• Journal of Physiology & Pathology in Korean Medicine
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• v.25 no.3
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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.

• YAKHAK HOEJI
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• v.49 no.2
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• pp.168-173
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• 2005

Alzheimers disease (AD) is the most prevalent form of neurodegenerations associated with aging in the human population. This disease is characterized by the extracellular deposition of beta-amyloid (A ${\beta}$) peptide in cerebral plaques. The A ${\beta}$ peptide is derived from the ${\beta}$-amyloid precursor protein ( ${\beta}$APP). Photolytic processing of ${\beta}$APP by ${\beta}$-secretase(beta-site APP-cleaving enzyme, BASE) and ${\gamma}$-secretase generates the A ${\beta}$ peptide. Several lines of evidence support that A ${\beta}$-induced neuronal cell death is major mechanisms of development of AD. Accordingly, the ${\beta}$-and ${\gamma}$-secretase have been implicated to be excellent targets for the treatment of AD. We previously found that sesaminol glucosides have improving effect on memory functions through anti-oxidative mechanism. In this study, to elucidate possible other mechanism (inhibition of ${\beta}$-and ${\gamma}$-secretase) of sesaminol glucosides, we examined the improving effect of sesaminol glucosides in the scopolamine (1 mg/kg/mouse)-induced memory dysfunction using water maze test in the mice. Sesaminol glucosides (3.75, 7.5 mg/kg/6ml/day p.o., for 3 weeks) reversed the latency time, distance and velocity by scopolamine in dose dependent manner. Next, ${\beta}$-and ${\gamma}$-secretase activities were determined in different regions of brain. Sesaminol glucosides dose-dependently attenuated scopolamine-induced ${\beta}$-secretase activities in cortex and hippocampous and ${\gamma}$-secretase in cortex. This study therefore suggests that sesaminol glucosides may be a useful agent for prevention of the development or progression of AD, and its inhibitory effect on secretase may play a role in the improving action of sesaminol glucosides on memory function.

• Korean Journal of Acupuncture
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• v.35 no.4
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• pp.187-202
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• 2018

Objectives : Non-invasive transcranial electrical stimulation is one of therapeutic interventions to change in neural excitability of the cortex. Transcranial electro-acupuncture (TEA) can modulate brain functions through changes in cortical excitability as a model of non-invasive transcranial electrical stimulation. Some composites of fermented Scutellaria baicalenis (FSB) can activate intercellular signaling pathways for activation of brain-derived neurotrophic factor that is critical for formation of neural plasticity in stroke patients. This study was aimed at evaluation of combinatory treatment of TEA and FSB on behavior recovery and cortical neural excitability in rodent focal stroke model. Methods : Focal ischemic stroke was induced by photothrombotic injury to the motor cortex of adult rats. Application of TEA with 20 Hz and $200{\mu}A$ in combination with daily oral treatment of FBS was given to stroke animals for 3 weeks. Motor recovery was evaluated by rotating bean test and ladder working test. Electrical activity of cortical pyramidal neurons of stroke model was evaluated by using multi-channel extracellular recording technique and thallium autometallography. Results : Compared with control stroke group who did not receive any treatment, Combination of TEA and FSB treatment resulted in more rapid recovery of forelimb movement following focal stroke. This combination treatment also elicited increase in spontaneous firing rate of putative pyramidal neurons. Furthermore expression of metabolic marker for neural excitability was upregulated in peri-infract area under thallium autometallography. Conclusions : These results suggest that combination treatment of TEA and FSB can be a possible remedy for motor recovery in focal stroke.

• The Korean Journal of Physiology and Pharmacology
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• v.6 no.3
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• pp.143-147
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• 2002

Granule cells in dentate gyrus of hippocampus relay information from entorhinal cortex via perforant fiber to pyramidal cells in CA3 region. Their electrical activities are known to be closely associated with seizure activity as well as memory acquisition. Since action potential is a stereotypic phenomena which is based on all-or-none principle of $Na^+$ current, the neuronal firing pattern is mostly dependent on afterpotentials which follows the stereotypic $Na^+$ spike. Granule cells in dentate gyrus show afterdepolarization (ADP), while interneurons in dentate gyrus have afterhyperpolarizaton. In the present study, we investigated the ionic mechanism of afterdepolarization in hippocampal dentate granule cell. Action potential of dentate granule cells showed afterdepolarization, which was characterized by a sharp notch followed by a depolarizing hump starting at about $-49.04{\pm}1.69\;mV\;(n=43,\;mean{\pm}SD)$ and lasting $3{\sim}7$ ms. Increase of extracellular $Ca^{2+}$ from 2 mM to 10 mM significantly enhanced the ADP both in amplitude and in duration. A $K^+$ channel blocker, 4-aminopyridine (4-AP, 2 mM), enhanced the ADP and often induced burst firings. These effects of 10 mM $Ca^{2+}$ and 4-AP were additive. On the contrary, the ADP was significantly suppressed by removal of external $Ca^{2+},$ even in the presence of 4-AP (2 mM). A $Na^+$ channel blocker, TTX (100 nM), did not affect the ADP. From these results, it is concluded that the extracellular $Ca^{2+}$ influx contributes to the generation of ADP in granule cells.

• Journal of Physiology & Pathology in Korean Medicine
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• v.33 no.2
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• pp.131-140
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• 2019

The objective of present study is to evaluate concentration-dependent in vitro anti-osteoarthritic (OA) effects of synergic mixed formula consisted of dried pomegranate juice concentrate powder, Eucommiae Cortex aqueous extract and Achyranthis Radix aqueous extract 5:4:1 (g/g) mixture on the primary cultured rat articular chondrocytes. First, any cytotoxic effect of mixture was observed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium Bromide) assay. Next, cyto-protective effect of test substances was evaluated by using the recombinant human interleukin $(rhIL)-1{\alpha}$ induced chondrocytes. In addition, anti-inflammatory effects were also observed on the lipopolysaccaride (LPS) treated chondrocytes through prostaglandin $E_2(PGE_2)$ productions and 5-lipoxygenase (LPO) activities, and inhibitory effects on matrix metalloproteinase (MMP)-2 and MMP-9 activities were observed on $rhIL-1{\alpha}$ treated chondrocytes with their extracellular matrix (ECM) related mRNA expressions. No obvious cytotoxic effects of mixture were demonstrated. Inflammatory damages of chondrocytes and related ECM degradations induced by treatment of LPS or $rhIL-1{\alpha}$ were significantly and concentration-dependently inhibited by pretreatment of mixture from a concentration level of 0.001 mg/ml to 1 mg/ml. In addition, mixture showed $IC_{50}$ for $rhIL-1{\alpha}-induced$ MMP-2 and MMP-9 activities as 44.01 and $162.47{\mu}g/ml$, and also showed $EC_{50}$ for $rhIL-1{\alpha}-induced$ inhibition of collagen type II, SOX9 and aggrecan mRNA expression as 8.61, 10.79 and $4.47{\mu}g/ml$, respectively. It is observed that mixture showed concentration-dependent anti-inflammatory and cytoprotective ECM preserved effects on the primary cultured rat articular chondrocytes without cytotoxicity.

• Molecules and Cells
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• v.40 no.9
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• pp.613-620
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• 2017

The most common form of senile dementia is Alzheimer's disease (AD), which is characterized by the extracellular deposition of amyloid ${\beta}-peptide$ ($A{\beta}$) plaques and the intracellular formation of neurofibrillary tangles (NFTs) in the cerebral cortex. Tau abnormalities are commonly observed in many neurodegenerative diseases including AD, Parkinson's disease, and Pick's disease. Interestingly, tau-mediated formation of NFTs in AD brains shows better correlation with cognitive impairment than $A{\beta}$ plaque accumulation; pathological tau alone is sufficient to elicit frontotemporal dementia, but it does not cause AD. A growing amount of evidence suggests that soluble $A{\beta}$ oligomers in concert with hyperphosphorylated tau (pTau) serve as the major pathogenic drivers of neurodegeneration in AD. Increased $A{\beta}$ oligomers trigger neuronal dysfunction and network alternations in learning and memory circuitry prior to clinical onset of AD, leading to cognitive decline. Furthermore, accumulated damage to mitochondria in the course of aging, which is the best-known nongenetic risk factor for AD, may collaborate with soluble $A{\beta}$ and pTau to induce synapse loss and cognitive impairment in AD. In this review, I summarize and discuss the current knowledge of the molecular and cellular biology of AD and also the mechanisms that underlie $A{\beta}-mediated$ neurodegeneration.

• Biomolecules & Therapeutics
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• v.22 no.3
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• pp.232-238
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• 2014

Alzheimer's disease (AD) is the most common neurodegenerative disease without known ways to cure. A key neuropathologic manifestation of the disease is extracellular deposition of beta-amyloid peptide (Ab). Specific mechanisms underlying the development of the disease have not yet been fully understood. In this study, we investigated effects of 4-O-methylhonokiol on memory dysfunction in APP/PS1 double transgenic mice. 4-O-methylhonokiol (1 mg/kg for 3 month) significantly reduced deficit in learning and memory of the transgenic mice, as determined by the Morris water maze test and step-through passive avoidance test. Our biochemical analysis suggested that 4-O-methylhonokiol ameliorated $A{\beta}$ accumulation in the cortex and hippocampus via reduction in beta-site APP-cleaving enzyme 1 expression. In addition, 4-O-methylhonokiol attenuated lipid peroxidation and elevated glutathione peroxidase activity in the double transgenic mice brains. Thus, suppressive effects of 4-O-methylhonokiol on $A{\beta}$ generation and oxidative stress in the brains of transgenic mice may be responsible for the enhancement in cognitive function. These results suggest that the natural compound has potential to intervene memory deficit and progressive neurodegeneration in AD patients.

• Journal of Ginseng Research
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• v.40 no.4
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• pp.445-452
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• 2016

Background: Red ginseng and ginsenosides have shown plethoric effects against various ailments. However, little is known regarding the effect of red ginseng on morphine-induced dependence and tolerance. We therefore investigated the effect of red ginseng extract (RGE) and biotransformed ginsenosides Rh2, Rg3, and compound K on morphine-induced dependence in mice and rats. Methods: While mice were pretreated with RGE and then morphine was injected intraperitoneally, rats were infused with ginsenosides and morphine intracranially for 7 days. Naloxone-induced morphine withdrawal syndrome was estimated and conditioned place preference test was performed for physical and psychological dependence, respectively. Western blotting was used to measure protein expressions. Results: Whereas RGE inhibited the number of naloxone-precipitated jumps and reduced conditioned place preference score, it restored the level of glutathione in mice. Likewise, ginsenosides Rh2, Rg3, and compound K attenuated morphine-dependent behavioral patterns such as teeth chattering, grooming, wet-dog shake, and escape behavior in rats. Moreover, activated N-methyl-D-aspartate acid receptor subunit 1 and extracellular signal-regulated kinase in the frontal cortex of rats, and cultured cortical neurons from mice were downregulated by ginsenosides Rh2, Rg3, and compound K despite their differential effects. Conclusion: RGE and biotransformed ginsenosides could be considered as potential therapeutic agents against morphine-induced dependence.

• Biomolecules & Therapeutics
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• v.15 no.1
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• pp.16-26
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• 2007

Tissue plasminogen activator (tPA) is a serine protease catalyzing the proteolytic conversion of plasminogen into plasmin, which is involved in thrombolysis. During last two decades, the role of tPA in brain physiology and pathology has been extensively investigated. tPA is expressed in brain regions such as cortex, hippocampus, amygdala and cerebellum, and major neural cell types such as neuron, astrocyte, microglia and endothelial cells express tPA in basal status. After strong neural stimulation such as seizure, tPA behaves as an immediate early gene increasing the expression level within an hour. Neural activity and/or postsynaptic stimulation increased the release of tPA from axonal terminal and presumably from dendritic compartment. Neuronal tPA regulates plastic changes in neuronal function and structure mediating key neurologic processes such as visual cortex plasticity, seizure spreading, cerebellar motor learning, long term potentiation and addictive or withdrawal behavior after morphine discontinuance. In addition to these physiological roles, tPA mediates excitotoxicity leading to the neurodegeneration in several pathological conditions including ischemic stroke. Increasing amount of evidence also suggest the role of tPA in neurodegenerative diseases such as Alzheimer's disease and multiple sclerosis even though beneficial effects was also reported in case of Alzheimer's disease based on the observation of tPA-induced degradation of $A{\beta}$ aggregates. Target proteins of tPA action include extracellular matrix protein laminin, proteoglycans and NMDA receptor. In addition, several receptors (or binding partners) for tPA has been reported such as low-density lipoprotein receptor-related protein (LRP) and annexin II, even though intracellular signaling mechanism underlying tPA action is not clear yet. Interestingly, the action of tPA comprises both proteolytic and non-proteolytic mechanism. In case of microglial activation, tPA showed non-proteolytic cytokine-like function. The search for exact target proteins and receptor molecules for tPA along with the identification of the mechanism regulating tPA expression and release in the nervous system will enable us to better understand several key neurological processes like teaming and memory as well as to obtain therapeutic tools against neurodegenerative diseases.

• Nutrition Research and Practice
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• v.14 no.5
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• pp.438-452
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• 2020

BACKGROUND/OBJECTIVES: Brain senescence causes cognitive impairment and neurodegeneration. It has also been demonstrated that curcumin (Cur) and hesperetin (Hes), both antioxidant polyphenolic compounds, mediate anti-aging and neuroprotective effects. Therefore, the objective of this study was to investigate whether Cur, Hes, and/or their combination exert anti-aging effects in D-galactose (Dg)-induced aged neuronal cells and rats. MATERIALS/METHODS: SH-SY5Y cells differentiated in response to retinoic acid were treated with Cur (1 μM), Hes (1 μM), or a combination of both, followed by 300 mM Dg. Neuronal loss was subsequently evaluated by measuring average neurite length and analyzing expression of β-tubulin III, phosphorylated extracellular signal-regulated kinases, and neurofilament heavy polypeptide. Cellular senescence and related proteins, p16 and p21, were also investigated, including their regulation of antioxidant enzymes. In vivo, brain aging was induced by injecting 250 mg/kg body weight (b.w.) Dg. The effects of supplementing this model with 50 mg/kg b.w. Cur, 50 mg/kg b.w. Hes, or a combination of both for 3 months were subsequently evaluated. Brain aging was examined with a step-through passive avoidance test and apoptosis markers were analyzed in brain cortex tissues. RESULTS: Cur, Hes, and their combination improved neuron length and cellular senescence by decreasing the number of β-gal stained cells, down-regulated expression of p16 and p21, and up-regulated expression of antioxidant enzymes, including superoxide dismutase 1, glutathione peroxidase 1, and catalase. Administration of Cur, Hes, or their combination also tended to ameliorate cognitive impairment and suppress apoptosis in the cerebral cortex by down-regulating Bax and poly (ADP-ribose) polymerase expression and increasing Bcl-2 expression. CONCLUSIONS: Cur and Hes appear to attenuate Dg-induced brain aging via regulation of antioxidant enzymes and apoptosis. These results suggest that Cur and Hes may mediate neuroprotective effects in the aging process, and further study of these antioxidant polyphenolic compounds is warranted.