• 대한한의학회지
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• 제35권4호
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• pp.10-23
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• 2014

Objectives: This study evaluated the effects of Guibi-tang (GBT) on neuronal apoptosis and cognitive impairment induced by beta amyloid ($A{\beta}$), (1-42) injection in the hippocampus of ICR mice. Methods: $A{\beta}$ (1-42) was injected unilaterally into the lateral ventricle using a Hamilton syringe and micropump ($2{\mu}g/3{\mu}{\ell}$, $0.6{\mu}{\ell}/min$). Water extract of GBT was administered orally once a day (500 mg/kg) for 3 weeks after the $A{\beta}$ (1-42) injection. Acquisition of learning and retention of memory were tested using the Morris water maze. Neuronal damage and $A{\beta}$ accumulation in the hippocampus was observed using cresyl violet and Congo red staining. The anti-apoptotic effect of GBT was evaluated using TUNEL labeling in the hippocampus. Results: GBT significantly shortened the escape latencies during acquisition training trials. GBT significantly increased the number of target headings to the platform site, the swimming time spent in the target quadrant, and significantly shortened the time for the 1st target heading during the retention test trial. GBT significantly attenuated the reduction in thickness and number of CA1 neurons, and $A{\beta}$ accumulation in the hippocampus produced by $A{\beta}$ (1-42) injection. GBT significantly reduced the number of TUNEL-labeled neurons in the hippocampus. Conclusion: These results suggest that GBT improved cognitive impairment by reducing neuronal apoptosis and $A{\beta}$ accumulation in the hippocampus. GBT may be a beneficial herbal formulation in treating cognitive impairment including Alzheimer's disease.

• 대한한방내과학회지
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• 제21권2호
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• pp.235-241
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• 2000

호도(胡桃)(Juglandis semen)가 치매에 미치는 영향을 알아보기 위하여 치매(Alzheimer's disease) 유발물질로 알려진 amyloid-{$\beta}(A{\beta})$ 25-35를 흰쥐의 뇌 신경세포의 일종인 astrocyte에 처리한 후 뇌의 신경세포에 대한 독성 및 세포막에서의 지질 과산화에 미치는 영향을 검토하였다. 호도(胡桃)는 $A{\beta})$ 25-35로 인한 신경세포의 파괴를 억제하는 것으로 나타나 신경세포의 손상을 예방하고 보호하는 효과가 있었다. 그리고, 지질의 과산화 지표인 malondialdehyde 생성은 $A{\beta})$ 25-35 처리로 크게 증가하였으나, 호도(胡桃)의 전처리와 후처리로 크게 감소되어 호도(胡桃)가 세포막 파괴로 인한 뇌세포의 손상을 방지하는 것으로 나타났다. 이러한 결과들을 볼 때, 호도(胡桃)는 신경세포의 하나인 astrocyte에 대한 보호효과와 세포막에서 지질의 과산화를 저해 및 $A{\beta})$ 25-35 처리와 같은 치매 유발 독성에 대한 적응능력 향상을 통하여 뇌 신경세포를 보호하는 효과가 있음을 보여주는 것으로 노인성 치매 등의 임상적 응용에 그 효과가 기대된다.

• Natural Product Sciences
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• 제21권2호
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• pp.134-140
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• 2015

The present study aims to investigate the effect of methanol extract of Korean mistletoe (KM; Viscum album var. coloratum), on amyloid $\beta$ protein ($A\beta$) (25-35), a synthetic 25-35 amyloid peptide, -induced neurotoxicity in cultured rat cerebral cortical neurons and memory impairment in mice. Exposure of cultured neurons to $10{\mu}M$ $A\beta$ (25-35) for 24 h induced a neuronal cell death, which was measured by a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assay and Hoechst 33342 staining. KM (10, 30 and $50{\mu}g/ml$) significantly inhibited the $A\beta$ (25-35)-induced apoptotic neuronal death. KM ($50{\mu}g/ml$) inhibited 10 μM Aβ (25-35)-induced elevation of intracellular calcium concentration ([Ca²⁺]_i), which was measured by a fluorescent dye, Fluo-4 AM. Glutamate release into medium and generation of reactive oxygen species (ROS) induced by $10{\mu}M$ $A\beta$ (25-35) were also inhibited by KM (10, 30 and $50{\mu}g/ml$). These results suggest that KM may mitigate the $A\beta$ (25-35)-induced neurotoxicity by interfering with the increase of [Ca²⁺]_i and then inhibiting glutamate release and generation of ROS in cultured neurons. In addition, orally administered KM (25 and 50 mg/kg, 7 days) significantly prevented memory impairment induced by intracerebroventricular injection of $A\beta$ (25-35) (8 nmol). Taken together, it is suggested that anti-dementia effect of KM is due to its neuroprotective effect against $A\beta$ (25-35)-induced neurotoxicity and that KM may have therapeutic role in prevention of the progression of Alzheimer's disease.

• 한국약용작물학회지
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• 제20권1호
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• pp.8-15
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• 2012

The present study investigated an ethanol extract of Chaenomeles sinensis fruit (CSF) for possible neuroprotective effects on neurotoxicity induced by amyloid ${\beta}$ protein ($A{\beta}$) (25-35) in cultured rat cortical neurons and also for antidementia activity in mice. Exposure of cultured cortical neurons to $10{\mu}M\;A{\beta}$ (25-35) for 36 h induced neuronal apoptotic death. At $0.1-10{\mu}g/m{\ell}$, CSF inhibited neuronal death, elevation of intracellular calcium concentration ($[Ca^{2+}]_i$), and generation of reactive oxygen species (ROS) induced by $A{\beta}$ (25-35) in primary cultures of rat cortical neurons. Memory loss induced by intracerebroventricular injection of mice with 15 nmol $A{\beta}$ (25-35) was inhibited by chronic treatment with CSF (10, 25 and 50 mg/kg, p.o. for 7 days) as measured by a passive avoidance test. CSF (50 mg/kg) inhibited the increase of cholinesterase activity in $A{\beta}$ (25-35)-injected mice brain. From these results, we suggest that the antidementia effect of CSF is due to its neuroprotective effect against $A{\beta}$ (25-35)-induced neurotoxicity and that CSF may have a therapeutic role for preventing the progression of Alzheimer's disease.

• Biomolecules & Therapeutics
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• 제32권1호
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• pp.77-83
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• 2024

Alzheimer's disease (AD) is a neurodegenerative disease characterized by neuronal cell death and memory impairment. Corticosterone (CORT) is a glucocorticoid hormone produced by the hypothalamic-pituitary-adrenal axis in response to a stressful condition. Excessive stress and high CORT levels are known to cause neurotoxicity and aggravate various diseases, whereas mild stress and low CORT levels exert beneficial actions under pathophysiological conditions. However, the effects of mild stress on AD have not been clearly elucidated yet. In this study, the effects of low (3 and 30 nM) CORT concentration on Aβ_25-35-induced neurotoxicity in SH-SY5Y cells and underlying molecular mechanisms have been investigated. Cytotoxicity caused by Aβ_25-35 was significantly inhibited by the low concentration of CORT treatment in the cells. Furthermore, CORT pretreatment significantly reduced Aβ_25-35-mediated pro-apoptotic signals, such as increased Bim/Bcl-2 ratio and caspase-3 cleavage. Moreover, low concentration of CORT treatment inhibited the Aβ_25-35-induced cyclooxygenase-2 and pro-inflammatory cytokine expressions, including tumor necrosis factor-α and interleukin-1β. Aβ_25-35 resulted in intracellular accumulation of reactive oxygen species and lipid peroxidation, which were effectively reduced by the low CORT concentration. As a molecular mechanism, low CORT concentration activated the nuclear factor-erythroid 2-related factor 2, a redox-sensitive transcription factor mediating cellular defense and upregulating the expression of antioxidant enzymes, such as NAD(P)H:quinone oxidoreductase, glutamylcysteine synthetase, and manganese superoxide dismutase. These findings suggest that low CORT concentration exerts protective actions against Aβ_25-35-induced neurotoxicity and might be used to treat and/or prevent AD.

• 한국약용작물학회지
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• 제22권2호
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• pp.105-112
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• 2014

The present study investigated an ethanol extract (SSB) of a mixture of three medicinal plants of Vitis amurensis, Aralia cordata, and Glycyrrhizae radix for possible neuroprotective effects on neurotoxicity induced by Amyloid ${\beta}$ protein ($A{\beta}$) (25-35) in cultured rat cortical neurons and antidementia activity in mice. Exposure of cultured cortical neurons to $15{\mu}M$ $A{\beta}$ (25-35) for 36 h induced neuronal apoptotic death. At $1-30{\mu}g/m{\ell}$, SSB inhibited neuronal death, elevation of intracellular calcium concentration ($[Ca^{2+}]_i$), and generation of reactive oxygen species (ROS) induced by $A{\beta}$ (25-35) in cultured cortical neurons. Memory impairment and increase of acetylcholinesterase activity induced by intracerebroventricular injection of mice with 16 nmol $A{\beta}$ (25-35) was inhibited by chronic treatment with SSB (25, 50 and 100 mg/kg, p.o., for 8 days). From these results, it is suggested that antidementia effect of SSB is due to its neuroprotective effect against $A{\beta}$ (25-35)-induced neurotoxicity and that SSB may have a therapeutic role in preventing the progression of Alzheimer's disease.

• 대한본초학회지
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• 제30권1호
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• pp.67-75
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• 2015

Objectives : The aim of this study is to examine the neuroprotective effect of wheat bran extract (WBE) against ${\beta}$-amyloid ($A{\beta}$)-induced apoptotic cell death in SH-SY5Y human neuroblastoma cells and memory impairment in triple transgenic animal model's of Alzheimer's disease (3xTg AD mice). Methods : In SH-SY5Y cells, MTT assay and TUNEL staining were conducted to evaluate the protective effect of WBE against $A{\beta}_{25-35}$-induced neurotoxicity and apoptosis. Alterations in mitochondrial transmembrane potential (MMP), expression of proapoptotic Bax and antiapoptotic Bcl-2 proteins, cleavage of PARP, and brain-derived neurotrophic factor (BDNF) levels were analyzed to elucidate the neuroprotective mechanism of WBE. To further investigate the memory enhancing effect of WBE, Morris water maze test was performed in 3xTg AD mice. Results : In SH-SY5Y cells, WBE protected against $A{\beta}_{25-35}$-caused cytotoxicity and apoptosis as shown by the restoration of cell viability in MTT assay and inhibition of DNA fragmentation in TUNEL staining. $A{\beta}_{25-35}$-induced apoptotic signals such as dissipation of MMP, decreased Bcl-2/Bax ratio, and cleavage of PARP were suppressed by WBE. Moreover, WBE up-regulated the protein levels of BDNF, which seemed to be mediated by activation of cAMP response element-binding protein (CREB). In 3xTg AD mice, oral administration of WBE attenuated learning and memory deficit as verified by reduced mean escape latency in water maze test. Conclusions : WBE protects neuronal cells from $A{\beta}_{25-35}$-induced apoptotic cell death and restores learning and memory impairments in 3xTg AD mice. These findings suggest that WBE exhibit neuroprotective potential for the management of AD.

• 통합자연과학논문집
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• 제5권2호
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• pp.107-119
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• 2012

Polymerization of monomeric amyloid-${\beta}$ peptides ($A{\beta}$) into soluble oligomers and insoluble fibrils is one of the major pathways triggering the pathogenesis of Alzheimer's disease (AD). Using small molecules to prevent the polymerization of $A{\beta}$ peptides can, therefore, be an effective therapeutic strategy for AD. In this study, we investigated the effects of mono- and bi-flavonoids on $A{\beta}42$ toxicity and fibrillogenesis and found that the bi-flavonoid, taiwaniaflavone (TF) effectively and specifically inhibits $A{\beta}$ toxicity and fibrillogenesis. Compared to TF, the mono-flavonoid apigenin (AP) is less effective and less specific. Our data showed that differential effects of the mono- and bi-flavonoids on $A{\beta}$ fibrillogenesis correlate with their varying cytoprotective efficacies. We also found that other bi-flavonoids, namely 2',8"-biapigenin, amentoflavone, and sumaflavone, can also effectively inhibit $A{\beta}$ toxicity and fibrillogenesis, implying that the participation of two mono-flavonoids in a single bi-flavonoid molecule enhanced their activity. Bi-flavonoids, while strongly inhibited $A{\beta}$ fibrillogenesis, accumulated nontoxic $A{\beta}$ oligomeric structures, suggesting that these are off-pathway-oligomers. Moreover, TF abrogated the toxicity of preformed $A{\beta}$ oligomers and fibrils, indicating that TF and other bi-flavonoids may also reduce the toxicity of toxic $A{\beta}$ species. Altogether, our data clearly show that bi-flavonoids, possibly due to the possession of two $A{\beta}$ binders separated by an appropriate size linker, are likely to be promising therapeutics to suppress $A{\beta}$ toxicity.

• 약학회지
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• 제47권6호
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• pp.369-375
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• 2003

Xiaoshuan Zaizao Wan (XZW) has been used in China to improve hemiplegia, deviation of eye and mouth, and dysphasia due to cerebral thrombosis. To characterize pharmacological actions of XZW, we evaluated its effects on neuronal cell damage induced in primary cultured rat cortical cells by various oxidative insults, glutamate or N-methyl-D-aspartate (NMDA), and $\beta$-amyloid fragment ($A_{\beta(25-35)}$). XZW was found to inhibit the oxidative neuronal damage induced by $H_2O_2$, xanthine/xanthine oxidase, or $Fe^{2+}$/ascorbic acid. It also attenuated the excitotoxic damage induced by glutamate or NMDA. The NMDA-induced neurotoxicity was more effectively inhibited than the glutamate-induced toxicity. In addition, we found that XZW protected neurons against the $A_{\beta(25-35)}$-induced toxicity. Moreover; XZW exhibited dramatic inhibition of lipid peroxidation in rat brain homogenates and mild 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity. Taken together; these results demonstrate that XZW exerts neuroprotective effects against oxidative, excitotoxic, or $A_{\beta(25-35)}$-induced neuronal damage. These findings may provide pharmacological basis for its clinical usage treating the sequelae caused by cerebral thrombosis. Furthermore, XZW may exert beneficial effects on Alzheimer's disease and other oxidative stress-related neurodegenerative disorders.

• 동의신경정신과학회지
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• 제21권2호
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• pp.125-140
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• 2010

Objectives : The purpose of this study is to examine from various angles the protective effect of Gastrodia elata Blume (GEB) against nerve cell death induced by $\beta$-amyloid by using the cell line SH-SY5Y, which is commonly utilized for toxicity testing in nerve cells, and to find out its mechanism of action. Methods : To begin with, as a result of assessing the rate of cell survival by employing MTT reduction assay, the treatment with $\beta$-amyloid at different concentrations caused cytotoxicity, which was inhibited by preprocessing GEB extract. In addition, after $\beta$-amyloid was processed with the cell SH-SY5Y, apoptosis progressed, which was reduced effectively by processing GEB extract. Results : When cytotoxicity was caused by using hydrogen peroxide, a representative ROS, in order to examine the antioxidant effect of GEB, its protective effect was also observed. Apart from ROS, reactive nitrogen species (RNS) are also known to play a crucial role in nerve cell death. The treatment with the NO donor SNAP increased the production of nitric oxide and the expression of iNOS, which was also inhibited by GEB extract. Meanwhile, as an attempt to find out the mechanism of action explaining the antioxidant effect, the intracellular antioxidant enzyme expressions were measured by RT-PCR, which showed that GEB extract increased the expressions of heme oxygenase-1, GAPDH and $\gamma$-glutamate cysteine ligase. Lastly, GEB extract had a protective effect against impaired memory induced by scopolamine in animal models (in vivo). Conclusions : These findings indicate that GEB has a protective effect against the death of cranial nerve cells, suggesting possibilities for the prevention and treatment of AD.