• Toxicological Research
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• v.31 no.1
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• pp.17-23
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• 2015

Excessive manganese (Mn) in the brain promotes a variety of abnormal behaviors, including memory deficits, decreased motor skills and psychotic behavior resembling Parkinson's disease. Hereditary hemochromatosis (HH) is a prevalent genetic iron overload disorder worldwide. Dysfunction in HFE gene is the major cause of HH. Our previous study has demonstrated that olfactory Mn uptake is altered by HFE deficiency, suggesting that loss of HFE function could alter manganese-associated neurotoxicity. To test this hypothesis, Hfe-knockout ($Hfe^{-/-}$) and wild-type ($Hfe^{+/+}$) mice were intranasally-instilled with manganese chloride ($MnCl_2$ 5 mg/kg) or water daily for 3 weeks and examined for memory function. Olfactory Mn diminished both short-term recognition and spatial memory in $Hfe^{+/+}$ mice, as examined by novel object recognition task and Barnes maze test, respectively. Interestingly, $Hfe^{-/-}$ mice did not show impaired recognition memory caused by Mn exposure, suggesting a potential protective effect of Hfe deficiency against Mn-induced memory deficits. Since many of the neurotoxic effects of manganese are thought to result from increased oxidative stress, we quantified activities of anti-oxidant enzymes in the prefrontal cortex (PFC). Mn instillation decreased superoxide dismutase 1 (SOD1) activity in $Hfe^{+/+}$ mice, but not in $Hfe^{-/-}$ mice. In addition, Hfe deficiency up-regulated SOD1 and glutathione peroxidase activities. These results suggest a beneficial role of Hfe deficiency in attenuating Mn-induced oxidative stress in the PFC. Furthermore, Mn exposure reduced nicotinic acetylcholine receptor levels in the PFC, indicating that blunted acetylcholine signaling could contribute to impaired memory associated with intranasal manganese. Together, our model suggests that disrupted cholinergic system in the brain is involved in airborne Mn-induced memory deficits and loss of HFE function could in part prevent memory loss via a potential up-regulation of anti-oxidant enzymes in the PFC.

• Korean Journal of Pharmacognosy
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• v.49 no.2
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• pp.182-187
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• 2018

Many plant derived phytochemicals have been considered as the main therapeutic strategy against Alzheimer's disease (AD). AD is a progressive neurodegenerative disorder, and the most predominant cause of dementia in the elderly. Cholinergic deficit, senile plaque/${\beta}$-amyloid ($A{\beta}$) peptide deposition and oxidative stress have been identified as three main pathogenic pathways which contribute to the progression of AD. We screened many different plant species for their effective use in both modern and traditional system of medicines. In this study, we tested that MeOH extract of the stem bark of Hopea chinensis (Merr.) Hand.-Mazz. (HCM) affects on the processing of Amyloid precursor portein (APP) from the APPswe over-expressing Neuro2a cell line. We showed that HCM reduced the secretion level of $A{\beta}42$ and $A{\beta}40$ in a dose dependent manner. We found that HCM increased over 1.5 folds of the secretion level of $sAPP{\alpha}$, a metabolite of ${\alpha}$-secretase. Furthermore, we found that HCM inhibited acetylcholinesterase activity in vitro. We suggest that the stem bark of Hopea chinensis may be a useful source to develop a therapeutics for AD.

• The Journal of Dong Guk Oriental Medicine
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• v.4
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• pp.67-80
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• 1995

This study was done in order to investigate the treatment of occidental and oriental medicine on dementia(mainly senile dementia and cerobrovascular dementia). The results were as follows ; 1. Dementia must treat a direct causes, but uncountable dementia(senile dementia) and cerobrovascular dementia can't treat at present. 2. Sciopsychological treatment in very important in dementia patient ; maintance of appropriate stimulation, psychological rest, physical examination, dietary cure and safety device is needed. On secondary mental disorder, antipsychotics, anxiolytics and antidepressants have to prescribe properly. 3. Treatments of Senile dementia(uncountable cerebral degenerative disease) proscribed hydergine which is peripheral vasodilator and physostigmine which increase cholinergic activity of brain, but this have slight effect on some patients. On treatments of cerobrovascular dementia, the medication that improved the cell metabolism and circulation of brain, this improved only a subjective symptom, but isn't foundamental treatment. 4. A tonic medicine is used basically, the methods are as follows. 1) Kenwihwadam(健胃火痰)-Sesimtang(洗心湯) 2) Bosiniksu(補腎益髓)-Hwansodan(還少丹) 3) Bosimiksin(補心益腎)-Gyuibitang(歸脾湯), Singyuo(神交湯) 4) Boheoansin(補虛安神)-Cilbokem(七福飮), sanggitang(生氣湯) 5) geoeohwalhyel(祛瘀活血)-tonggyuhwalhyeltang(通竅活血湯), 5. Acupuncture therapy on dementia used follow acupuncture point ; Yamen(啞門 GVl5), Laokung(勞宮 HC8), Tsusanli(足三里 ST36), Shenshu(腎兪 BL23), Tachui(大椎 GVl4), Chiuwei(鳩尾 CVl5), Sanyinchiao(三陰交 SP6), Yungchuan(涌泉 KI1), Shipsun(十宣), Shousanli(手三里 LI10), Taichong(太衝 LV3) In moxibustion therapy, Dachui(大椎 GVl4) point is used.

• YAKHAK HOEJI
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• v.22 no.3
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• pp.163-174
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• 1978

Plantaginis seed has been applied in Chinese medicine a as well as in folk remedy. It was advocated that Plantaginis S Semeη exerts good therapeutic effects as anti-inflammatory, antitussive, obstipant and diuretic agent in some cases of alimentary, respiratory a and renal disorders. This study was carried out in order to r re-evaluate the pharmacological action, especially the hypotensive a action of Plantaginis Semen and to elucidate the mechanism of its a action, making use of Plantaginis Semen methanol extract (PME), because its basic pharmacological action, i. e., hypotensive action is n not clear. 1) PME, when administered into intravenous route, elicited the h hypotensive response dependent on the dose of PME given to the rabbit anesthetized with urethane. 2) This hypotensive response of P PME was inhibited by atropine and potentiated by physostigmine, but not influ$\varepsilon$need by vagotomization. 3) Depressor effect of PME was blocked by chlorisondamine, phentolamine, and bethanicline, while not altered by cyproheptadine, diphenhydramine and propran¬olol. 4) The secondary pressor response after blocking the depressor e effect of PME by chlorisondamine was produced, but this pressor response was deminished by atropine. 5) PME augmented the pressor e effect of norepinephrine and angiotensin, on the other hand, reduced b blood pressure elevated by carotid occlusion reflex. 6) These observa¬t tions suggest that PME may induce the hypotensive response via dual mechanisms of parasympathomimetic and sympatholytic action, that the positions of this action are cholinergic peripheral site and sympathetic ganglia respectively, and that PME may possess the pressor activity caused by stimulation of "atropine-sensitive site" which seems to existsin the sympathetic ganglia.

• Korean Journal of Medicinal Crop Science
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• v.25 no.6
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• pp.353-360
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• 2017

Background: A critical features of Alzheimer's disease (AD) is cognitive dysfunction, which partly arises from decreased in acetylcholine levels. AD afftected brains are characterized by extensive oxidative stress, which is thought to be primarily induced by the amyloid beta ($A{\beta}$) peptide. In a previous study, Cinnamomum loureiroi tincture inhibited acetylcholinesterase (AchE) activity. That study identified AChE inhibitor in the C. loureiroi extract. Furthermore, the C. loureiroi extract enhanced memory in a trimethyltin (TMT)-induced model of cognitive dysfunction, as assessed via two behavioral tests. Rosa laevigata extract protected against oxidative stress-induced cytotoxicity. Administrating R. laevigata extracts to mice significantly reversed $A{\beta}$-induced learning and memory impairment, as shown in behavioral tests. Methods and Results: We conducted behavioral to examine the synergistic effects of C. loureiroi and R. laevigata extracts in inhibiting AChE and counteracting TMT-induced learning and memory losses. We also performed biochemical assays. The biochemical results showed a relationship between increased oxidative stress and cholinergic neurons damage in TMT-treated mice. Conclusions: A diet containing C. loureiroi and R. laevigata extracts ameliorated learning and memory impairments in the Y-maze and passive avoidance tests, and exerted synergistic inhibitory effect against AChE and lipid peroxidation.

• Journal of Neurogastroenterology and Motility
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• v.24 no.4
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• pp.643-655
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• 2018

Background/Aims Irritable bowel syndrome (IBS) is a common disease characterized by intestinal dysmotility, the mechanism of which remains elusive. We aim to determine whether the high-affinity choline transporter 1 (CHT1), a determinant of cholinergic signaling capacity, modulates intestinal motility associated with stress-induced IBS. Methods A rat IBS model was established using chronic water avoidance stress (WAS). Colonic pathological alterations were evaluated histologically and intestinal motility was assessed by intestinal transit time and fecal water content (FWC). Visceral sensitivity was determined by visceromotor response to colorectal distension. RT-PCR, western blotting, and immunostaining were performed to identify colonic CHT1 expression. Contractility of colonic muscle strips was measured using isometric transducers. enzyme-linked immunosorbent assay was used to measure acetylcholine (ACh). We examined the effects of MKC-231, a choline uptake enhancer, on colonic motility. Results After 10 days of WAS, intestinal transit time was decreased and fecal water content increased. Visceromotor response magnitude in WAS rats in response to colorectal distension was significantly enhanced. Protein and mRNA CHT1 levels in the colon were markedly elevated after WAS. The density of CHT1-positive intramuscular interstitial cells of Cajal and myenteric plexus neurons in WAS rats was higher than in controls. Ammonium pyrrolidine dithiocarbamate partly reversed CHT1 upregulation and alleviated colonic hypermotility in WAS rats. Pharmacological enhancement of CHT1 activity by MKC-231 enhanced colonic motility in control rats via upregulation of CHT1 and elevation of ACh production. Conclusion Upregulation of CHT1 in intramuscular interstitial cells of Cajal and myenteric plexus neurons is implicated in chronic stress-induced colonic hypermotility by modulation of ACh synthesis via nuclear factor-kappa B signaling.

• Korean Journal of Medicinal Crop Science
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• v.19 no.6
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• pp.456-463
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• 2011

The present study examined the effects of Korean white ginseng (WG, Panax ginseng C. A. Meyer) on the learning and memory function and the neural activity in rats with trimethyltin (TMT)-induced memory deficits. The rats were administered with saline or WG (WG 100 or 300 mg/kg, p.o.) daily for 21 days. The cognitive improving efficacy of WG on the amnesic rats, which was induced by TMT, was investigated by assessing the Morris water maze test and by performing immunohistochemistries on choline acetyltransferase (ChAT), acetylcholinesterase (AchE), cAMP responsive element binding protein (CREB) and brain derived neurotrophic factor (BDNF). The rats treated with TMT injection (control group) showed impaired learning and memory of the tasks, but the rats treated with TMT injection and WG administration produced significant improvement of the escape latency to find the platform in the Morris water maze at the 2nd and 4th days compared to that of the control group. In the retention test, the WG 100 and WG 300 groups showed significantly increased crossing number around the platform compared to that of the control group (p < 0.001). Consistently with the behavioral data, result of immunohistochemistry analysis showed that WG 100 mg/kg significantly alleviated the loss of BDNF-ir neurons in the hippocampus compared to that of the control group (p < 0.01). Also, treatment with WG has a trend to be increased the cholinergic neurons in the hippocampal CA1 and CA3 areas as compared to that of the control group. These results suggest that WG may be useful for improving the cognitive function via regulation of neurotrophic activity.

• The Journal of Internal Korean Medicine
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• v.29 no.1
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• pp.117-129
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• 2008

Background & Objective : Naeso-san(NSS) has been used for the treatment of functional dyspepsia, regarded as a gastric dysmotility disease. A main cause of gastric dysmotility is antral dilatation or antroduodenal uncoordination. Therefore, we investigated the effect of NSS on gastric motility and its mechanism of action, as well as the morphologic changes in antral dilatated rats. Methods : Antral dilatated rats were induced by wrapping a nonabsorbable rubber ring(D:6mm, W:4mm, T:1mm) around the 1st portion of the duodenum for 8 weeks. Then morphologic changes were investigated and compared with normal intact rats before and after 8 weeks. Gastric emptying was measured by administration of normal saline(NS) or NSS in normal intact and antral dilatated rats. In another series of experiments to evaluate the mechanism of NSS under delayed conditions, normal intact rats were treated with atropine sulfate(1mg/kg, s.c.), quinpirole HCl(0.3mg/kg, i.p.), $NAME(N^{G}-nitro-L-arginine$ methyl ester, 75mg/kg, s.c.) and cisplatin(10mg/kg, i.p.), respectively. The myoelectrical activity of the gastric smooth muscle was recorded in normal intact and antral dilatated rats. The contractile waves were measured for 30 minutes before and after administration of each solution(NS, NSS). Results : Body weight gain of antral dilatated rats was significantly lower than that of the controls. Futhermore, we found the thickness of the mucosal and muscular layers and surface area of the stomach increased significantly compared with controls. NSS 278㎎/㎏ improved gastric emptying more than normal saline or NSS 93mg/kg in normal intact(p=0.026) and antral dilatated rats(p=0.03). NSS enhanced gastric emptying significantly in the NAME treated group(p=0.002). NSS 278mg/kg increased the significant postprandial dominant power than that of NS in normal intact rats, whereas there was no statistical significance in antral dilatated rats. Conclusions : NSS stimulates gastric motility through the cholinergic pathway. We expect that pathologic model with antral dilatation can be used as an exprimental tool which is similar to dyspepsia and NSS would be effective especially in dysmotility-like functional dyspepsia with antral dilatation or impaired reservoir functions such as gastric adaptive relaxation.

• Journal of Ginseng Research
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• v.33 no.4
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• pp.349-354
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• 2009

This study was conducted to develop a new method for enhancing ginsenoside $Rg_3$, which is abundant in black ginseng. The cognition-enhancing effect of black ginseng extract was investigated via the assay of acetylcholinesterase (AChE) activity. Black ginseng I was prepared through the traditional method (by steaming and drying nine times repetitions). Black ginseng II, on the other hand, was prepared by steaming the ginseng three times at $120^{\circ}C$ for 30 min after soaking it in grape juice for 24 h. The ginsenosides of white, red, and black ginseng I, and II were investigated using the HPLC method, respectively. In black ginseng II, the ginsenoside $Rg_3$ contents, which cannot be found in white ginseng, amounted to 10.91 mg/g, approximately 18 times more than that in red ginseng. In the in-vivo study, black ginseng extract (200 mg/kg, p.o.) inhibited the AChE activity after 24 h by a single administration in the brain. Thus, the new manufacturing method for black ginseng was found to more effective in the conversion of ginsenoside $Rg_3$ compared to the traditional method. Black ginseng may also have the effect of preventing the cognitive impairment induced by cholinergic dysfunction.

• Proceedings of the Ginseng society Conference
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• 1998.06a
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• pp.1-11
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• 1998

Ameliorating mechanisms of red ginseng on learning deficits were investigated in the following 3 experiments; its effects on 1) place learning deficits in aged rats and in young rats with selective hippocampal lesions (behavioral study), 2) long-term potentiation in the hippocampal formation (neuro- physiological study), and 3) ChAT (choline acetyl transferase) activity in various brain regions of aged rats (pharmacological study). In the behavioral study, first, performance in the place learning tasks were compared among 3 groups of young and aged rats; control young intact rats (10-12 week old) treated with water, aged rats (28-32 month old) treated with water, and aged rats (28-32 month old) treated with red ginseng (100 mghglday) suspended in water. Second, performance in the place learning tasks was compared among 3 groups of young rats; control intact rats treated with water, rats with bilateral hippocampal lesions treated with water, and rats with bilateral hippocampal lesions treated with red ginseng (100 mg/kg/day). Each rat in these 2 behavioral experiments was tested with the 3 types of the place learning tasks in a circular open field using intracranial self-stimulation (ICSS) as reward. The ICSS reward was delivered if the rat (1) moved distance of 100-160 cm (DMT): (2) entered an experiment-determined reward place within the open field, and this place was randomly varied in sequential trials (RRPST); or (3) entered 2 specific places, and did a shuttle behavior between the 2 places (PLT). Performance of the aged rats in the ginseng group was not significantly different from that of control young rats in ICSS (current intensity, bar press rates), DMT and RRPST. However, treatment with red ginseng significantly ameliorated place-navigation learning deficits in aged rats in the PLT. Similarly, red ginseng ameliorated learning and memory deficits in young rats with hippocampal lesions in the same tasks. In the neurophysiological study using young rats, perfusion of hippocampal slices with non-sapon in fraction of red ginseng significantly enhanced magnitudes of the long-term potentiation (LfP) in the CA3 subfield. In the pharmacological study, treatment with red ginseng did not affect ChAT activity in aged rat brain including the hippocampal formation. These results strongly suggest that red ginseng ameliorates learning and memory deficits in aged rats through actions on the CA3 subfield of the hippocampal formation, which were independent of the presynaptic components of the cholinergic system