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Peroxiredoxin 2 (Prx2) regulates oxidative stress response in neuronal injury. The present study examined the effects of Prx2 deletion on transient global ischemia-induced hippocampal-dependent memory impairment. First, 20-min bilateral common carotid artery occlusion (BCCAO)-reperfusion and sham-operated control procedures were conducted in 6- or 7-month-old Prx2 knockout and wild-type mice. The cognitive status of these mice was assessed using the Morris water maze task with a hidden platform and a novel object recognition task 7 days after the 20-min BCCAO. Next, to evaluate neuronal degeneration and oxidative stress in the CA1 subregion of the hippocampus critical for learning and memory, we measured immunoreactive Fluoro-jade C (FJC)-positive signals and 4-hydroxy-2-trans-nonenal (4-HNE) levels, respectively. The 20-min BCCAO induced cognitive impairments and increased the intensity of FJC-positive signals and 4-HNE levels of CA1 in Prx2 knockout mice but not in wild-type mice. These results suggest that Prx2 deficiency reduces resilience to transient global ischemia.

Cerebrovascular lesions are widely prevalent in patients with Alzheimer’s disease (AD), but their relationship to the pathophysiology of AD remains poorly understood. An improved understanding of the interaction of cerebrovascular damage with AD is crucial for the development of therapeutic approaches. Herein, we investigated the effects of chronic cerebral hypoperfusion (CCH) in a 5XFAD transgenic (Tg) mouse model of AD. We established CCH conditions in both Tg and non-Tg mice by inducing unilateral common carotid artery occlusion (UCCAO). Cognitive performance in mice was evaluated, and their brain tissue was examined for amyloid-beta (Aβ) pathology to elucidate possible mechanisms. We found that UCCAO-operated Tg mice showed impaired cognitive flexibility in the reversal phase of the hidden-platform water maze task compared to sham-operated Tg mice. Interestingly, UCCAO-operated Tg mice used fewer spatial cognitive strategies than sham-operated Tg mice during reversal learning. These cognitive deficits were accompanied by increased Aβ plaque burden and Aβ42 levels in the hippocampus and prefrontal cortex, 2 regions that play essential roles in the regulation of cognitive flexibility. Furthermore, changes in cognitive flexibility are strongly correlated with the expression levels of enzymes related to Aβ clearance, such as neprilysin and insulin-degrading enzymes. These findings suggest that, in 5XFAD mice, impaired cognitive flexibility is related to CCH, and that Aβ clearance might be involved in this process.

Genetically modified mouse models are being used predominantly to understand brain functions and diseases. Well-designed and controlled behavioral analyses of genetically modified mice have successfully led to the identification of gene functions, understanding of brain diseases, and development of treatments. Recently, complex and higher cognitive functions have been examined in mice with genetic mutations. Therefore, research strategies for cognitive phenotyping should be sophisticated and evolve to convey the exact meaning of the findings and provide robust translational tools for testing hypotheses and developing treatments. This review addresses issues of experimental design and discusses studies that have examined cognitive function using mouse strain differences, genetically modified mice, and transgenic mice for Alzheimer's disease., Graphical Abstract

Oxidative stress was implicated in the functional impairment of the frontal cortex observed in early Alzheimer&rsquo, s disease (AD). To elucidate this role in an animal AD model, we assessed cognitive function of 4-month-old five familial AD (5XFAD) transgenic (Tg) mice using a learning strategy-switching task requiring recruitment of the frontal cortex and measuring levels of 4-hydroxy-2-trans-nonenal (4-HNE), a marker of oxidative stress, in their frontal cortex. Mice were sequentially trained in cued/response and place/spatial versions of the water maze task for four days each. 5XFAD and non-Tg mice exhibited equal performance in cued/response training. However, 5XFAD mice used spatial search strategy less than non-Tg mice in the spatial/place training. Immunoblot and immunofluorescence staining showed that 4-HNE levels increased in the frontal cortex, but not in the hippocampus and striatum, of 5XFAD mice compared to those in non-Tg mice. We report early cognitive deficits related to the frontal cortex and the frontal cortex&rsquo, s oxidative damage in 4-month-old 5XFAD mice. These results suggest that 4-month-old 5XFAD mice be a useful animal model for the early diagnosis and management of AD.

Mumefural is a bioactive compound derived from the processed fruit of Prunus mume Sieb. et Zucc., a traditional health food, however, its safety has not been evaluated. We investigated the toxicity of mumefural through single and repeated oral administration at doses of 1250, 2500, and 5000 mg/kg in Institute of Cancer Research (ICR) mice. The acute toxicity assessment was not associated with adverse effects or death. Similarly, the subacute (four weeks) toxicity assessment did not reveal any mumefural-associated mortality, abnormal organ damage, or altered clinical signs, body weight, food consumption, or hematological parameters. However, albumin/globulin ratio and chloride ion levels were significantly increased in male mice treated with mumefural at &ge, 2500 mg/kg. Female mice exhibited significantly higher levels of chloride, sodium, and potassium ions, at a dose of 5000 mg/kg. Furthermore, the administration of 2500 and 5000 mg/kg mumefural decreased the absolute weight of spleen in male mice. These findings indicated that the approximate lethal dose of mumefural in ICR mice was &gt, 5000 mg/kg. No significant mumefural toxicity was observed at &le, 5000 mg/kg. Our findings provide a basis for conducting future detailed studies to evaluate reproductive, neurological, genetic, and chronic toxicity of mumefural.

Angiogenic factors contribute to cerebral angiogenesis following cerebral hypoperfusion, and understanding these temporal changes is essential to developing effective treatments. The present study examined temporal alterations in angiogenesis-related matrix metalloproteinase-9 (MMP-9) and angiopoietin-2 (ANG-2) expression in the hippocampus following bilateral common carotid artery occlusion (BCCAo). Male Wistar rats (12 weeks of age) were randomly assigned to sham-operated control or experimental groups, and expression levels of MMP-9 and ANG-2 were assessed after BCCAo (1 week, 4 weeks, and 8 weeks), using western blotting. Protein expression increased 1 week after BCCAo and returned to control levels at 4 and 8 weeks. In addition, immunofluorescence staining demonstrated that the MMP-9- and ANG-2-positive signals were primarily observed in the NeuN-positive neurons with very little labeling in non-neuronal cells and no labeling in endothelial cells. In addition, these cellular locations of MMP-9- and ANG-2-positive signals were not altered over time following BCCAo. Other angiogenic factors such as vascular endothelial growth factor and hypoxia-inducible factor did not differ from controls at 1 week; however, expression of both factors increased at 4 and 8 weeks in the BCCAo group compared to the control group. Our findings increase understanding of alterations in angiogenic factors during the progression of cerebral angiogenesis and are relevant to developing effective temporally based therapeutic strategies for chronic cerebral hypoperfusion-associated neurological disorders such as vascular dementia., Graphical Abstract

In the present study, 48 hydrolysable tannins and 12 polyhydroxytriterpenoid derivatives were isolated from Terminalia chebula fruit and assessed for their inhibitory activities on cholinesterases in vitro. Among them, phyllanemblinin F (compound 35), chebulanin (36), 23-Galloyl arjunolic acid (55), and Arjunetin (=24-deoxy sericoside) (56) showed strong inhibition against acetylcholinesterase (AChE) with IC 50 values of 24.02, 21.36, 67.25, and 47.85 μM, respectively. Though corilagin (15) and several gallotannins (8, 12, 14) exhibited weak inhibitory activity against butyrylcholinesterase, the majority of compounds from T. chebula showed inhibition of AChE. Since cognitive dysfunction is closely related to diminution of cholinergic transmission, our results suggest that compounds from T. chebula could be used as potential treatment for dementia.

Background Cinnamomum cassia bark is the outer skin of an evergreen tall tree belonging to the family Lauraceae containing several active components such as essential oils (cinnamic aldehyde and cinnamyl aldehyde), tannin, mucus and carbohydrate. They have various biological functions including anti-oxidant, anti-microbial, anti-inflammation, anti-diabetic and anti-tumor activity. Previously, we have reported that anti-cancer effect of cinnamon extracts is associated with modulation of angiogenesis and effector function of CD8+ T cells. In this study, we further identified that anti-tumor effect of cinnamon extracts is also link with enhanced pro-apoptotic activity by inhibiting the activities NFκB and AP1 in mouse melanoma model. Methods Water soluble cinnamon extract was obtained and quality of cinnamon extract was evaluated by HPLC (High Performance Liquid Chromatography) analysis. In this study, we tested anti-tumor activity and elucidated action mechanism of cinnamon extract using various types of tumor cell lines including lymphoma, melanoma, cervix cancer and colorectal cancer in vitro and in vivo mouse melanoma model. Results Cinnamon extract strongly inhibited tumor cell proliferation in vitro and induced active cell death of tumor cells by up-regulating pro-apoptotic molecules while inhibiting NFκB and AP1 activity and their target genes such as Bcl-2, BcL-xL and survivin. Oral administration of cinnamon extract in melanoma transplantation model significantly inhibited tumor growth with the same mechanism of action observed in vitro. Conclusion Our study suggests that anti-tumor effect of cinnamon extracts is directly linked with enhanced pro-apoptotic activity and inhibition of NFκB and AP1 activities and their target genes in vitro and in vivo mouse melanoma model. Hence, further elucidation of active components of cinnamon extract could lead to development of potent anti-tumor agent or complementary and alternative medicine for the treatment of diverse cancers.

Chronic cerebral hypoperfusion (CCH) has been proposed to contribute to the progression of memory loss, which is the main symptom of vascular cognitive impairment (VCI). Accumulating evidence indicates that underlying pathophysiology, such as neurodegeneration, may lead to memory loss. However, the underlying molecular basis of memory loss in CCH remains unclear. Here, we investigated the roles of canonical Wnt signaling, which modulates hippocampal function, in a CCH model. CCH was induced by unilateral common carotid artery occlusion (UCCAO). Mice were randomly divided into a sham-operated group or one of three UCCAO groups with different endpoints (1.5, 2.5, and 3.5 months) after UCCAO. Memory function and hippocampal levels of Wnt-related proteins were measured. A Wnt activator, lithium, was administered intraperitoneally to assess memory improvements. In the groups examined 2.5 and 3.5 months after UCCAO, impaired object recognition memory was accompanied by inhibition of Wnt signaling and decreased expression of synaptic/neural activity-related proteins. Recognition memory and Wnt signaling were significantly positive correlated. Moreover, activation of Wnt signaling with lithium significantly attenuated memory loss and recovered synaptic/neural marker expression after UCCAO. Our results suggest that CCH may affect synaptic plasticity via dysregulation of signaling pathways, including canonical Wnt signaling, which could be partly involved in memory loss. As Wnt activator administration alleviated the effects of CCH on memory loss, modulation of Wnt signaling may be a promising therapeutic strategy for VCI.

Fructus mume (F. mume), the unripe fruit of Prunus mume, has long been used in Asian countries to treat cough and chronic diarrhea. We previously reported that F. mume exerts anti-inflammatory effects in a model of chronic cerebral hypoperfusion (CCH), a key etiological factor of vascular dementia (VaD). The present study was performed to investigate the protective effects of an ethanolic extract of F. mume on the inflammatory response and cholinergic dysfunction in a model of CCH induced by bilateral common carotid artery occlusion (BCCAo) in Wistar rats. Rats were assigned to three treatment groups: sham plus vehicle, BCCAo plus vehicle, and BCCAo plus F. mume extract (200 mg/kg). F. mume was administered by oral gavage from days 21 to 42 following BCCAo. Glial cell numbers were measured in the white matter and hippocampus. The hippocampal expressions of proinflammatory cytokines, angiotensin-II (Ang-II), receptor for advanced glycation end products (RAGE), and mitogen-activated protein kinase (MAPKs) were also evaluated. Choline acetyltransferase (ChAT) levels in the hippocampus and basal forebrain were examined. Rats with BCCAo showed an increase in the number of glial cells and levels of proinflammatory cytokines, Ang-II, RAGE, and MAPKs, all of which were significantly attenuated by F. mume treatment. F. mume administration also restored ChAT expression in the basal forebrain and hippocampus following chronic BCCAo. These results suggest that F. mume is a potentially valuable drug or nutraceutical for the treatment of VaD.

Early diagnosis and treatment of AD are critical for delaying its progression. The present study, therefore, examined the cognitive status and neuropathological characteristics of 4-month-old 5X familial AD (5XFAD) transgenic (Tg) mice, as an early stage of AD animal model. The novel object recognition task was performed with retention tests at varying intervals (i.e., 10 min, 1 h, 4 h, and 24 h) to measure the retention capacity of recognition memory of 5XFAD mice. At the 4h retention interval, 5XFAD mice exhibited worse performances than non-Tg control mice. Therefore, using amyloid-beta (Aβ) 42- and 4G8-immunoreactive plaques, the accumulation of Aβ was examined in the gray and white matter of the system that was necessary for the retention of recognition memory, with a focus on the hippocampus and retrosplenial cortex. The expression of ionized calcium-binding adapter molecule-1 (Iba-1) was also examined to measure microglial activation. The immunohistological analysis of Aβ and Iba-1 revealed that the retrosplenial cortex was the most affected region in the brains of 4-month-old 5XFAD mice. These findings indicate that the cognitive and neuropathological characteristics of 4-month-old 5XFAD mice would provide a research platform for studying early diagnosis and treatment of AD.

In this study, the chemical diversity of polyphenols in Iris lactea var. chinensis seeds was identified by combined MS/MS-NMR analysis. Based on the annotated chemical profile, the isolation of stilbene oligomers was conducted, and consequently, stilbene oligomers (1-10) were characterized. Of these, compounds 1 and 2 are previously undescribed stilbene dimer glycoside (1) and tetramer glycoside (2), respectively. Besides, to evaluate this plant seed as a rich source of stilbene oligomers, we quantified three stilbene oligomers of I. lactea var. chinensis seeds. The contents of three major stilbene oligomers&mdash, trans-&epsilon, viniferin (3), vitisin A (6), and vitisin B (9)&mdash, in I. lactea var. chinensis seeds were quantified as 2.32 (3), 4.95 (6), and 1.64 (9) mg/g dry weight (DW). All the isolated compounds were tested for their inhibitory activities against influenza neuraminidase. Compound 10 was found to be active with the half maximal inhibitory concentration (IC50) values at 4.76 &mu, M. Taken together, it is concluded that I. lactea var. chinensis seed is a valuable source of stilbene oligomers with a human health benefit.

Apios americana is an important food crop producing edible tubers with high nutritional and medicinal values and is widely cultivated in many countries. Despite its usefulness, research on its secondary metabolites and biological activities has been limited. In the present study, a new coumaronochromone, (2 R,3 S)-3,7,4'-trihydroxy-5-methoxycoumaronochromone (1), and two new isoflavone glucosides, 7,2',4'-trihydroxy-5-methoxyisoflavone-4'- O-β-d-glucopyranoside (3) and 5,7,4'-trihydroxyisoflavone-7- O-β-d-gentiotrioside (5), were isolated from the tubers of A. americana via chromatographic separation. Seventeen known compounds (2, 4, and 6-20) were also obtained from this plant part. The chemical structures of 1, 3, and 5 were determined by the interpretation of spectroscopic data. The absolute structure of the new compound 1 was established from experimental and calculated electronic circular dichroism spectra. This is the first study to determine the absolute configuration of a 3-hydroxycoumaronochromone derivative. The potential anti-inflammatory activity of the 20 isolates obtained was evaluated by measuring their inhibitory effects on nitric oxide production in lipopolysaccharide-stimulated RAW 264.7 macrophages. Among the isolates, seven compounds (1, 3, 6-8, 15, and 20) showed substantial inhibition of nitric oxide production in RAW 264.7 cells, with the most active being compound 1 (IC

Background Terminalia chebula Retz. (Combretaceae) is a traditional herbal medicine that is widely used in the treatment of diabetes, immunodeficiency diseases, and stomach ulcer in Asia. However, the anti-amnesic effect of T. chebula has not yet been investigated. The present study was designed to determine whether T. chebula extract (TCE) alleviates amnesia induced by scopolamine in mice. We also investigated possible mechanisms associated with cholinergic system and anti-oxidant effects. Methods TCE (100 or 200 mg/kg) was orally administered to mice for fourteen days (days 1–14), and scopolamine was intraperitoneally injected to induce memory impairment for seven days (days 8–14). Learning and memory status were evaluated using the Morris water maze. Hippocampal levels of acetylcholine (ACh), acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) were measured ex vivo. Levels of reactive oxygen species (ROS), nitric oxide (NO), and malondialdehyde (MDA) in the hippocampus were also examined. Results In the Morris water maze task, TCE treatment reversed scopolamine-induced learning and memory deficits in acquisition and retention. TCE reduced hippocampal AChE activities and increased ChAT and ACh levels in the scopolamine-induced model. Moreover, TCE treatment suppressed scopolamine-induced oxidative damage by ameliorating the increased levels of ROS, NO, and MDA. Conclusion These findings suggest that TCE exerts potent anti-amnesic effects via cholinergic modulation and anti-oxidant activity, thus providing evidence for its potential as a cognitive enhancer for amnesia. Electronic supplementary material The online version of this article (10.1186/s12906-018-2212-y) contains supplementary material, which is available to authorized users.

Objectives: The study aimed to test the validity and reliability of the questionnaire for cold-heat & defi-ciency-excess pattern identification of dementia and establish a new version of the questionnaire.Methods: Mean, standard deviation, skewness, internal consistency, correlation and t-test of the 26 items derived from previous study was analyzed in 20 dementia patients. The items with Cronbach- α coefficient below 0.7 were modified. Thus, we established a new version of the questionnaire consist-ing of 20 items.Results: Cronbach-α of each cold, heat, deficiency and excess questionnaire was 0.662, −0.229, 0.722 and 0.778, respectively. The correlation coefficient between cold, heat, deficiency and excess was less than 0.4 and correlation coefficient between dementia and cold, deficiency was 0.518. On t-test, the t-value of cold, deficiency and dementia was −2.196.Conclusions: The results indicated that cold-heat, deficiency-excess questionnaires showed sat-isfactory discriminant validity. In addition, there was correlation between dementia and cold, deficiency. Finally, we established a new version of the questionnaire for cold-heat, deficiency-excess pattern identification that consisted of 20 items.Key Words: Pattern identification, Dementia, Neurocognitive disorder, Cold-Heat, Deficiency-Excess.

This work was financially supported by grants from the National Research Council of Science and Technology (NST) by the Korean government (MSIP) (CRC-15-04-KIST, G15120, G16230, K16850 and K17850).

Learning strategy preference was assessed in 5XFAD mice, which carry 5 familial Alzheimer's disease (AD) mutations. Mice were sequentially trained in cued and place/spatial versions of the water maze task. After training, a strategy preference test was conducted in which mice were required to choose between the spatial location where the platform had previously been during the place/spatial training, and a visible platform in a new location. 5XFAD and non-transgenic control mice showed equivalent escape performance in both training tasks. However, in the strategy preference test, 5XFAD mice preferred a cued strategy relative to control mice. When the training sequence was presented in the reverse order (i.e., place/spatial training before cued training), 5XFAD mice showed impairments in place/spatial training, but no differences in cued training or in the strategy preference test comparing to control. Analysis of regional Aβ42 deposition in brains of 5XFAD mice showed that the hippocampus, which is involved in the place/spatial learning strategy, had the highest levels of Aβ42 and the dorsal striatum, which is involved in cued learning strategy, showed a small increase in Aβ42 levels. The effect of training protocol order on performance, and regional differences in Aβ42 deposition observed in 5XFAD mice, suggest differential functional recruitment of brain structures related to learning in healthy and AD individuals.

Korean television dramas have become one of the types of broadcasting content most in demand in many Asian countries since the late 1990s. This research examines how the Korean broadcasters...

Chronic cerebral hypoperfusion (CCH) causes cognitive impairment and neurogenic inflammation by reducing blood flow. We previously showed that Fructus mume (F. mume) improves cognitive impairment and inhibits neuroinflammation in a CCH rat model. One of the components of F. mume, Mumefural (MF), is known to improve blood flow and inhibit platelet aggregation. Whether MF affects cerebral and cognitive function remains unclear. We investigated the effects of MF on cognitive impairment and neurological function-related protein expression in the rat CCH model, established by bilateral common carotid arterial occlusion (BCCAo). Three weeks after BCCAo, MF (20, 40, or 80 mg/kg) was orally administrated once a day for 42 days. Using Morris water maze assessment, MF treatment significantly improved cognitive impairment. MF treatment also inhibited cholinergic system dysfunction, attenuated choline acetyltransferase-positive cholinergic neuron loss, and regulated cholinergic system-related protein expressions in the basal forebrain and hippocampus. MF also inhibited myelin basic protein degradation and increased the hippocampal expression of synaptic markers and cognition-related proteins. Moreover, MF reduced neuroinflammation, inhibited gliosis, and attenuated the activation of P2X7 receptor, TLR4/MyD88, NLRP3, and NF-&kappa, B. This study indicates that MF ameliorates cognitive impairment in BCCAo rats by enhancing neurological function and inhibiting neuroinflammation.

Objectives : The aim of this study was to examine anti-thrombotic effect of traditional herbal extracts in a rat model of ferric chloride (FeCl3)-induced carotid arterial thrombosis. Methods : Thirty minutes prior to a 35% FeCl3 application, Sprague Dawley(SD) rats were injected with the 10 types of traditional herbal extracts (100mg/kg, intraperitoneal injection), respectively. The effect of these herbal extracts was examined for time to occlusion(TTO) using the Lase r doppler flow meter and measured for thrombus weight (TW) in FeCl3-induced thrombosis model. Results : In the TTO, Salvia miltiorrhiza (Sm, 2.30±0.28 min, p

Objectives: The aim of this study was to examine the antithrombotic effects of the four herbal ingredients (Mume Fructus, MF; Santali Albi Lignum, SAL; Amomi Tsao-Ko Fructus, ATF; and Amomi Fructus, AF) of modified Jeho-tang (MJHT) in a ferric chloride (FeCl₃)-induced carotid arterial thrombosis model. Methods: Thirty minutes prior to a 35% FeCl₃ application, Sprague-Dawley (SD) rats were injected with saline, MF, SAL, ATF or AF (100 mg/kg, intraperitoneal injection), respectively. The effect of the MJHT ingredients was examined for time to occlusion (TTO) and thrombus weight (TW) in a FeCl₃-induced thrombosis model. Histological analysis was performed to examine the effect of the MJHT ingredients on collagen fiber damage using hematoxylin & eosin and Masson’s trichrome staining. Results: Compared with vehicle treatment, MF, SAL and ATF treatment delayed TTO (vehicle, 8.11 ± 0.60 min; MF, 16.67 ± 1.03 min; SAL, 17.50 ± 1.52 min and ATF, 13.33 ± 1.21 min; P Conclusions: Altogether, these results are the first evidence that the MJHT ingredients MF, SAL and ATF have the ability to prevent vascular damage and thrombus formation in FeCl₃-induced carotid arterial thrombosis.

Objectives: This study examined the effects of 8 types of herbal prescriptions prescribed to alleviate dementia symptoms in a rat model of arterial thrombosis induced by ferric chloride (FeCl3). Methods: Thirty minutes before 35% FeCl3 treatment, SD rats were intraperitoneally injected with the 8 types of herbal prescriptions, respectively. We tested the effects of the herbal prescriptions on time to occlusion (TTO) in an arterial thrombosis model using a laser Doppler flow meter. In addition, thrombus weight (TW) and collagen fiber damages were evaluated in the same condition. Results: Herbal prescriptions showed the following rank-order based on their TTO: Chong-myung-tang (CMT) > modified Jangwonhan 02 (LMK02) > Toki-shakuyaku-san (TSS) Oren-gedoku-to (OGT) Yokukansan (YKS). In particular, CMT (100 mg/kg, i.p.) and LMK02 (100 mg/kg, i.p.) delayed the TTO the most (14.83 ± 0.98 and 13.67 ± 1.03 min, respectively) compared with the vehicle group (7.95 ± 0.78 min, P

Objectives : Recently, the elderly population and dementia prevalence have been rapidly increasing in Korea. Dementia is a concept of syndrome composed of characteristic symptoms. However, there have been no approved treatments for dementia with proven efficacy. Therefore, we investigated Korean traditional treatment being used in clinic and collaborative practice for dementia in the professional group. Methods : We conducted a survey using questionnaires to professors of oriental neuropsychiatry for a month. Items of the questionnaire consisted of overall Korean traditional medical treatment for dementia, which included herbal medicine, acupuncture, moxibustion, cupping, psychotherapy and others. Results : 1. It was shown that Yukmijihwangtanggamibang, Jowiseungcheongtang, Seonghyangjeonggisan have been used the most in herbal medicine. 2. Chechim, Saamchimbeop, and scalp acupuncture have been used the most in acupuncture treatment. 3. In Korean traditional psychotherapy, Ijeongbyeongi, Jieongoronyobeop, Gigongyobeop have been used, and effective in anxiety, agitation, improvement of comprehension for caregiver and environment. 4. Most professors answered that collaborative practice between Korean traditional medicine and western medicine has been needed for dementia. They suggested that herbal medicine, followed by acupuncture, and moxibustion can be used with western medicine simultaneously. Conclusions : The survey revealed that professors use herbal medicine and acupuncture as main treatments for dementia. They share perspective regarding the need of long period to treat dementia patients, and there are needs of collaborative practice for dementia.

Background Ginkgo biloba extract (GBE)—a widely used nutraceutical—is reported to have diverse functions, including positive effects on memory and vasodilatory properties. Although numerous studies have assessed the neuroprotective properties of GBE in ischemia, only a few studies have investigated the neuro-pharmacological mechanisms of action of GBE in chronic cerebral hypoperfusion (CCH). Purpose In the present study, we sought to determine the effects of GBE on CCH-induced neuroinflammation and cholinergic dysfunction in a rat model of bilateral common carotid artery occlusion (BCCAo). Methods Chronic BCCAo was induced in adult male Wistar rats to reflect the CCH conditions. On day 21 after BCCAo, the animals were treated orally with saline or GBE (5, 10, 20, and 40 mg/kg) daily for 42 days. After the final treatment, brain tissues were isolated for the immunohistochemical analysis of glial markers and choline acetyltransferase (ChAT), as well as for the western blot analysis of proinflammatory cytokines, toll-like receptor (TLR)-related pathway, receptor for advanced glycation end products (RAGE), angiotensin-II (Ang-II), and phosphorylated mitogen-activated protein kinases (MAPKs). Results BCCAo increased glial proliferation in the hippocampus and white matter, whereas proliferation was significantly attenuated by GBE treatment. GBE also attenuated the BCCAo-related increases in the hippocampal expression of proinflammatory cytokines (TNF-α, IL-1β, and IL-6), TLR4, myeloid differentiation primary response gene 88, RAGE, Ang-II, and phosphorylated MAPKs (ERK, p38, and JNK). Furthermore, GBE treatment restored the ChAT expression in the basal forebrain following BCCAo. Conclusions These findings suggest that GBE has specific neuroprotective effects that may be useful for the treatment of CCH. The pharmacological mechanism of GBE partly involves the modulation of inflammatory mediators and the cholinergic system.

Fructus mume (F. mume) has been used as a traditional treatment for ulcer, cough, and digestive problems for many years in Asian countries. Previous studies have demonstrated that F. mume extracts alleviate cognitive deficits in rats with chronic cerebral hypoperfusion and in mice with scopolamine treatments. The present experiment was conducted to examine the effects of F. mume on cognitive impairments in 5XFAD transgenic mice with five familial Alzheimer’s disease (AD) mutations. F. mume was administered daily to 5XFAD mice at 12 weeks of age and continued for 90 days. Cognitive function was evaluated using a spatial memory version of the Morris water maze task, the object/location novelty recognition test, and contextual fear conditioning at 24 weeks of age. To elucidate the possible mechanisms underlying the memory improving effects of F. mume in 5XFAD mice, we examined alterations in hippocampal cholinergic function. Vehicle-treated 5XFAD mice exhibited hippocampus-dependent memory impairments compared with non-transgenic littermates, which was reversed in F. mume-treated 5XFAD mice. In addition, reduced hippocampal choline acetyltransferase (ChAT) levels in 5XFAD mice were reversed by F. mume treatment, indicating that F. mume enhances the effects of cholinergic neuronal function. F. mume may have therapeutic effects on cognitive impairments in AD.

Objectives : The purpose of this study was to obtain some knowledge concerning the scalp acupuncture treatment on patients with dementia for the future practice and research from clinical studies in China. Methods : The literatures were searched using the data base-China Academic Journals(CAJ) (2001-2011). Results : We found out 1 case study, and 17 randomized controlled trials(RCT) which met the inclusion criteria in most studies. There were 3 types of scalp acupuncture-applying method, cho-si scalp acupuncture(焦氏頭鍼法), combination of using ordinary acupoints(正經鍼) and extraordinary acupoints(經外寄穴), standard method of scalp acupuncture(標準頭鍼法). The often used acupoints are Yundongqu(運動區), Ganjuequ(感覺區), Yuntingqu(暈聽區), Zuyunganqu(足運感區), Sishencong (HN23), Baihui(GV20), Shenting(GV24), Fengchi(GB20), Dingnieqianxiexian(MS6), and Dingniehouxiexian(MS7). Conclusions : There were significant improvements on the scalp acupuncture-treated groups, compared to the control groups(western medication group or other acupuncture treatment group). Results of this study could be used for future studies concerning the scalp acupuncture for dementia.

Fructus mume(F. mume) has been used as a medicinal food in Japan and has been reported to have anti-inflammatory effects in inflammatory bowel disease and macrophage-mediated inflammation. We investigated the effects ofF. mumeextracts on cognitive dysfunction in rats with chronic cerebral hypoperfusion and the molecular mechanisms underlying these effects. Chronic cerebral hypoperfusion was induced in male Wister rats by bilateral common artery occlusion (BCCAo). Daily administration ofF. mumeextracts was started on day 20 after post-BCCAo and continued for 40 days. The status of hippocampus-dependent memory was evaluated in control rats, rats with chronic cerebral hypoperfusion, and rats with chronic cerebral hypoperfusion that were administeredF. mume. The levels of microglial activation were measured in the hippocampus and the fimbria of hippocampus, and expression levels of hippocampal mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) were examined. Rats that received chronic cerebral hypoperfusion showed spatial memory impairments relative to the control rats; these impairments were reduced by daily administration ofF. mume. Administration ofF. mumemitigated the microglial activation and alterations of hippocampal MAPK and NF-κB signaling in the rats with chronic cerebral hypoperfusion. These results indicate thatF. mumemay possess therapeutic potential for the prevention of vascular dementia via inhibition of inflammatory processes.

Objectives : As the number of patient with dementia increases, interest in mild cognitive impairment (MCI), which is a pre-dementia stage, has been expanding. In this study, we investigated the effects from selected clinical research articles to evaluate the effectiveness of non-pharmacological interventions. Methods : We searched MCI related articles on MEDLINE and the Web of Science using keywords related to MCI. We selected 26 articles, and 13 evaluated efficiency using the Jadad score. Results : Physical exercise and cognitive remediation techniques were effective for improving MCI. Transcutaneous electrical nerve stimulation, taichi, and music belonged to "perhaps" effectiveness group. Many of the 13 articles that evaluated MCI using the Jadad score evaluated them as "good" or "poor", and only three articles evaluated MCI as "excellent". Conclusions : The present evidence suggests that cognitive remediation techniques to improve memory and physical exercise were effective for people with MCI. However, further studies are needed to identify the physical exercise effects.

Objectives : This study was aimed to review the trend of clinical studies in Journal of Oriental Neuropsychiatry since 2001 to 2010. Methods : We collected 260 clinical studies and analyzed them for publish year, sorts of disease or symptoms, pattern identification diagnosis, and classification of clinical studies. Among them, we selected 46 clinical experimental studies and these studies were further analyzed for publish year, research institution, sort of disease or symptoms, sorts of treatments, number of subject, and pattern identification diagnosis. Results : The number of clinical studies in Journal of Oriental Neuropsychiatry have increased since the year of 2001. There were 62 kinds of diseases and symptoms and Hwa-Byung had the highest number of studies followed by depression, headache, insomnia and so on. The clinical experimental studies, which took up 17% of the clinical studies, have increased since 2001 and was varied with year. There were 13 reserch institutions for clinical experimental studies and they studied about stress, dementia, Hwa-Byung, and so on. Most of studies researched treatment about acupuncture, herb medicine, and meditation treatment for persons under 144. There are only 22% of studies using pattern identification diagnosis. Conclusions : For the development of oriental medicine for psychiatric disease, we need more qualifying clinical studies like RCT. We hope more researchers for psychiatry disease of oriental medicine will be interested in the publication of clinical studies and this will serve to produce advance of oriental medicine as evidence based medecine.

Objectives : Trend of R&D of herbal medicine for dementia treatment was examined based on the quantitative information analysis for establishing the national strategy of research on dementia treatment with oriental medicine. Methods : Definition was made to clarify the technology for development of herbal medicine for dementia treatment. Based on the initial keyword provided by experts in the field, queries were compounded to conduct search in the search engines of WoS and DWPI. The raw data (papers or patents) extracted from the initial search were examined by expert-review before objects of analysis were determined. Then, the accumulated data was analyzed in terms of year, country and organization, which led to examination of the trend of R&D. And the research performance evaluation for dementia treatment technologies was also made in terms of country, organization and researcher based on the forward citation analysis. The international cooperation intensity was examined on the basis of analysis of network by researcher before analysis results were put together to select lead researchers. Results : According to the quantitative information analysis of 1,330 articles that were selected as analysis objects, the number of papers on natural products research for dementia treatment has increased by around 4.6 times in recent five years. This indicates that the intensive studies have been underway recently. It was found to be the US that had the highest level in research filed of herbal medicine for dementia treatment and the highest capacity of international cooperation for that purpose. On the contrary, Korea had the share of papers at 5.1%, the number of countries in cooperation research at 8, and the article quality index at 0.40, showing that the qualitative level was insufficient, compared to the quantitative outcome. In particular, Korea was found to have no intensity of international cooperation among researchers. In case of patent, the results of information analysis of 305 patents selected as analysis objects demonstrated that China had the highest share while Korea had the very low frequency of patent application quantitatively. Conclusions : In this study, the research to develop herbal medicine for dementia treatment has recently drawn much attention that has spread around the globe. Therefore, these results suggest establishing the strategy to develop technology for dementia treatment with oriental medicine in the future based on quantitative information analysis.

Ethnopharmacological relevance Extracts of the roots of Scutellaria baicalensis Georgi (Labiatae) have been widely used to relieve fever related to bacterial infection and inflammatory diseases in traditional Korean medicine and have been reported to be effective in brain diseases. These experiments were conducted to examine the effects of oral administration of Scutellaria baicalensis extracts on the rescue of memory impairments induced by chronic cerebral hypoperfusion or chronic lipopolysaccharide (LPS) infusion. In addition, the underlying mechanisms of these effects were investigated. Materials and methods In the first experiment, chronic cerebral hypoperfusion was induced in male Wister rats by bilateral common carotid artery occlusion (BCCAo). Daily administration of Scutellaria baicalensis extracts was started on 20 day after BCCAo and given for 40 days. A Morris water maze was then used to evaluate the status of the hippocampal-dependent spatial learning and hippocampal mitogen-activated protein kinase (MAPK) signaling was examined in control rats, rats with chronic cerebral hypoperfusion, and rats with chronic cerebral hypoperfusion that was administered Scutellaria baicalensis . In the second experiment, hippocampal microglial activation was induced by chronic infusions of LPS into the fourth ventricle of Fisher-344 rat brains. Daily administration of Scutellaria baicalensis extracts was started on 7 day after the surgery of LPS infusion and given for 32 days. Spatial memory and hippocampal microglial activation was then examined in control rats with an artificial cerebrospinal fluid infusion, rats with chronic LPS infusion, and rats with chronic LPS infusion that were administered Scutellaria baicalensis . Results Rats that received chronic cerebral hypoperfusion or chronic LPS infusion showed spatial memory impairments relative to their control rats; however, these symptoms were reduced by daily administration of Scutellaria baicalensis . Administration of Scutellaria baicalensis mitigated alterations of hippocampal MAPK signaling by chronic cerebral infusion and microglial activation by chronic LPS infusion. Conclusions These results indicate that Scutellaria baicalensis may possess therapeutic potential for the prevention of Alzheimer's disease and vascular dementia.

In the current investigation, the status of the septo­hippocampal cholinergic pathway and hippocampal mitogen­activated protein kinase (MAPK) signaling was examined in male Wistar rats with chronic cerebral hypoperfusion, which showed cognitive deficits based on assessment on a version of the Morris water maze. Chronic cerebral hypoperfusion was induced by bilateral common artery occlusion and maintained for 12 weeks until behavioral testing. Chronic cerebral hypoperfusion was shown to induce memory impairments and microglial activation in regions of white matter, including the fimbria of hippocampus. Choline acetyltransferase expression of the basal forebrain and expression of hippocampal MAPKs was decreased in rats with BCCAo compared to control rats. The results of this study suggest that cognitive decline induced by chronic cerebral hypoperfusion could be related to dysfunction of the basal forebrain cholinergic system and reduction of hippocampal MAPK activities.

isolation, structure determination, and inhibitory effects of the new noreudesmane-type sesquiterpenoid 4-methoxy-oxyphyllenone A (I) and fifteen known compounds on NO production in LPS-induced RAW 264.7 cells

To examine the efficacy of modified Je-Ho-Tang extract in terms of its effects on arterial thrombosis and peripheral circulation, in vivo models of both FeCl3-induced thrombosis and peripheral circulatory disturbance induced by cooling were developed. MJHT extract showed potent anti-thrombotic effects and improvement of peripheral blood flow.

To evaluate immunomodulators from herbal medicines that affect the expression of IL-10 and TNF-α, we developed a cell-based high throughput screening system and tested 17 kinds of herbal medicine. We found that extracts of Coptidis Rhizoma can be used to stimulate TNF-α and IL-10 expression.

An in vivo model for assessing the efficacy of aspirin on the improvement of peripheral circulatory was developed by obtaining the cold-induced peripheral blood flow in mice using laser Doppler flowmetry (LDF) and temperature-controlled chambers. ICR mice (w=6) were placed in a temperature-controlled chamber and anesthetized with 1.5% isoflurane. LDF was used to measure the peripheral blood flow during whole-body warming for 10 min (37°C, baseline) and cooling for 40 min (until 13°C). Peripheral blood flow ratio showed significant difference between baseline and whole-body cooling after a lapse of 20 (0.92±0.20) and 40 min (0.33±0.13, p

We investigated the in vitro effect of modified Je-Ho-Tang (MJHT) hot-water extract on platelet aggregation and activation induced by agonists in human whole blood, and on platelet adhesion to a collagen-coated surface under flow shear stress conditions. MJHT extract potently inhibited the collagen-induced platelet aggregation in human whole blood in a dose-dependent manner, with a half-maximal inhibitory dose (IC(50)) value of 526 microg/mL. We accessed several markers of platelet activation using receptor expression on platelet membranes, including GPIIb/IIIa-like expression (PAC-1) and P-selectin (CD62); we monitored the intracellular calcium mobilization response by flow cytometry in healthy subjects. A significant decrease in PAC-1 (P=0.002), CD62 (P=0.002), and intracellular calcium mobilization (P0.001) were seen in the presence of MJHT extract. In addition, we have used image analysis to study human platelet adhesion to collagen under physiologic flow conditions in a perfusion chamber. MJHT extract markedly decreased platelet adhesion to the collagen-coated surface. These results show that MJHT has potent anti-platelet activity.

Studies of rats with chronic bilateral common carotid artery occlusion (BCCAo), an animal model for vascular dementia (VaD), have reported hippocampus-dependent memory impairment and associated neuropathologies. Patients with VaD also experience attentional shifting dysfunction. However, animal models of VaD have not been used to study attentional function. Therefore, the present study examined attentional function in rats with BCCAo, using attentional set-shifting task (ASST) that required rats to choose a food-baited pot from 2 possible pots. ASST included 6 consecutive sessions including simple discrimination, compound discrimination, intradimensional shifting, extradimensional shifting, and reversals. The BCCAo rats were significantly slower at learning the intradimensional set-shifting task compared to control rats. Previous studies have demonstrated that the cingulate cortex and medial prefrontal cortex are critical to intradimensional and extradimensional set-shifting, respectively. Additionally, inflammatory responses and neuronal dysfunction were observed in rats with chronic BCCAo. In addition, OX-6 positive microglia significantly increased in the forceps minor white matter of BCCAo rats, and glutamate decarboxylase signals co-localized with NeuN were reduced in the anterior cingulate cortex of BCCAo rats, compared to control rats. Impaired neuronal and GABAergic neuronal integrity in the anterior cingulate cortex, damage to white matter, and attentional impairments observed in BCCAo rats suggest dysfunction of brain structures that are associated with attentional impairments observed in patients with VaD.

Background Despite the recent identification of several prognostic gene signatures, the lack of common genes among experimental cohorts has posed a considerable challenge in uncovering the molecular basis underlying hepatocellular carcinoma (HCC) recurrence for application in clinical purposes. To overcome the limitations of individual gene-based analysis, we applied a pathway-based approach for analysis of HCC recurrence. Results By implementing a permutation-based semi-supervised principal component analysis algorithm using the optimal principal component, we selected sixty-four pathways associated with hepatitis B virus (HBV)-positive HCC recurrence (p