되어 전체적인 인지능 개선에 극적인 영향을 준 것으로 판단된다. 특히 $A{\beta}42$를 뇌 실로 주입(intracranial injection) 하여 나타나는 뇌세포 손상이 PGBC 투여를 통해 보호된 것으로 사료되었으며, 이는 주요 뇌세포 중 하나인 성상세포에서 관찰되는 GFAP 분석을 통해 확인되었다. 뇌 균질액을 이용한 AChE 활성 연구에서도 PGBC가 AChE를 현저하게 저해하는 것으로 확인되어, AD 환자에게 처방이 가능한 2대 의약품 군중 하나인 시냅스 내 신경전달물질 ACh bioavailability 증가 목적의 처방 보조요법 적용이 기대된다(${\check{C}}olovi{\acute{c}}$ 등, 2013). 결론적으로, 본 연구에 사용된 PGBC는 학습 및 기억력을 개선하는 활성물질을 포함하고 있어 1차적인 퇴행성 뇌질환 보조재로서 직간접적인 대증요법 역할과 2차적으로는 뇌 세포 보호를 통한 질병 악화 지연 소재로 개발이 기대되며, 보다 심도 있는 기전연구를 통해 천연물 신소재 개발도 가능할 것으로 사료된다.

• 대한한의학회지
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• 제23권2호
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• pp.125-138
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• 2002

Learning and memory are essential requirements for every living organism in order to cope with environmental demands, and cholinergic systems are known to be involved in learning and memory. Scutellaria baicalensis (SB) and Gastrodia elata (GE) as a traditional Oriental medicine have been clinically used to treat or prevent memory deficits, including Alzheimer's disease. In the present study, we investigated the effects of SB and GE on learning and memory in the Morris water maze task and the central cholinergic system of the rats with excitotoxic medial septum lesions. In the water maze test, the animals were trained to find a platform at a fixed position over 6 days and then received a 60-s probe trial in which the platform was removed from the pool on the 7th day. Ibotenic lesion of the medial septum (MS) impaired their performance in the maze test (latency of acquisition test on the 3rd day, $27.6{\pm}$4.4 sec vs. $61.7{\pm}17.7$ sec; retention test, $7.9{\pm}1.3%$ vs. $5.7{\pm}1.0%$: sharn vs. ibotenic lesioned groups, respectively) and reduced choline acetyltransferase (ChAT) - immunoreactivity in the MS and the hippocarnpus, which is a marker for degeneration of the central cholinergic system (number of cells, $21.1{\pm}1.1$ vs. $13.2{\pm}1.3$: sham vs. ibotenic lesioned group). Daily administrations of SB (100mg/kg, p.o.) and GE (100mg/kg, p.o.) for 21 consecutive days produced significant reversals of ibotenic acid-induced deficit in learning and memory. These treatments also reduced the loss of cholinergic immunoreactivity in the MS and the hippocarnpus induced by ibotenic acid. These results demonstrated that SB and GE ameliorated learning and memory deficits through effects on the central nervous system, partly through effect on the acetylcholine system. Our studies suggest an evidence of SB and GE as treatment for Alzheimer's disease.

• 동의생리병리학회지
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• 제25권4호
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• pp.691-696
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• 2011

In order to the neuroprotective effect of electroacupuncture (EA), the present study examined the effects of electroacupuncture inacupoint ST36 (Stomach 36) on trimethyltin chloride (TMT)-induced cognitive impairments rat using the Morris water maze (MWM) task and immunohistochemistry staining. The rats were randomly divided into the following groups: naive rat (Normal), TMT injection rat (Control), TMT injection + EA treated rat inacupoint ST36 (ST36) and TMT injection + EA treated rat in non-acupoint, base of tail (Non-AC). Electroacupuncture (2Hz, 2mA, and 10 minutes)was applied either to the acupuncture point ST36 or the nonacupuncture point in the tail for the last 14 days. In the water maze test, the animals were trained to find a platform in a fixed position during 4d and then received 60s probe trial on the $5^{th}$ day following removal of platform from the pool. Rats with TMT injection showed impaired learning and memory of the tasks and treatment with EA in acupoint ST36 (P<0.05) produced a significant improvement in escape latency to find the platform after $2^{nd}$ day and retention trial in the Morris water maze. Consistent with behavioral data, treatment with EA in acupoint ST36 also significantly increased expression of Choline acetyltransferase (ChAT) and Acetylcholinesterase (AChE) immunoreactive neurons in the hippocampus compared to the Control group. These results demonstrated that EA in acupoint ST36 has a protective effect against TMT-induced neuronal and cognitive impairments. The present study suggests that EA in acupoint ST36 might be useful in the treatment of TMT-induced learning and memory deficit.

• 대한한의학회지
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• 제30권2호
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• pp.1-16
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• 2009

Objectives: This study investigated the effect of Yukmijihwangtang on cerebral ischemia-induced learning and memory impairment by middle cerebral artery (MCA) occlusion in rats. Methods: The ability of learning and memory of rats was measured using the eight-arm radial maze and the passive avoidance test, and profile of cholinergic neuron was assessed in the medial septum and hippocampus region by immuno-histochemistry. Results: 1. No differences were found between groups in the number of correct choices in acquisition performance during the eight-arm radial maze task. 2. No differences were found between groups on day 1 in the error rate in acquisition performance, which is defined as the number of enters into the same arm more than once within five minutes. After 5 to 6 days of test, the number of errors was significantly reduced in the Yukmijihwangtang group (forebrain ischemia group with Yukmijihwangtang treatment), compared with the ischemia group. 3. The memory processes significantly improved in the Yukmijihwangtang group according to results of the passive avoidance test. 4. The appearance of AchE (acetylcholinesterase) in the CA1 region of hippocampus significantly decreased in the ischemia group, compared with the sham group (untreated group). The appearance of AchE in the same region significantly increased in the Yukmijihwangtang group, compared with the ischemia group. 5. The appearance of ChAT (choline acetyltransferase) in the CA1 region of the hippocampus and medial septum decreased in the ischemia group, compared with the sham group. The appearance of ChAT in the same region significantly increased in the Yukmijihwangtang group, compared with the ischemia group Conclusions: This study provides evidence that Yukmijihwangtang is effective for reviving the ability of learning and memory and damaged neurons in rats with experimental cerebral ischemia.

• 대한의생명과학회지
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• 제21권2호
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• pp.92-102
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• 2015

This work aimed to study whether rice bran extract fermented with Lactobacillus plantarum (LW) promotes functional recovery and reduces cognitive impairment after ischemic brain injury. Ischemic brain injury was induced by middle cerebral artery occlusion (MCAO) in rats. Four groups were studied, namely the (1) sham, (2) vehicle, (3) donepezil, and (4) LW groups. Animals were injected with LW once a day for 7 days after middle cerebral artery occlusion. LW group showed significantly improved neurological function as compared to the vehicle group, as well as enhanced learning and memory in the Morris water maze. The LW group showed the greatest functional recovery. Moreover, the LW group showed an enhanced more survival cells anti-apoptotic effect in the cortex and neural cell densities in the hippocampal DG and CA1. In addition, this group showed enhanced expression of neurotrophic factors, antioxidant genes, and the acetylcholine receptor gene, as well as synaptophysin (SYP), Fox-3 (NeuN), doublecortin (DCX), and choline acetyltransferase (ChAT) proteins. Our findings indicate that LW treatment showed the largest effects in functional recovery and cognitive improvement after ischemic brain injury through stimulation of the acetylcholine receptor, antioxidant genes, neurotrophic factors, and expression of NeuN, SYP, DCX, and ChAT.

• 동의생리병리학회지
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• 제25권3호
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• pp.406-416
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• 2011

In this study, we have verified the memory and cognitive enhancing effect of Longanae Arillus, the fruit of Euphoria longana Lamarck, which has been used as a tonic and for the treatment of amnesia, insomnia, and palpitations in oriental medicine. To investigate the effect of Longanae Arillus water extract(LAE) on the memory and cognitive dysfunction, scopolamine (1 mg/kg, i.p.) was injected in C57BL/6 mice and several behavior tests including Y-maze, Morris water-maze, passive avoidance and fear conditioning tests were conducted. Administration of LAE (100 or 200 mg/kg/day, p.o.) effectively improved scopolamine-induced memory impairment and dysfunction. To further determine the possible molecule mechanism of LAE, we have examined the activity and/or mRNA expression of diverse proteins involved in the acetylcholine metabolism. LAE particularly increased the amount of acetylcholine in the cortex which was mediated by suppression of acetylcholine esterase (AchE) activity. In addition, LAE elevated the mRNA expression of muscarinic acetylcholine receptors (mAchRs) without affecting the mRNA levels of choline acetyltransferase (ChAT) and acetylcholine esterase (AchE). In another experiment, LAE effectively inhibited mRNA expression of pro-inflammatory cytokines such as tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) and interleukin-$1{\beta}$ (IL1-${\beta}$), which seemed to be mediated by inhibition of upstream transcription factor NF-${\kappa}B$ and extracellular-regulated kinase 1/2 (ERK1/2). These results demonstrate that Longanae Arillus can increase acetylcholine amount the cortex via regulation of AchE activity as well as mAchRs expression and decrease pro-inflammatory responses via inhibition of NF-${\kappa}B$ signaling pathway, thereby having therapeutic potential to improve memory and cognitive deficit in amnesia.

• 한국식품영양과학회지
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• 제42권8호
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• pp.1190-1196
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• 2013

연구에서는 백삼이나 홍삼의 기억력 개선 효과 연구를 기초로 흑삼의 기억력 개선효과 여부를 판단하고자 scopolamine으로 유도된 시험동물에게 7주간 시료 물질(백삼, WG; 홍삼, RG; 흑삼, BG) 추출액을 투여한 후, 행동학적인 평가 및 뇌 조직 내 malondialdehyde 농도, ChAT 활성 변화를 비교 분석하여 기억력 및 학습능력 손상에 대한 개선효과를 알아보고자 하였다. 수동회피시험에서 BG군과 RG군의 latency time이 scopolamine 투여한 PC군(positive control)에 비해서 유의적으로 길어지는 결과를 나타냈다. 수중미로시험에서도 BG군과 RG군의 scopolamine에 의한 기억 손상이 유의적으로 개선되어 NC군의 escape latency 수준 정도로 낮아짐을 확인할 수 있었다. 또한 probe test에서도 BG군과 RG군에서 장기 기억력 손상이 유의적으로 개선됨이 확인되었다. BG군과 RG군의 뇌조직 ChAT 효소 활성은 PC군에 비해 각각 42%, 71% 수준의 유의성 있는 활성증가를 보였다. 지질 과산화도 malondialdehyde 측정 결과에서 PC군 대비 RG군과 BG군에서 각각 37%, 33% 수준의 유의성 있는 감소를 보였다. 이상의 결과를 요약하면 시험물질 가운데 흑삼의 반복 경구투여는 scopolamine으로 유도된 흰쥐에서 기억력 감퇴를 개선하는 데 가장 효과적인 것으로 사료된다.

• 동의생리병리학회지
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• 제24권2호
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• pp.228-235
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• 2010

This study was performed to investigate the memory enhancing effect of Poria cocos Wolf (Hoelen cum radix) against scopolamine-induced amnesia in Sprague-Dawley (SD) rats. To induce amnesia, scopolamine (0.75 mg/kg) was intraperitonically injected into SD rats 30 min before starting behavior tests. We have conducted Morris water-maze and Y-maze tests to monitor learning and memory functions. Poria cocos effectively reversed scopolamine-induced memory impairment in SD rats which was represented by an improvement of mean escape latency in water-maze test and spontaneous alterations in Y-maze test. To elucidate possible molecule mechanism, we have measured mRNA as well as protein expression of acetylcholine esterase (AchE), choline acetyltransferase (ChAT), muscarinic acetylcholine receptor (mAchR), and brain-derived neurotrophic factor (BDNF) using RT-PCR and Western blot analysis, respectively. Poria cocos increased mRNA levels of ChAT and mAchR in rat hippocampus compared with those in the scopolamine-injected amnesic group. In addition, protein expression of ChAT and BDNF was also elevated by Poria cocos intake. Furthermore, as an upstrem regulator, the activation of cAMP response element-binding protein (CREB) was assessed by immunohistochemistry. In this immunohistochemical analysis, the phosphorylation of CREB (p-CREB) was reduced by scopolamine injection, which was restored back to control levels by administration of Poria cocos. These results suggest that Poria cocos may improve memory and cognitive deficit in amnesia and have therapeutic potentials through up-regulation of ChAT, mAchR, and BDNF, which seemed to be mediated by activation of CREB.

• Journal of Microbiology and Biotechnology
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• 제21권8호
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• pp.874-883
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• 2011

Many studies have shown that the steamed root of Rehmannia glutinosa (SRG), which is widely used in the treatment of various neurodegenerative diseases in the context of Korean traditional medicine, is effective for improving cognitive and memory impairments. The purpose of this study was to examine whether SRG extracts improved memory defects caused by administering scopolamine (SCO) into the brains of rats. The effects of SRG on the acetylcholinergic system and proinflammatory cytokines in the hippocampus were also investigated. Male rats were administered daily doses of SRG (50, 100, and 200 mg/kg, i.p.) for 14 days, 1 h before scopolamine injection (2 mg/kg, i.p.). After inducing cognitive impairment via scopolamine administration, we conducted a passive avoidance test (PAT) and the Morris water maze (MWM) test as behavioral assessments. Changes in cholinergic system reactivity were also examined by measuring the immunoreactive neurons of choline acetyltransferase (ChAT) and the reactivity of acetylcholinesterase (AchE) in the hippocampus. Daily administration of SRG improved memory impairment according to the PAT, and reduced the escape latency for finding the platform in the MWM. The administration of SRG consistently significantly alleviated memory-associated decreases in cholinergic immunoreactivity and decreased interleukin-$1{\beta}$ (IL-$1{\beta}$) and tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) mRNA expression in the hippocampus. The results demonstrated that SRG had a significant neuroprotective effect against the neuronal impairment and memory dysfunction caused by scopolamine in rats. These results suggest that SRG may be useful for improving cognitive functioning by stimulating cholinergic enzyme activities and alleviating inflammatory responses.

• The Korean Journal of Physiology and Pharmacology
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• 제15권6호
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• pp.333-338
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• 2011

Black ginseng (BG) has been widely used as herbal treatment for improving physiological function. In order to investigate the neuroprotective action of this herbal medicine, we examined the influence of BG on the learning and memory of rats using the Morris water maze, and we studied the effects of BG on the central cholinergic system and neural nitric oxide synthesis in the hippocampus of rats with neuronal and cognitive impairment. After middle cerebral artery occlusion was applied for 2h, the rats were administered BG (100 or 400 $mgkg^{-1}$, p.o.) daily for 2 weeks, followed by training and performance of the Morris water maze test. The rats with ischemic insults showed impaired learning and memory on the tasks. Treatment with BG produced improvement in the escape latency to find the platform. Further, the BG groups showed a reduced loss of cholinergic immunoreactivity and nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d)-positive neurons in the hippocampus compared to that of the ISC group. These results demonstrated that BG has a protective effect against ischemia-induced neuronal and cognitive impairment. Our results suggest that BG might be useful for the treatment of vascular dementia.