Search

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.

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.

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

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.

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.

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.

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.

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.

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

A substantial number of studies on basal forebrain (BF) cholinergic neurons (BFCN) have provided compelling evidence for their role in the etiology of stress, cognitive aging, Alzheimer’s disease (AD), and other neurodegenerative diseases. BFCN project to a broad range of cortical sites and limbic structures, including the hippocampus, and are involved in stress and cognition. In particular, the hippocampus, the primary target tissue of the glucocorticoid stress hormones, is associated with cognitive function in tandem with hypothalamic-pituitary-adrenal (HPA) axis modulation. The present review summarizes glucocorticoid and HPA axis research to date in an effort to establish the manner in which stress affects the release of acetylcholine (ACh), glucocorticoids, and their receptor in the context of cognitive processes. We attempt to provide the molecular interactive link between the glucocorticoids and cholinergic system that contributes to BFCN degeneration in stress-induced acceleration of cognitive decline in aging and AD. We also discuss the importance of animal models in facilitating such studies for pharmacological use, to which could help decipher disease states and propose leads for pharmacological intervention.

We investigated whether two-kinds of mixture (NHDT-1 and NHDT-2) mainly composed of Hovenia dulcis Thunb had beneficial actions for alcohol and acetaldehyde degradation in acute alcohol treatment and liver protection from fatty liver induced by chronic alcohol administration. In acute alcohol degradation experiment, serum alcohol and acetaldehyde concentrations exhibited lower 1, 3 and 5 hours after taking 3 g ethanol per kg body weight in NHDT-1 treated rats, but not NHDT-2 including ginseng. On the contrast to the acute effect on alcohol degradation, the long-term alcohol administration revealed that NHDT-2, not NHDT-1, protected the increase in serum concentration of aspartate aminotransferase, alanine aminotrasferase and metabolism similar to the rats not consuming alcohol, leading to decreased triglyceride accumulation in blood and liver. In liver morphological study, NHDT-1 preserved the regular hepatocyte morphology, decreased fat accumulation and reduced sinusoidal leukocyte infiltration in hepatocytes. In conclusion, NHDT-1 plays an important role in alcohol and acetaldehyde degradation without protecting liver damage while NHDT-2 works as hepatocyte protector from alcohol mediated damage.

Neuroinflammation plays a key role in the initiation and progression of neurodegeneration in Alzheimer’s disease (AD). Chronic neuroinflammation results in diminished synaptic plasticity and loss of GluN1 N-methyl-D-aspartate (NMDA) receptors in the hippocampus, leading to the cognitive deficits that are the most common symptoms of AD. Therefore, it is suggested that chronic inflammation may alter expression levels of GluN2A and GluN2B subunits of NMDA receptors and associated intracellular signalling. Chronic neuroinflammation was induced by chronic infusion of lipopolysaccharide (LPS) into the fourth ventricle in Fischer-344 rats. The status of hippocampus-dependent memory was evaluated in control rats and rats chronically infused with LPS. Microglial activation in the hippocampus was examined using immunohistochemical staining. Western blot analysis was used to measure membrane levels of GluN2A and GluN2B subunits of NMDA receptors and mitogen-activated protein kinase (MAPK) in the hippocampi of these rats, and immunofluorescent double labeling was used to assess the cellular location of MAPK. Microglial activation was observed in the hippocampi of rats that showed memory impairments with chronic LPS infusion. Chronic LPS infusion reduced the levels of GluN2A and GluN2B and increased the levels of phosphorylated MAPKs in the hippocampus. MAPK-positive immunoreactivity was observed mostly in the neurons and also in non-neuronal cells. Reductions in GluN2A and GluN2B subunits of NMDA receptors coupled with altered MAPK signaling, in response to inflammatory stimuli may be related to the cognitive deficits observed in AD.

Background: Chronic cerebral hypoperfusion induced by permanent occlusion of the bilateral common carotid artery (BCCAO) in rats has been commonly used for the study of Alzheimer's disease and vascular dementia. Despite the apparent cognitive dysfunction in rats with BCCAO, the molecular markers or pathways involved in the pathological alternation have not been clearly identified. Methods: Temporal changes (sham, 21, 35, 45, 55 and 70 days) in gene expression in the hippocampus of rats after BCCAO were measured using time-course microarray analysis. Gene Ontology (GO) and pathway analyses were performed to identify the functional involvement of temporally regulated genes in BCCAO. Results: Two major gene expression patterns were observed in the hippocampus of rats after BCCAO. One pattern, which was composed of 341 early up-regulated genes after the surgical procedure, was dominantly involved in immune-related biological functions (false discovery rate [FDR]

To identify the position of traditional herbal medicine in dementia research field using mapping technology. Keywords for dementia and traditional herbal medicine for treating dementia were used to extract scientific articles from the Web of Science database from January 2000 to July 2010. A co-occurrence matrix was created based on the concurrent set of author’s keywords occurring in each scientific article, and technology network maps were created from similarity index matrices. Twenty specialized research areas were identified in the dementia field, and the relationship strength was 0.2–0.6. Many research fields were associated with diagnosis and risk factors for dementia. Additionally, the mechanism or cause of dementia is an actively studied field. Traditional herbal medicine for treating dementia was located on a map near the cortical dementia diagnosis and therapy, and frontotemporal dementia research field with a relationship strength of 0.53 and 0.31–0.33 respectively, which demonstrates that traditional herbal medicine for dementia occupies an independent research area with a relationship to existing scientific research fields. Traditional herbal medicine can provide an alternative and complementary approach for treating dementia as evidenced by a scientific mapping analysis.

We hypothesized that roasted Glycyrrhizae Radix (Glycyrrhizin Radix Praeparata, GRP) might modify anti-diabetic action due to compositional changes. Then we examined the anti-diabetic effect and mechanism of raw Glycyrrhizae Radix (GR) and GRP extracts and their major respective components, glycyrrhizin and glycyrrhetinic acid. In partial pancreatectomized (Px) diabetic mice, both GR and GRP improved glucose tolerance, but only GRP enhanced glucose-stimulated insulin secretion as much as exendin-4. Both GR and GRP extracts enhanced insulin-stimulated glucose uptake through peroxisome proliferation-activated receptor (PPAR)-gamma activation in 3T3-L1 adipocytes. Consistently with the results of the mice study, only GRP and glycyrrhetinic acid enhanced glucose-stimulated insulin secretion in isolated islets. In addition, they induced mRNA levels of insulin receptor substrate-2, pancreas duodenum homeobox-1, and glucokinase in the islets, which contributed to improving beta-cell viability. In conclusion, GRP extract containing glycyrrhetinic acid improved glucose tolerance better than GR extract by enhancing insulinotropic action. Thus, GRP had better anti-diabetic action than GR.

The receptor for advanced glycation end products (RAGE) has been reported to have a pivotal role in the pathogenesis of Alzheimer's disease (AD). This study investigated RAGE levels in the hippocampus and cortex of a triple transgenic mouse model of AD (3xTg-AD) using western blotting and immunohistochemical double-labeling to assess cellular localization. Analysis of western blots showed that there were no differences in the hippocampal and cortical RAGE levels in 10-month-old adult 3xTg-AD mice, but significant increases in RAGE expression were found in the 22- to 24-month-old aged 3xTg-AD mice compared with those of age-matched controls. RAGE-positive immunoreactivity was observed primarily in neurons of aged 3xTg-AD mice with very little labeling in non-neuronal cells, with the notable exception of RAGE presence in astrocytes in the hippocampal area CA1. In addition, RAGE signals were co-localized with the intracellular amyloid precursor protein (APP)/amyloid beta (Aβ) but not with the extracellular APP/Aβ. In aged 3xTg-AD mice, expression of human tau was observed in the hippocampal area CA1 and co-localized with RAGE signals. The increased presence of RAGE in the 3xTg-AD animal model showing critical aspects of AD neuropathology indicates that RAGE may contribute to cellular dysfunction in the AD brain.

Background The cardiotonic pill (CP) is a herbal medicine composed of Salvia miltiorrhiza (SM), Panax notoginseng (PN), and Dryobalanops aromatica Gaertner (DAG) that is widely used to treat cardiovascular diseases. The present experiment was conducted to examine the effects of CP on white matter and hippocampal damage induced by chronic cerebral hypoperfusion. Methods Chronic cerebral hypoperfusion was induced in male Wistar rats by permanent bilateral common carotid artery occlusion (BCCAo). Daily oral administration of CP (200 mg/kg) began 21 days after BCCAo and continued for 42 days. The levels of microglial activation and myelin basic protein (MBP) were measured in the white matter and hippocampus of rats with chronic BCCAo, and the expression levels of mitogen-activated protein kinases (MAPKs) and inflammatory markers such as cyclooxygenase-2, interleukin-1β, and interleukin-6 were examined. Results MBP expression was reduced in the white matter and hippocampal regions of rats that received BCCAo. In contrast, reduced levels of MBP were not observed in BCCAo rats given CP treatments. The administration of CP alleviated microglial activation, the alteration of ERK and p38 MAPK signaling, and inflammatory mediator expression in rats with chronic BCCAo. Conclusion These results suggest that CP may have protective effects against chronic BCCAo-induced white matter and hippocampal damage by inhibiting inflammatory processes including microglial activation and proinflammatory mediator expression, and downreguating the hyperphosphorylation of ERK and p38 MAPK signaling.

Background Fructus mume (F. mume) has been used as a traditional medicine for many years in Asian countries. The present study was designed to determine the effect of a 70% ethanol extract of F. mume on white matter and hippocampal damage induced by chronic cerebral hypoperfusion. Methods Permanent bilateral common carotid artery occlusion (BCCAo) was performed on male Wistar rats to induce chronic cerebral hypoperfusion. Daily oral administration of F. mume (200 mg/kg) was initiated 21 days after BCCAo and continued for 42 days. The experimental groups in this study were divided into three groups: a sham-operated group, a BCCAo group, and a BCCAo group that was administered with the F. mume extract. The activation of glial cells, including microglia and astrocytes, and the levels of myelin basic protein (MBP), inflammatory mediators, Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and p38 mitogen-activated protein kinase (MAPK) phosphorylation were measured in brains from rats subjected to chronic BCCAo. Results Our results revealed that F. mume alleviates the reduction in MBP expression caused by chronic BCCAo in the white matter and the hippocampus and significantly attenuates microglial and astrocytic activation induced by chronic BCCAo in the optic tract of white matter. In addition, F. mume treatment reduced the increased expression of cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β) and interleukin-6 (IL-6), as well as the activation of TLR4/MyD88 and p38 MAPK signaling, in the hippocampus of rats subjected to chronic BCCAo. Conclusion Taken together, our findings demonstrate that brain injury induced by chronic BCCAo is ameliorated by the anti-inflammatory effects of F. mume via inhibition of MBP degradation, microglial and astrocytic activation, increased inflammatory mediator expression, and activated intracellular signalings, including TLR4 and p38 MAPK, implying that F. mume is potentially an effective therapeutics for the treatment of vascular dementia. Electronic supplementary material The online version of this article (doi:10.1186/s12906-015-0652-1) contains supplementary material, which is available to authorized users.