• Journal of Radiopharmaceuticals and Molecular Probes
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• v.6 no.2
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• pp.69-74
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• 2020

PIB is the first amyloid plaque PET image tracer reported for the first time in 2003, and is considered to be the best and is still being utilized due to its very high uptake and kinetic properties. Initially, it was synthesized by radioisotope labeling using a precursor containing a methoxy methyl protection group, but now it is synthesized using a 6-OH precursor that can be easily synthesized in one step using [¹¹C]methyl triflate. Carbon-11 has several limitations in clinical studies using PET because its half-life is as short as 20 minutes. In this study, in order to overcome the difficulty of this half-life, a rapid method using Sep-Pak was adopted instead of HPLC purification to significantly reduce the burden of the purification process and attempted synthesis. As a result, the synthesis time was shortened by more than 50%, and the yield of the final compound was higher than the previous result and showed relatively high specific radioactivity, confirming that it is a strategic method with high applicability for various precursors having primary amines.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2004.11a
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• pp.124-128
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• 2004

We have assessed amyloid ${\beta}-peptide$ $(A{\beta})-induced$ neurotoxicity in primary neurons and organotypic hippocampal slice cultures (OHC) in rat. Exposing cultured hippocampal and cerebellar granule neurons to $A{\beta}$ resulted in a decrease of MTT reduction, and in destruction of neuronal integrity. Treatment of these neurons with tunicamycin, an inhibitor of N-glycosylation in the endoplasmic reticulum (ER), also decreased MTT reduction in these neurons. S-allyl-L-cysteine (SAC), an active organosulfur compound in aged garlic extract, protected hippocampal but not cerebellar granule neurons against $A{\beta}$- or tunicamycin-induced toxicity. In the hippocampal neurons, protein expressions of casapse-12 and GRP 78 were significantly increased after $A{\beta}_{25-35}$ or tunicamycin treatment. The increase in the expression of caspase-12 was suppressed by simultaneously adding $1{\mu}M$ SAC in these neurons. In contrast, in the cerebellar granule neurons, the expression of caspase-12 was extremely lower than that in the hippocampal neurons, and an increase in the expression by $A{\beta}_{25-35}$ or tunicamycin was not detected. In OHC, ibotenic acid (IBO), a NMDA receptor agonist, induced concentration-dependent neuronal death. When $A{\beta}$ was combined with IBO, there was more intense cell death than with IBO alone. SAC protected neurons in the CA3 area and the dentate gyrus (DG) from the cell death induced by IBO in combination with $A{\beta}$, although there was no change in the CA1 area. Although protein expression of casapse-12 in the CA3 area and the DG was significantly increased after the simultaneous treatment of AI3 and IBO, no increase in the expression was observed in the CA1 area. These results suggest that SAC could protect against the neuronal cell death induced by the activation of caspase-12 in primary cultures and OHC. It is also suggested that multiple mechanisms may be involved in neuronal death induced by AI3 and AI3 in combination with IBO.

• Journal of Ginseng Research
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• v.44 no.1
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• pp.67-78
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• 2020

Background: Gintonin (GT), a novel ginseng-derived exogenous ligand of lysophosphatidic acid (LPA) receptors, has been shown to induce cell proliferation and migration in the hippocampus, regulate calcium-dependent ion channels in the astrocytes, and reduce β-amyloid plaque in the brain. However, whether GT influences autophagy in cortical astrocytes is not yet investigated. Methods: We examined the effect of GT on autophagy in primary cortical astrocytes using immunoblot and immunocytochemistry assays. Suppression of specific proteins was performed via siRNA. LC3 puncta was determined using confocal microscopy. Results: GT strongly upregulated autophagy marker LC3 by a concentration- as well as time-dependent manner via G protein-coupled LPA receptors. GT-induced autophagy was further confirmed by the formation of LC3 puncta. Interestingly, on pretreatment with an mammalian target of rapamycin (mTOR) inhibitor, rapamycin, GT further enhanced LC3-II and LC3 puncta expression. However, GT-induced autophagy was significantly attenuated by inhibition of autophagy by 3-methyladenine and knockdown Beclin-1, Atg5, and Atg7 gene expression. Importantly, when pretreated with a lysosomotropic agent, E-64d/peps A or bafilomycin A1, GT significantly increased the levels of LC3-II along with the formation of LC3 puncta. In addition, GT treatment enhanced autophagic flux, which led to an increase in lysosome-associated membrane protein 1 and degradation of ubiquitinated p62/SQSTM1. Conclusion: GT induces autophagy via mTOR-mediated pathway and elevates autophagic flux. This study demonstrates that GT can be used as an autophagy-inducing agent in cortical astrocytes.

• Korean Journal of Exercise Nutrition
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• v.23 no.4
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• pp.26-31
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• 2019

[Purpose] Numerous epidemiological studies have shown that it is possible to prescribe exercise for neurodegenerative disease, such as Alzheimer's disease and Parkinson's disease. However, despite the availability of diverse scientific knowledge, the effects of exercise in this regard are still unclear. Therefore, this study attempted to investigate a substance, such as black chokeberry (Aronia melanocapa L.) that could improve the ability of the treatment and enhance the benefits of exercising in neurodegenerative diseases. [Methods] The cell viability was tested with 2,3-bis[2-methyloxy-4-nitro-5-sulfophenyl]-2H-tetrazolim-5-carboxanilide and the cells were stained with ethidium homodimer-1 solution. The mRNA expression levels were evaluated by microarray. The active compounds of black chokeberry ethanolic extract (BCE) were analyzed by gas chromatography. The chemical shift analysis in the brain was performed using magnetic resonance spectroscopy. [Results] BCE treatment decreased hydrogen peroxide-induced L6 cell death and beta amyloid induced primary neuronal cell death. Furthermore, BCE treatment significantly reduced the mRNA levels of the inflammatory factors, such as IL-1α, Cxcl13, IL36rn, Itgb2, Epha2, Slamf8, Itgb6, Kdm6b, Acvr1, Cd6, Adora3, Cd27, Gata3, Tnfrsf25, Cd40lg, Clec10a, and Slc11a1, in the primary neuronal cells. Next, we identified 16 active compounds from BCE, including D-mannitol. In vivo, BCE (administered orally at a dosage of 50 mg/kg) significantly regulated chemical shift in the brain. [Conclusion] Our findings suggest that BCE can serve as a candidate for neurodegenerative disease therapy owing to its cyto-protective and anti-inflammatory effects. Therefore, BCE treatment is expected to prevent damage to the muscles and neurons of the athletes who continue high intensity exercise. In future studies, it would be necessary to elucidate the effects of combined BCE intake and exercise.

• Journal of Life Science
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• v.30 no.12
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• pp.1118-1127
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• 2020

Alzheimer's disease causes progressive neuronal loss that leads to cognitive disturbances. It is not currently curable, and there is no way to stop its progression. However, since medical treatment for Alzheimer's disease is most effective in the early stages, early detection can provide the best chance for symptom management. Biomarkers for the diagnosis of Alzheimer's disease include amyloid β (Aβ) deposition, pathologic tau, and neurodegeneration. Aβ deposition and phosphorylated tau can be detected by cerebrospinal fluid (CSF) analysis or positron emission tomography (PET). However, CSF sampling is quite invasive, and PET analysis needs specialized and expensive equipment. During the last decades, blood-based biomarker analysis has been studied to develop fast and minimally invasive biomarker analysis method. And one of the remarkable findings is the involvement of platelets as a primary source of Aβ in plasma. Aβ can be transported across the blood - brain barrier, creating an equilibrium of Aβ levels between the brain and blood under normal condition. Interestingly, a number of clinical studies have unequivocally demonstrated that plasma Aβ42/Aβ40 ratios are reduced in mild cognitive impairment and Alzheimer's disease. Together, these recent findings may lead to the development of a fast and minimally invasive early diagnostic approach to Alzheimer's disease. In this review, we summarize recent advances in the biomarkers of Alzheimer's disease, especially the involvement of platelets as a source of peripheral Aβ production and its potential as a blood-based biomarker.

• Nutrition Research and Practice
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• v.17 no.2
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• pp.371-385
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• 2023

BACKGROUND/OBJECTIVES: Soy isoflavone (SIF) and soy lecithin (SL) have beneficial effects on many chronic diseases, including neurodegenerative diseases. Regretfully, there is little evidence to show the combined effects of these soy extractives on the impairment of cognition and abnormal cerebral blood flow (CBF). This study examined the optimal combination dose of SIF + SL to provide evidence for improving CBF and protecting cerebrovascular endothelial cells. MATERIALS/METHODS: In vivo study, SIF50 + SL40, SIF50 + SL80 and SIF50 + SL160 groups were obtained. Morris water maze, laser speckle contrast imaging (LSCI), and hematoxylin-eosin staining were used to detect learning and memory impairment, CBF, and damage to the cerebrovascular tissue in rat. The 8-hydroxy-2'-deoxyguanosine (8-OHdG) and the oxidized glutathione (GSSG) were detected. The anti-oxidative damage index of superoxide dismutase (SOD) and glutathione (GSH) in the serum of an animal model was also tested. In vitro study, an immortalized mouse brain endothelial cell line (bEND.3 cells) was used to confirm the cerebrovascular endothelial cell protection of SIF + SL. In this study, 50 µM of Gen were used, while the 25, 50, or 100 µM of SL for different incubation times were selected first. The intracellular levels of 8-OHdG, SOD, GSH, and GSSG were also detected in the cells. RESULTS: In vivo study, SIF + SL could increase the target crossing times significantly and shorten the total swimming distance of rats. The CBF in the rats of the SIF50 + SL40 group and SIF50 + SL160 group was enhanced. Pathological changes, such as attenuation of the endothelium in cerebral vessels were much less in the SIF50 + SL40 group and SIF50 + SL160 group. The 8-OHdG was reduced in the SIF50 + SL40 group. The GSSG showed a significant decrease in all SIF + SL pretreatment groups, but the GSH showed an opposite result. SOD was upregulated by SIF + SL pretreatment. Different combinations of Genistein (Gen)+SL, the secondary proof of health benefits found in vivo study, showed they have effective anti-oxidation and less side reaction on protecting cerebrovascular endothelial cell. SIF50 + SL40 in rats experiment and Gen50 + SL25 in cell test were the optimum joint doses on alleviating cognitive impairment and regulating CBF through protecting cerebrovascular tissue by its antioxidant activity. CONCLUSIONS: SIF+SL could significantly prevent cognitive defect induced by β-Amyloid through regulating CBF. This kind of effect might be attributed to its antioxidant activity on protecting cerebral vessels.

• Journal of Oriental Neuropsychiatry
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• v.12 no.2
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• pp.173-183
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• 2001

Substance P can stimulate secretion of tumor necrosis $factor-\;{\alpha}\;(TNF-\;{\alpha}\;)$ from astrocytes stimulated with lipopolysaccharide (LPS). Here I report that Chilbogeum can modulate cytokines secretion from primary cultures of rat astrocytes. Chilbogeum $(10\;{\mu}g/ml)$ significantly inhibited the $TNF-\;{\alpha}$ secretion by astrocytes stimulated with LPS and Substance P. Interleukin-1 (IL-1) has been shown to elevate $TNF-\;{\alpha}$ secretion from LPS-stimulated astrocytes while having no effect on astrocytes in the absence of LPS. Treatment of Chilbogeum $(10,\;100\;{\mu}g/ml)$ to astrocytes stimulated with both LPS and Substance P decreased IL-1 secretion significantly. The secretion of $TNF-\;{\alpha}$ by LPS and Substance P in astrocytes was progressively inhibited with increasing amount of IL-1 neutralizing antibody. Upon stimulation from various agents, these cells adopt a reactive phenotype, a morphological hallmark in Alzheimer's disease (AD) pathology, during which they themselves may produce still more inflammatory cytokines. Chilbogeum $(10,\;100\;{\mu}g/ml)$ significantly inhibited the $TNF-\;{\alpha}$ secretion by CCF-STTG1 astrocytoma cells stimulated with $A\;{\beta}$ and IL-1. These results suggest that Chilbogeum may inhibit $TNF-\;{\alpha}$ secretion by inhibiting IL-1 secretion and that Chilbogeum has an antiinflammatory activity in AD brain.

• Nutrition Research and Practice
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• v.12 no.1
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• pp.13-19
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• 2018

BACKGROUND/OBJECTIVES: One of the mechanisms considered to be prevalent in the development of Alzheimer's disease (AD) is hyper-stimulation of microglia. Black chokeberry (Aronia melanocapa L.) is widely used to treat diabetes and atherosclerosis, and is known to exert anti-oxidant and anti-inflammatory effects; however, its neuroprotective effects have not been elucidated thus far. MATERIALS/METHODS: We undertook to assess the anti-inflammatory effect of the ethanolic extract of black chokeberry friut (BCE) in BV2 cells, and evaluate its neuroprotective effect in the lipopolysaccharide (LPS)-induced mouse model of AD. RESULTS: Following stimulation of BV2 cells by LPS, exposure to BCE significantly reduced the generation of nitric oxide as well as mRNA levels of numerous inflammatory factors such as inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), interleukin 1 beta ($IL-1{\beta}$), and tumor necrosis factor alpha ($TNF-{\alpha}$). In addition, AD was induced in a mouse model by intraperitoneal injection of LPS ($250{\mu}g/kg$), subsequent to which we investigated the neuroprotective effects of BCE (50 mg/kg) on brain damage. We observed that BCE significantly reduced tissue damage in the hippocampus by downregulating iNOS, COX-2, and $TNF-{\alpha}$ levels. We further identified the quinic acids in BCE using liquid chromatography-mass spectrometry (LCMS). Furthermore, we confirmed the neuroprotective effect of BCE and quinic acid on amyloid beta-induced cell death in rat hippocampal primary neurons. CONCLUSIONS: Our findings suggest that black chokeberry has protective effects against the development of AD.

• Journal of Ginseng Research
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• v.47 no.6
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• pp.735-742
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• 2023

Background: Gintonin is a new material of ginseng that acts through the ginseng-derived lysophosphatidic acid (LPA) receptor ligand. The gintonin-enriched fraction (GEF) inhibits amyloid plaque accumulation in the cortex and hippocampus, improves cognitive dysfunction by increasing acetylcholine levels, and promoted hippocampal neurogenesis in an animal model of Alzheimer's disease. We evaluated the effect of the GEF on the cognitive performance of subjects with subjective memory impairment (SMI). Methods: In this eight-week, randomized, assessor- and participant-blinded, placebo-controlled study, participants with SMI were assigned to three groups receiving placebo, GEF 300 mg/day or GEF 600 mg/day. The Korean versions of the Alzheimer's Disease Assessment Scale (K-ADAS), Mini-Mental State Examination (K-MMSE), and Stroop color-word test (K-SCWT) were also evaluated along with the safety profiles. Results: One hundred thirty-six participants completed the study. After eight weeks, we analyzed intergroup differences in primary or secondary outcome score changes. When we compared the GEF group with the placebo group, we observed significant improvements in the K-ADAS and K-SCWT scores. The GEF group did not show a significant improvement in K-MMSE and BDI scores compared to the placebo group. No adverse events were observed in the gintonin and placebo groups for eight weeks. Conclusion: The GEF is safe and effective in improving subjective cognitive impairment related to both the K-ADAS and K-SCWT in this study. However, further large-scale and randomized controlled studies are warranted to secure other cognitive function tests besides the K-ADAS and K-SCWT, and to confirm the findings of the current study.

• The Korean Journal of Physiology and Pharmacology
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• v.72 no.4
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• pp.517-528
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• 2021

Aamylin or islet amyloid polypeptide (IAPP) is a peptide synthesized and secreted with insulin by the pancreatic β-cells. A role for amylin in the pathogenesis of type 2 diabetes (T2D) by causing insulin resistance or inhibiting insulin synthesis and secretion has been suggested by in vitro and in vivo studies. These studies are consistent with the effect of endogenous amylin on pancreatic β-cells to modulate and/or restrain insulin secretion. Here, we reported the correlation between amylin and insulin in rat insulinoma inS-1e cells by treating 2-deoxy-ᴰ-glucose (2-DG) and/or mannose. Cell viability was not affected by 24 h treatment with 2-DG and/or mannose, but it was significantly decreased by 48 h treatment with 5 and 10 mm 2-DG. in the 24 h treatment, the synthesis of insulin in the cells and the secretion of insulin into the media showed a significant inverse association. in the 48-h treatment, amylin synthesis vs. the secretion and insulin synthesis vs. the secretion showed a significant inverse relation. The synthesis of amylin vs. insulin and the secretion of amylin vs. insulin showed a significant inverse relationship. The p-ERK, antioxidant enzymes (Cu/Zn-superoxide dismutase (SOD), Mn-SOD, and catalase), and endoplasmic reticulum (ER) stress markers (cleaved caspase-12, CHOP, p-SAPK/JNK, and BiP/GRP78) were significantly increased or decreased by the 24 h and 48 h treatments. These data suggest the relative correlation to the synthesis of amylin by cells vs. the secretion into the media, the synthesis of amylin vs. insulin, and the secretion of amylin vs. insulin under 2-DG and/or mannose in rat insulinoma INS-1E cells. Therefore, these results can provide primary data for the hypothesis that the amylin-insulin relationships may be involved with the human amylin toxicity in pancreatic beta cells.