• Journal of Life Science
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• v.15 no.2 s.69
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• pp.169-175
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• 2005

Resveratrol (3,4',5-trihydroxy-trans-stilbene), a phytoalexin found in grape skins, peanuts, and red wine, has been reported to have a wide range of biological and pharmacological properties. $Amyloid-\beta$ deposition and senile plaque-associated astrocytes are common neuropathological features of Alzheimer's disease. In this study, we have explored the effects of resveratrol on $amyloid-\beta-peptide-mediated$ cytotoxicity in vitro and modulation of cell growth-regulatory gene products in astroglioma C6 cells to elucidate its possible mechanism for anti-cytotoxicity. Exposure of C6 cells to $Amyloid-\beta$ resulted in dose-dependent growth inhibition and morphological changes of C6 cells, which were recovered by pre-treatment with resveratrol. The anti-proliferative effect of $amyloid-\beta$ was associated with the induction of tumor suppressor p53 and cyclin-dependent kinase (Cdk) inhibitor p21 (WAF1/CIP1) expression assessed by RT-PCR and Western blot analysis in time-dependent manner in C6 cells. In addition, the pro-apoptotic Bax expression was also up-regulated in $amyloid-\beta-treated$ C6 cells without alteration of anti-apoptotic Bcl-2 and $Bcl-X_L$ expression. However, pre-treatment of resveratrol significantly inhibited $amyloid-\beta-induced$ p53, p21 and Bax levels, suggesting that the modulation of p53, p21 and Bax levels could be one of the possible pathways by which resveratrol functions as anti-cytotoxic agent. Our results demonstrate that resveratrol may enhance the protection against $amyloid-\beta-induced$ cytotoxicity by promoting the survival of glial cells.

• Journal of the Korea Society of Computer and Information
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• v.25 no.6
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• pp.165-170
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• 2020

In this paper, it was confirmed that scopoletin inhibits neuroinflammation induced by amyloid beta oligomer (Aβ_1-42) in microglial BV-2. The mechanisms of inflammatory cytokines and inflammatory mediators by scopoletin were identified. Alzheimer's disease is the most common neurodegenerative disease, but it is a disease whose specific etiology is unknown, and many studies are trying to solve it. We first measured the cell viability with the CCK-8 assay method to confirm that scopoletin and Aβ_1-42 are toxic to BV-2 cells. Expression levels of interleukin 1 beta (IL-1β), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and nuclear factor-κB (NF-κB) in inflammatory reactions induced by Aβ_1-42 with western blot were analyzed. The ANOVA assay was used to compare protein expression differences between BV-2 cells treated with Aβ_1-42 alone and BV-2 cells pretreated with Aβ_1-42 and scopoletin. Therefore, this study suggested that scopoletin is worth developing as a neuroinflammatory protection agent for Alzheimer's disease in the future.

• Journal of Ginseng Research
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• v.42 no.4
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• pp.401-411
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• 2018

Longevity in medicine can be defined as a long life without mental or physical deficits. This can be prevented by Alzheimer's disease (AD). Current conventional AD treatments only alleviate the symptoms without reversing AD progression. Recent studies demonstrated that Panax ginseng extract improves AD symptoms in patients with AD, and the two main components of ginseng might contribute to AD amelioration. Ginsenosides show various AD-related neuroprotective effects. Gintonin is a newly identified ginseng constituent that contains lysophosphatidic acids and attenuates AD-related brain neuropathies. Ginsenosides decrease amyloid ${\beta}$-protein ($A{\beta}$) formation by inhibiting ${\beta}$- and ${\gamma}$-secretase activity or by activating the nonamyloidogenic pathway, inhibit acetylcholinesterase activity and $A{\beta}$-induced neurotoxicity, and decrease $A{\beta}$-induced production of reactive oxygen species and neuro-inflammatory reactions. Oral administration of ginsenosides increases the expression levels of enzymes involved in acetylcholine synthesis in the brain and alleviates $A{\beta}$-induced cholinergic deficits in AD models. Similarly, gintonin inhibits $A{\beta}$-induced neurotoxicity and activates the nonamyloidogenic pathway to reduce $A{\beta}$ formation and to increase acetylcholine and choline acetyltransferase expression in the brain through lysophosphatidic acid receptors. Oral administration of gintonin attenuates brain amyloid plaque deposits, boosting hippocampal cholinergic systems and neurogenesis, thereby ameliorating learning and memory impairments. It also improves cognitive functions in patients with AD. Ginsenosides and gintonin attenuate AD-related neuropathology through multiple routes. This review focuses research demonstrating that ginseng constituents could be a candidate as an adjuvant for AD treatment. However, clinical investigations including efficacy and tolerability analyses may be necessary for the clinical acceptance of ginseng components in combination with conventional AD drugs.

• Proceedings of the Korean Society of Toxicology Conference
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• 2003.05a
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• pp.73-74
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• 2003

Familial form of Alzheimer's disease (FAD) is caused by mutations in presenilin-1 and presenilin-2 (PS2). PS1 and PS2 mutation are known to similar effects on the production of amyloid $\beta$ peptide (A$\beta$) and cause of cell death in the Alzheimer's brain. The importance of the alternation of calcium homeostasis in the neuronal cell death by PS1 mutation in a variety of experimental system has been demonstrated. (omitted)

• The Korean Journal of Physiology and Pharmacology
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• v.24 no.4
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• pp.299-310
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• 2020

Alzheimer's disease (AD) is a multi-faceted neurodegenerative disease. Thus, current therapeutic strategies require multitarget-drug combinations to treat or prevent the disease. At the present time, single drugs have proven to be inadequate in terms of addressing the multifactorial pathology of AD, and multitarget-directed drug design has not been successful. Based on these points of views, it is judged that combinatorial drug therapies that target several pathogenic factors may offer more attractive therapeutic options. Thus, we explored that the combination therapy with lower doses of cilostazol and aripiprazole with add-on donepezil (CAD) might have potential in the pathogenesis of AD. In the present study, we found the superior efficacies of donepezil add-on with combinatorial mixture of cilostazol plus aripiprazole in modulation of expression of AD-relevant genes: Aβ accumulation, GSK-3β, P300, acetylated tau, phosphorylated-tau levels, and activation of α-secretase/ADAM 10 through SIRT1 activation in the N2a Swe cells expressing human APP Swedish mutation (N2a Swe cells). We also assessed that CAD synergistically raised acetylcholine release and choline acetyltransferase (CHAT) expression that were declined by increased β-amyloid level in the activated N2a Swe cells. Consequently, CAD treatment synergistically increased neurite elongation and improved cell viability through activations of PI3K, BDNF, β-catenin and α7-nicotinic cholinergic receptors in neuronal cells in the presence of Aβ_1-42. This work endorses the possibility for efficient treatment of AD by supporting the synergistic therapeutic potential of donepezil add-on therapy in combination with lower doses of cilostazol and aripiprazole.

• Ocean and Polar Research
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• v.39 no.1
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• pp.45-49
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• 2017

During the search for anticholinesterase compounds from marine organisms, we were able to isolate 6,6'-bieckol from a red alga, Grateloupia elliptica. This compound showed moderate acetylcholinesterase (AChE) inhibitory activity in a micromole range ($IC_{50}$ $44.5{\mu}M$). However, for butyrylcholinesterase (BuChE), a new target for the treatment of Alzheimer's disease (AD), it showed particularly potent inhibitory activity ($IC_{50}$ $27.4{\mu}M$), which is more potent compared to AChE. It also inhibits BACE-1, a new target for reducing the generation of ${\beta}-amyloid$.

• Biomolecules & Therapeutics
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• v.20 no.3
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• pp.332-339
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• 2012

The components of Magnolia officinalis have well known to act anti-inflammatory, anti-oxidative and neuroprotective activities. These efficacies have been sold many products as nutritional supplement extracted from bark of Magnolia officinalis. Thus, to assess and compare neuroprotective effect in the nutritional supplement (Magnolia $Extract^{TM}$, Health Freedom Nutrition LLC, USA) and our ethanol extract of Magnolia officinalis (BioLand LTD, Korea), we investigated memorial improving and anti-Alzheimer's disease effects of extract products of Magnolia officinalis in a transgenic AD mice model. Oral pretreatment of two extract products of Magnolia officinalis (10 mg/kg/day in 0.05% ethanol) into drinking water for 3 months ameliorated memorial dysfunction and prevented $A{\beta}$ accumulation in the brain of Tg2576 mice. In addition, extract products of Magnolia officinalis also decreased expression of ${\beta}$-site APP cleaving enzyme 1 (BACE1), amyloid precursor protein (APP) and its product, C99. Although both two extract products of Magnolia officinalis could show preventive effect of memorial dysfunction and $A{\beta}$ accumulation, our ethanol extract of Magnolia officinalis (BioLand LTD, Korea) could be more effective than Magnolia $Extract^{TM}$ (Health Freedom Nutrition LLC, USA). Therefore, our results showed that extract products of Magnolia officinalis were effective for prevention and treatment of AD through memorial improving and anti-amyloidogenic effects via down-regulating ${\beta}$-secretase activity, and neuroprotective efficacy of Magnolia extracts could be differed by cultivating area and manufacturing methods.

• Korean Journal of Pharmacognosy
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• v.53 no.2
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• pp.102-110
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• 2022

Alzheimer's disease (AD) is the most common form of dementia, and the accumulation of β-amyloid (Aβ) in the brain triggers AD, followed by hyperphosphorylation of tau protein, neurofibrillary tangles, and synapses loss, neuronal cell death, and cognitive decline occur in a chain. In APPswe neuronal cell line, 50 ㎍/ml of Campbell early (Vitis labruscana B.) leaves 50% ethanol extract (VLL) treatment inhibited the secretion of Aβ1-42 by about 63% and the secretion of Aβ1-40 by about 50%. VLL did not target the enzymatic activity of the amyloidogenic pathway and decreased the protein expression of APP. As a result of RT-qPCR (Reverse transcription-quantitative real-time PCR) of the APPswe cell line treated with VLL, it is thought that the protein expression of APP was reduced by inhibiting the transcription process of the APP gene. In addition, VLL inhibited acetylcholinesterase (AChE) enzyme activity in vitro by 27.6% and 54.7%, respectively, at 50 and 100 ㎍/ml concentrations. We found that VLL inhibited the production of Aβ, a dementia-inducing substance, by suppressing the transcription of the APP gene, and that VLL inhibited AChE activity. We suggest that VLL has the potential as a natural drug material that modulates the alleviation of dementia symptoms.

• Biomolecules & Therapeutics
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• v.32 no.3
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• pp.301-308
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• 2024

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder characterized by extracellular amyloid plaques composed of amyloid β-peptide (Aβ). Studies have indicated that Ca²⁺ dysregulation is involved in AD pathology. It is reported that decreased capacitative Ca²⁺ entry (CCE), a refilling mechanism of intracellular Ca²⁺, resulting in increased Aβ production. In contrast, constitutive activation of CCE could decrease Aβ production. Panax ginseng Meyer is known to enhance memory and cognitive functions in healthy human subjects. We have previously reported that some ginsenosides decrease Aβ levels in cultured primary neurons and AD mouse model brains. However, mechanisms involved in the Aβ-lowering effect of ginsenosides remain unclear. In this study, we investigated the relationship between CCE and Aβ production by examining the effects of various ginsenosides on CCE levels. Aβ-lowering ginsenosides such as Rk1, Rg5, and Rg3 potentiated CCE. In contrast, ginsenosides without Aβ-lowering effects (Re and Rb2) failed to potentiate CCE. The potentiating effect of ginsenosides on CCE was inhibited by the presence of 2-aminoethoxydiphenyl borate (2APB), an inhibitor of CCE. 2APB alone increased Aβ42 production. Furthermore, the presence of 2APB prevented the effects of ginsenosides on Aβ42 production. Our results indicate that ginsenosides decrease Aβ production via potentiating CCE levels, confirming a close relationship between CCE levels and Aβ production. Since CCE levels are closely related to Aβ production, modulating CCE could be a novel target for AD therapeutics.

• Biomolecules & Therapeutics
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• v.19 no.2
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• pp.181-186
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• 2011

Beta-amyloid (A${\beta}$) is considered as one of the major causes of Alzheimer's disease. This study examined the neuroprotective effects of chlorogenic acid, a naturally occurring polyphenol which is distributed widely in plants, fruits and vegetables, against A${\beta}$-induced toxicity. A${\beta}$ decreased significantly the viability of PC12 cells. This was accompanied by an increase in the intracellular calcium levels and cleaved caspase-3. In addition, A${\beta}$ induced an increase in Bax, and a decrease in Bcl-2 compared to the controls. However, a pre-treatment with chlorogenic acid rescued the PC12 cells from A${\beta}$ by attenuating the elevated intracellular calcium levels and reducing the levels of the apoptosis related proteins, including caspase-3, Bcl-2 and Bax. These results suggest that the protective effects of chlorogenic acid are, at least in parts, by attenuating the intracellular calcium influx and reducing apoptosis induced by A${\beta}$.