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Alzheimer’s Disease

Effect of electroacupuncture at governor vessel on learning-memory ability and serum levels of APP and Aβ 1-42 in patients with Alzheimer’s disease

XIA Kun-peng;PANG Jing;LI Shu-lin;ZHANG Miao;LI Hong-lin;WANG Yu-jue

Chinese Acupuncture & Moxibustion,2020,Vol 40,No. 04

【Abstract】 Objective To compare the therapeutic effect of electroacupuncture (EA) combined with donepezil hydrochloride with that of donepezil hydrochloride alone in improving learning-memory ability in patients with Alzheimer’s disease (AD), and to explore its action mechanism. Methods Sixty patients of AD were randomly divided into an observation group and a control group, with 30 cases in each group. The patients in the observation group were treated with EA at governor vessel combined with donepezil hydrochloride. EA was applied at Baihui (GV20) and Fengfu (GV16), and the dilatational wave was selected for bearable stimulation at the frequency of 10 Hz/50 Hz and the intensity of 0.5–5.0 mA. The needles were retained for 40 min. EA was given once a day. The donepezil hydrochloride tablet was taken orally, 5 mg per time, once a day, and after four weeks of treatment, the dosage might be increased to 10 mg per day according to the specific situation. All the treatments lasted for eight weeks. The patients in the control group were only treated with donepezil hydrochloride in the same way as that in the observation group. The Montreal Cognitive Assessment (MoCA) and Alzheimer’s disease Assessment Scale-cognitive Subscale (ADAS-Cog) were evaluated before and after treatment; P300 (latencies and amplitudes of N2 and P3) was detected by the electroencephalograph (EEG) / event-related brain potential (ERP) system, and amyloid precursor protein (APP) and β-amyloid protein 1-42 (Aβ1-4 2) were detected by ELISA. Results Compared with those before treatment, the MoCA scores were increased after treatment in the two groups ( P < 0.05), and the MoCA score in the observation group was higher than that in the control group ( P < 0.05). Compared with those before treatment, the ADAS-Cog scores were decreased after treatment in the two groups ( P < 0.05), and the ADAS-Cog score in the observation group was lower than that in the control group ( P < 0.05). Compared with those before treatment, the latencies of N2 and P3 were shortened and the amplitudes were increased after treatment in the two groups ( P < 0.05). After treatment, the latencies of N2 and P3 in the observation group were shorter than those in the control group and the amplitudes were higher than those in the control group ( P < 0.05). Compared with those before treatment, the serum levels of APP and Aβ1-4 2 were decreased after treatment in the two groups ( P < 0.05), and the serum levels of APP and Aβ1-4 2 in the observation group were lower than those in the control group ( P < 0.05). Conclusion EA at Baihui (GV 20) and Fengfu (GV 6) combined with donepezil hydrochloride can effectively reduce the serum levels of APP and Aβ1-4 2 and improve the scores of MoCA and ADAS-Cog as well as the levels of N2 and P3 of P300 in AD patients. Such combination is superior to donepezil hydrochloride alone in improving the learning and memory abilities of AD patients.

A network pharmacology study on mechanism of Tibetan medicine Byur d Mar Nyer lNga Ril Bu against Alzheimer’s disease

HU Xian-da

Chinese Pharmacological Bulletin,2019,Vol 35,No. 01

【Abstract】 Aim To investigate the underlying pharmacological mechanism of Tibetan medicine Byur dMar 25 (BM25) in the treatment of Alzheimer’s disease (AD) based on network pharmacology approaches. Methods The potential target of the main blood components after oral administration of BM25 was predicted through reverse pharmacophore mapping scheme, and the main biological functions and cell signaling pathways were systematically analyzed based on bioinformatics strategies. Results BM25, as a multi-component drug with numerous potential targets may mainly participate in MAPK, insulin, mTOR signaling pathways, contributing to different biological functions including inflammation, apoptosis, and expression and clearance of beta amyloid (Aβ). Conclusion BM25 could interfere the progress of Alzheimer's disease, and the mechanism is a concerted pharmacological intervention of multiple components and targets.

Effect of acupuncture on the ultrastructure of neurons and astrocytes in the hippocampal dentate gyrus in rats with Alzheimer’s disease induced by Aβ 1-42

TANG Shuang-hong;DU Yan-jun;TAO Yi-ming;TIAN Qing;KONG Li-hong

Chinese Acupuncture & Moxibustion,2019,Vol 39,No. 03

【Abstract】 Objective To observe the effects of acupuncture at “Baihui” (GV 20) and Shenshu (BL 23) on the ultrastructure of hippocampal dentate gyrus in rats with Alzheimer’s disease. Methods Forty SPF Wistar male rats were randomly divided into a normal group, a sham operation group, a model group and an acupuncture group, 10 rats in each one. The rats in the model group and the acupuncture group were treated with injection of 5 μL Aβ1–4 2 at bilateral hippocampus, while the rats in the sham operation group were treated with injection of 5 μL 0. 9% NaCl. Three days after modeling, the rats in the acupuncture group were treated with acupuncture at “Baihui” (GV 20) and Shenshu (BL 23) for 20 min, once a day, six treatments constituted a course, and totally two courses were given with an interval of 1 day between courses. The rats in the other groups received normal diet and no treatment was given. Before modeling, four days after modeling and after treatment, water maze test was performed to observe the escape latency and the number of crossing platforms. The hippocampal dentate gyrus was collected and transmission electron microscope was applied to observe the ultrastructure changes of neurons and astrocytes. Results ① Four days after modeling, compared with the normal group and the sham operation group, the escape latency was significantly prolonged and the number of crossing platforms was reduced in the model group (all P < 0.01); after treatment, compared with the model group, the escape latency was significantly reduced and the number of crossing platforms was increased in the acupuncture group (both P < 0.01). ② In the normal group and the sham operation group, the morphology of neurons and astrocytes was intact, the nuclear and membrane structure were clear, and the morphology of organelles such as mitochondria, endoplasmic reticulum and lysosomes was normal. In the model group, the morphology of neurons was irregular, the nucleus was severely constricted with edema in the cytoplasm, the color of heterochromatin was deepened, the endoplasmic reticulum was expanded, the granulation was removed and the number of mitochondria was decreased, even with malformed-like change in mitochondrial cristae; there was severe edema around astrocytes, few organelles in the cytoplasm, severe swelling of mitochondria and mild expansion of the endoplasmic reticulum. In the acupuncture group, the edema of the neuron and astrocytes was still evident, and the mitochondrial was mildly swollen but relieved compared with that in the model group, and there were no obvious abnormalities in neuronal endoplasmic reticulum and ribosomes. Conclusion Acupuncture could improve the ultrastructure of neurons and astrocytes in the hippocampal dentate gyrus in rats with Alzheimer’s disease induced by Aβ1–4 2.

Moxibustion improves learning-memory ability by promoting cellular autophagy and regulating autophagy-related proteins in hippocampus and cerebral cortex in APP/PS1 transgenic Alzheimer's disease mice

ZHU Cai-feng;ZHANG Li-da;SONG Xiao-ge;YANG Jun;PAN Hong-ping;HE Cheng-gong;YANG Kun;QIN Xiao-feng;ZHU Wan-li

Acupuncture Research,2019,Vol 44,No. 04

【Abstract】 Objective To observe the effect of moxibustion of acupoints of the governor vessel on the levels of cellular autophagy, amyloid β protein (Aβ) immunoactivity, and expression of LC3-Ⅰ, LC3-Ⅱ, p62 and p-P70S6K proteins in the hippocampal tissue of APPswe/PS1de9 (APP/PS1) double-transgenic Alzheimer’s disease (AD) mice, so as to reveal its underlying mechanisms in improving AD. Methods APP/PS1 double-AD transgenic mice were randomly divided into AD model, moxibustion, autophagy inducer (rapamycin) and autophagy-inhibitor (3-MA) + moxibustion groups ( n = 10 in each group), and other 10 C57BL/6J male mice (the same age) were used as the normal control group. Herbal-cake (made of Chuanwu [Radix Aconiti Praeparata]) partitioned moxibustion was applied to Baihui (GV20), Fengfu (GV16) and Dazhui (GV14), all for 20 min, once daily for 2 weeks, with one day’s off between two weeks. For mice of the autophagy-inducer and 3-MA + moxibustion groups, rapamycin (2 mg·kg −1·d −1) and 3-MA (1.5 mg·kg −1·d −1) were separately administered by intraperitoneal injection for 2 weeks. The cognitive ability was examined by Morris water maze tests, and the ultrastructural changes (including autophagic lysosomes, etc.) of hippocampal neurons were observed by using transmission electron microscopy. The immunoactivity of cerebral cortex and hippocampal Amyloid β peptide 1-42 (Aβ 1-42) was detected by immunohistochemistry, and the expression levels of hippocampal LC3-Ⅰ, LC3-Ⅱ, p62 and p-P70S6K proteins were detected by Western blot. Results After modeling, the escape latency of Morris water maze tasks was prolonged in the model group than in the normal control group ( P < 0.05) and obviously shortened in the moxibustion and autophagy-inducer groups (not the autophagy-inhibitor group) than in the model group ( P < 0.05). Results of transmission electron microscope showed deformed, irregular or atrophic neurons with rough and incomplete and fuzzy nuclear membrane, and decreased intracellular autophagosomes in the hippocampus in the model group, and partial irregular, atrophic neurons with more autophagic vesicles and lysosomes in the moxibustion group. The expression levels of Aβ 1-42 in both cerebral cortex and hippocampus tissues, and LC3-Ⅰ, p62 and p-P70S6K proteins in the hippocampus were considerably up-regulated in the model group relevant to the normal control group ( P < 0.01), and evidently down-regulated in both moxibustion and autophagy-inducer groups (not the autophagy-inhibitor group) than in the model group ( P < 0.01), while that of hippocampal LC3-Ⅱ protein and LC3-Ⅱ/Ⅰ ratio levels were obviously down-regulated in the model group relevant to the normal control group ( P < 0.01), and significantly up-regulated in both moxibustion and autophagy-inducer groups (not the autophagy inhibitor group) than in the model group ( P < 0.01). Conclusion Moxibustion can improve the cognitive ability of APP/PS1 double-AD transgenic mice, which is associated with its effects in promoting hippocampal and cerebral cortex autophagy level, and down-regulating the expression levels of Aβ 1-42, LC3-Ⅰ, p62and p-P70S6K proteins in the hippocampus.

Effects of cluster needling at the scalp points on the expression of ChAT and AchE of hippocampus in rats with Alzheimer’s disease

LI Hong-lin;GAO Wei;XIA Kun-peng;SUN Qi-yue;TONG Xiao-wei;LUAN Kai-di;ZHU Hong-qi;QI Hui-min;ZHU Bin;XU Fei

Chinese Acupuncture & Moxibustion,2019,Vol 39,No. 04

【Abstract】 Objective To explore the effects of cluster needling at the scalp points on the expression of choline acetyl transferase (ChAT) and choline cholinesterase (AchE). Methods A total of 60 Wistar rats were randomized into a sham-operation group, a model group, a medication group and a cluster needling group, with 15 rats in each one. In the model group, the medication group and the cluster needling group, the Alzheimer’s disease (AD) model was established by the injection of Aβ1-42 in the bilateral hippocampal CA1 areas in the rats. In the sham-operation group, the distilled water was injected in bilateral hippocampus of rats. In the medication group, the aricept was intragastrically administrated, once a day, for four weeks consecutively. In the cluster needling group, on the basis of the medication, the cluster needling at the scalp points was adopted, once a day, six times a week, for four weeks totally. In the sham-operation group and the model group, the normal feeding was provided. After intervention, the learning and memory ability was measured with Morris water maze in the rats of each group. The changes in the hippocampal gross structure were observed after HE staining. The changes in the positive expressions of hippocampal ChAT and AchE were determined with the immunohistochemical method. Results Compared with the sham-operation group, the escape latency was prolonged and the percentage of the second quadrant and the frequency of platform leaping were reduced in the rats of the model group (all P < 0.01). Compared with the model group, the escape latency was shortened and the percentage of the second quadrant and the frequency of platform leaping were increased in the rats of the cluster needling group and the medication group ( P < 0.05, P < 0.01). Compared with the medication group, the escape latency was shortened and the percentage of the second quadrant and the frequency of platform leaping were increased in the rats of the cluster needling group (all P < 0.05) . Compared with the sham-operation group, the expression of ChAT was decreased and that of AchE increased in the model group (both P < 0.01). Compared with the model group, the difference was not significant in ChAT expression ( P > 0.05) and the expression of AchE was reduced ( P < 0.05) in the medication group. The expression of ChAT was increased ( P < 0.05) and that of AchE was decreased ( P < 0.01) in the cluster needling group. Compared with the medication group, the expression of ChAT was increased and that of AchE was decreased in the cluster needling group (both P < 0.05). Conclusion The effect mechanism of cluster needling at the scalp points on AD could be related to the up-regulation of ChAT expression and down-regulation of AchE expression in the hippocampus. The combined treatment of the cluster needling with aricept achieves better therapeutic effect on AD.

Effect of acupuncture plus medication on expression of Bcl-2 and Bax in hippocampus in rats with Alzheimer’s disease

HUANG Rui;GONG Xin;NI Jin-zhong;JIA Yuan-wei;ZHAO Jian

Chinese Acupuncture & Moxibustion,2019,Vol 39,No. 04

【Abstract】 Objective To explore the mechanism of acupuncture plus medication on treatment of Alzheimer’s disease (AD). Methods Sixty adult SD rats were randomly divided into a normal group, a sham operation group, a model group, an electroacupuncture (EA) group, a gastrodin group and an EA + gastrodin group, 10 rats in each one. The rat model of AD was established by intraperitoneal injection of D-galactose and bilateral hippocampal injection of Aβ1–40. Two weeks after modeling, the rats in the EA group and EA + gastrodin group were treated with EA at “Baihui” (GV 20) “Dazhui” (GV 14) and bilateral “Zusanli” (ST 36), 30 min per treatment, once a day for consecutive 4 weeks. The rats in the gastrodin group and EA + gastrodin group were treated with intraperitoneal injection of gastrodin, once a day for consecutive 4 weeks. The rats in the normal group, model group and sham operation group were not treated. The morphology of hippocampal neurons was observed by using HE staining. The expression of Bcl-2 and Bax in the hippocampal CA1 area was detected by using immunohistochemical method. The expression of Bcl-2 and Bax protein in hippocampus was detected by using Western blot. Results The HE staining results showed the arrangement of neurons in the hippocampal CA1 area was regular in the normal group and the sham operation group, and the cytoplasm and nucleus were clearly visible. The neurons in the model group were severely damaged; the cell arrangement was not close, and the cell morphology was incomplete. Compared with the model group, the cell morphology of each intervention group was significantly improved. The immunohistochemistry results showed that, compared with the normal group and the sham operation group, the expression of Bcl-2 in the hippocampal CA1 region in the model group was decreased ( P < 0.05), but the expression of Bax was enhanced ( P < 0.05) ; compared with the model group, the expression of Bcl-2 was increased (all P < 0.05) and the expression of Bax was decreased (all P < 0.05) in all intervention group; compared with the EA group or the gastrodin group, the expression of Bcl-2 was enhanced ( P < 0.05) and the expression of Bax was decreased ( P < 0.05) in the EA + gastrodin group. The result of Western blot method was consistent with that of immunohistochemistry method. Conclusion EA and gastrodin could significantly inhibit the expression of Bax and up-regulate the expression of Bcl-2, and the combination of EA and gastrodin has the most significant effect. This indicates that EA combined with gastrodin has synergistic effect on inhibiting the apoptosis of neurons in hippocampus in AD rats, which may be one of the mechanisms of EA plus medication on AD lesions.

Repositioning drug discovery for Alzheimer’s disease based on global marketed drug data

ZHANG Bao-yue;PANG Xiao-cong;JIA Hao;WANG Zhe;LIU Ai-lin;DU Guan-hua

Acta Pharmaceutica Sinica,2019,Vol 54,No. 07

【Abstract】 Alzheimer’s disease (AD) is a neurodegenerative disease that seriously threatens the life of the elderly and there is no effective therapy to treat or delay the onset of this disease. Due to the multifactorial etiology of this disease, the multi-target-directed ligand (MTDL) approach is an innovative and promising method in search for new drugs against AD. In order to find potential multi-target anti-AD drugs through reposition of current drugs, the database of global drugs on market were mined by an anti-AD multi-target prediction platform established in our laboratory. As a result, inositol nicotinate, cyproheptadine, curcumin, rosiglitazone, demecarium, oxybenzone, agomelatine, codeine, imipramine, dyclonine, melatonin, perospirone, and bufexamac were predicted to act on at least one anti-AD drug target yet act against AD through various mechanisms. The compound–target network was built using the Cytoscape. The prediction was validated by molecular docking between agomelatine and its multiple targets, including ADORA2 A, ACHE, BACE1, PTGS2, MAOB, SIGMAR1 and ESR1. Agomelatine was shown to be able to act on all the targets above. In conclusion, the potential drugs for anti-AD therapy in the database for global drugs on market were partially uncovered using machine learning, network pharmacology, and molecular docking methods. This study provides important information for drug reposition in anti-AD therapy.

Molecular Mechanism for Predicting the Prevention and Treating of Alzheimer’s Disease with Fructus Broussonetiae Based on Network Pharmacology and Molecular Docking Method

HE Kun;YAN Bo;SUN Meng-sheng;HUANG Ying;ZHOU Yi-ming;YAO Li-hua;HUANG Li-ping

Chinese Pharmaceutical Journal,2019,Vol 54,No. 07

【Abstract】 OBJECTIVE To study the material basis and potential functional mechanism of Fructus Broussonetiae in treating Alzheimer’s disease based on network pharmacology and molecular docking method. METHODS The key targets responsible for the treatment of Alzheimer’s disease (AD) in Drug Bank and the literature reports were collected, and the chemical composition set of Fructus Broussonetiae was constructed using TCMSP. The DISCOVERY STUDIO software was used to perform molecular docking, and the chemical composition set in Fructus Broussonetiae that bound to the key targets of AD was virtually screened out, and the key pathways after virtual screening were enriched by the KEGG database. Finally, Cytoscape software was used to construct a Fructus Broussonetiae component-target-pathway network. RESULTS Sixty compounds were screened out from Fructus Broussonetiae, most of which were Fructus Broussonetiae oils such as palmitic acid, oleic acid, and 8,11-octadecadienoic acid, flavonoids such as luteolin and apigenin, as well as coumarins such as scutellarin, coumaric acid, and δ-tocopherol. These active ingredients interact strongly with 27 potential targets associated with AD, and four related pathways responsible for AD were identified, involving apoptosis, energy metabolism, calcium signaling pathway, tumor necrosis factor (TNF) signaling pathway, and insulin resistance. Conclusion The efficacy of Fructus Broussonetiae in treating AD might be related to its regulation of inflammation, oxidative stress, calcium signaling pathway, and TNF signaling pathway. The material bases might be Fructus Broussonetiae oil, luteolin, and δ-tocopherol.

Effect of Panaxatriol Saponin Enzymatic Hydrolysates from Panax ginseng Stem and Leaves on the Treatment of Alzheimer’s Mice Induced by Alchlor/D-Galactose

MA He-tong;ZHU Hong-yan;GAO Yu-gang;HE Zhong-mei;YANG He;ZHAO Yan;BI Yun-feng

Journal of Chinese Medicinal Materials,2019,Vol 42,No. 06

【Abstract】 Objective: To observe the therapeutical effect of panaxatriol saponin enzymatic hydrolysates from Panax ginseng stems and leaves (GSLPSH) on the treatment of Alzheimer’s disease (AD). Methods: The AD model was established by administration of alchlor combined with D-galactose. The changes in learning and memory abilities of mice were measured by step-down test. The activities of acetylcholinesterase (AChE), glutathione peroxidase (GSH-Px), as well as phospho-Tau (P-Tau) and acetylcholine (ACH) content in mouse hippocampus, were detected by ELASA. The expressions of Tau protein, cyclin-dependent-like kinase 5 (CDK5), microtubule-associated protein 2 (MAP2), nuclear factor NF-kappa-B p65 (NF-κB p65), and amyloid beta (Aβ) proteins in mouse hippocampus were observed by immunohistochemistry. Results: GSLPSH could improve the learning and memory ability, reduce the levels of AChE and P-Tau, increase the levels of GSH-Px and ACH, inhibit the expressions of Tau, CDK5, NF-κB p65, and Aβ proteins, and promote the MAP2 protein expression in the hippocampus of AD mice induced by alchlor/ D-galactose. Conclusion: GSLPSH has therapeutic effect on AD model mice induced by alchlor/ D-galactose. It improves symptoms in AD mice by inhibiting the deposition of Aβ protein and the excessive phosphorylation of Tau protein, enhancing the activity of GSH-Px, and reducing the expression of inflammatory factor NF-κB p65.

Kidney-reinforcing and Governor Vessel-regulating EA Intervention May Improve Learning-memory Possibly by Suppressing Formation of Senile Plaques in Hippocampus in APP/PS 1 Double Transgenic Alzheimer’s Disease Mice

YANG Qing-hua;GUO Ling;CHEN Qing;WU Kai-hui;WU Yan-jun;JIA Yan;ZHU Shu-juan;TANG Cheng-lin;SHENG Hua-jun

Acupuncture Research,2018,Vol 43,No. 04

【Abstract】 Objective To observe the effect of electroacupuncture (EA) intervention on learning-memory ability and the expression of senile plaques (SP), amyloid precursor protein (APP), β-secretase 1 (BACE 1) and insulin degrading enzyme (IDE) in the hippocampus in APP/presenilin 1(PS 1) double transgenic Alzheimer’s disease (AD) mice, so as to reveal its mechanisms underlying improvement of AD. Methods A total of 18 male APP/PS 1 double transgenic AD mice were randomly divided into model, two-course EA group and three-course EA group, with six in each group. The control group was consisted of six male wild mice. EA (2 Hz, 2 mA) was applied to “Baihui” (GV 20) and bilateral “Shenshu” (BL 23) once a day, each lasting for 15 min, seven days as a therapeutic course, for two or three courses altogether, with an interval of one day between every two courses. The spatial learning and memory ability was assessed using Morris water maze test during five days’ training. The immunoactivity of SP in the hippocampus tissue was detected by immunohistochemistry, and the expression levels of APP, BACE 1 and IDE in the hippocampus were analyzed by Western blot. Results Following modeling, the escape latency and path length of hidden platform tests were significantly increased ( P < 0.01, P < 0.05), and the platform crossing time of spatial probing test was significantly decreased ( P < 0.01) in the model group as compared with that in the control group. After EA intervention, the escape latency on the 5 th day of training, and the path length on the 4 th and 5 th day of training in both two-course EA group and three-course EA group were significantly shortened as compared with that in the model group ( P < 0.01), and those of the three-course EA group were considerably shorter than those of the two-course EA group in the escape latency and path length ( P < 0.05, P < 0.01). The platform crossing times of spatial probing test were significantly increased in both two-course EA and three-course EA groups in comparison with the that in the model group ( P < 0.01), and that of the three-course EA group was considerably increased as compared with that in the two-course EA group ( P < 0.05). Immunohistochemical staining showed that the number of SP in the hippocampus was markedly increased in the model group as compared with that in the control group ( P < 0.01), both markedly reduced in both two-course EA and three-course EA groups ( P < 0.01), and number of SP in the three-course EA group was significantly decreased as compared with that in the two-course EA group ( P < 0.01). The expression levels of hippocampal APP and BACE 1 proteins were significantly higher in the model group than those in the control group ( P < 0.01), and the level of hippocampal IDE was markedly lower in the model group than that in the control group ( P < 0.01). After EA, the increased expression levels of APP and BACE 1 proteins and the decreased expression level of IDE in the two-course EA and three-course EA groups were significantly inhibited ( P < 0.01). The effects of three-course EA treatment were significantly stronger than those of the two-course EA treatment in down-regulating the expression of APP and BACE 1 proteins and up-regulating the expression of IDE ( P < 0.01, P < 0.05). Conclusion EA stimulation at “Baihui” (GV 20) and bilateral “Shenshu” (BL 23) can improve the learning-memory ability in APP/PS 1 double transgenic AD mice, which may be related to its effects in down-regulating the expression of SP, APP and BACE 1 proteins and up-regulating the expression of IDE protein in the hippocampus.

Effects of Huangpu Tongqiao Capsule on Apoptosis in Alzheimer’s Disease Cell Model

CAI Biao;YE Shu;WANG Yan;WANG Ting-ting;WANG Liang;JIANG Ai-juan;FANG Zheng-qing;SHEN Guo-ming;XIE Dao-jun

China Journal of Chinese Materia Medica,2018,Vol 43,No. 11

【Abstract】 The loss of hippocampal neurons is one of the major pathological features of Alzheimer’s disease (AD), which is related to the apoptosis of hippocampal neurons. Huangpu Tongqiao capsule (HPTQC) is used for the treatment of AD, but the underlying mechanism is still unclear. This study was to investigate the mechanisms of neuroprotective effect of HPTQC in the treatment of AD, through observing the effect of HPTQC-containing serum on cell injury of primary cultured hippocampal neurons induced by A β25-35 via inhibiting cell apoptosis. Primary cultured hippocampal neurons were cultured and identified by MAP-2 immunofluorescence staining, and cell growth was observed by inverted microscope. The HPTQC-containing serum was prepared using the method of serum pharmacology. MTT assays were used to measure the optimal concentration of HPTQC-containing serum, and optimal A β concentration for establishing the AD model. After the establishment of primary cultured hippocampal neurons AD cell model induced by Aβ 25-35, cell survival rate was determined by MTT, cell apoptosis rate was assayed by flow cytometry, and protein expressions of Bax, Cyt C and caspase-3 were determined by western blot. The results showed that the primary cultured hippocampal neurons were cultured successfully, and cells matured on the seventh day. Compared with the control group, the survival rate of hippocampal neurons in the AD cell model group was decreased, the apoptosis rate of hippocampal neurons was increased, and the protein expressions of Bax, Cyt C and caspase-3 were increased ( P < 0.05, P < 0.01); Compared with the AD cell model group, the survival rate of hippocampal neurons in HPTQC-containing serum group was increased, the apoptosis rate of hippocampal neurons was decreased, and the protein expressions of Bax, Cyt C and caspase-3 were decreased ( P < 0.05, P < 0.01). These findings suggested that HPTQC-containing serum represented a neuroprotective effect on cell injury in the primary cultured hippocampal neurons induced by A β25-35, and the effect on the treatment of AD was associated with the inhibition the apoptosis in hippocampal neurons.

Trillium tschonoskii Maxim improves cognitive dysfunction in Alzheimer’s disease induced by okadaic acid in rats and its possible mechanism

XIE Wen-zhi;LUO Hong-bin;XIE Feng-feng;YANG Chen-yu

Chinese Pharmacological Bulletin,2018,Vol 34,No. 09

【Abstract】 Aim To assess the effects of Trillium Tschonoskii Maxim (TTM) decoction on learning and memory dysfunction in Alzheimer’s disease (AD) model rats induced by okadaic acid (OA) and its possible mechanism. Methods The SD rats were divided into ten groups, namely, one-week DMSO group, one-week OA group, one-week low- , medium- and high- dose TTM groups, two-week DMSO group, two-week OA group, two-week low- , medium- and high- dose TTM groups, with 10 in each group. Rats in the treatment groups were treated with intragastric administration of TTM decoction twice a day. After five days of Morris water maze training, the ones in the treatment groups and AD model group were injected with OA (0.392 mmol·L −1, 1.5 μL) in bilateral hippocampus. Those in the DMSO groups were injected with 10% DMSO. The spatial memory retention was detected by water maze at 24 h after injection. After the test, we prepared sample for Western blot and Nissl’s staining. The Western blotting test was used to detect the PP2A activity and the phosphorylation of Tau protein in the hippocampus. Nissl’s staining was used to observe the changes of the number of Nissl’s bodies in the hippocampal CA1 and CA3 regions. Results The Morris water maze test showed that after injection of OA, the latencies of TTM groups were shorter than that of OA groups. Western blot showed that the high-dose TTM could increase the activity of PP2A and decrease the phosphorylation level of Tau protein at PS-Tau396, and PT-Tau404 sites. The Nissl’s staining results showed that the numbers of Nissl’s bodies in the hippocampal CA1 and CA3 regions of OA groups were significantly attenuated as compared with those in the hippocampal CA1and CA3 regions than DMSO groups. The numbers of Nissl’s bodies in high groups were larger than that of OA group. Conclusion The results show that TTM can improve the learning and memory in AD model rats induced by OA, which might be due to the fact that TTM can increase PP2A activity, down-regulate the phosphorylation level of Tau protein, and improve neural development.

The study of the protective effect of panoxadiol on Alzheimer’s disease cells based on network pharmacology

LIANG Xi-cai;YAO Ying-jia;WANG Yu-ying;LI Xiu-li;WANG Ya-meng;LIN Ying;SHI Yue;YANG Jing-xian

Chinese Pharmacological Bulletin,2018,Vol 34,No. 09

【Abstract】 Aim To explore the therapeutic effects of main active compound panaxadiol (PD) from Radix Ginseng on Alzheimer’s disease (AD) via network pharmacological analysis and molecular docking. Methods Among the 107 prescriptions for AD treatment screened out by using network pharmacology, Radix Ginseng was selected due to the highest frequency together with its target for AD. The molecular docking technology was used to find out the components with the highest score in docking with non-receptor tyrosine kinase (FYN). APP-N2a cell model was established in vitro, and the cell viability was detected by MTT assay. Cell damage was detected by LDH method. Apoptosis and intracellular Ca 2+ concentration were detected by flow cytometry. Phosphorylated FYN protein expression was detected by Western blot. Results The 18 active ingredients and 29 AD related targets in Radix Ginseng were screened out by network pharmacology. The results of molecular docking showed that PD had strong binding effects with FYN. Experiments have shown that PD could increase the survival rate of cells, reduce the release of LDH, significantly reduce apoptosis, reduce Ca 2+ overload in AD cells, and reduce the expression of FYN-Y416 protein. Conclusion The prediction results of network pharmacology were verified by experiments. The protective effect of PD on AD may be related to the inhibition of FYN phosphorylation.

Effects and mechanisms of different frequencies of electroacupuncture for learning and memory ability of Alzheimer’s rats

WANG Ying;KONG Lihong;LI Wei;ZHANG Kangkang;SHEN Feng;WANG Yawen;ZHOU Hua;SUN Guojie

Chinese Acupuncture & Moxibustion,2017,Vol 37,No. 06

【Abstract】 Objective To observe the effects of different frequencies of electroacupuncture (EA) at “Baihui (GV 20)” and “Shenshu (BL 23)” for the learning and memory ability as well as glycogen synthase kinase-3β (GSK-3β) and growth associated protein-43 (GAP-43) in hippocampal tissue of rats with Alzheimer’s disease (AD), so as to explore the mechanism of different frequencies of EA for the prevention and treatment of AD. Methods One hundred and twelve healthy Wistar male rats were divided into seven groups by random number table, namely a normal group, a sham operation group, a model group, an acupuncture group, a 2 Hz EA group, a 30 Hz EA group, and a 50 Hz EA group, 16 rats in each one. The rats in the normal group were conventionally raised in the laboratory without any treatment. 0.9% NaCl solution was injected into bilateral dentate convolution of hippocampus in rats of the sham operation group. AD model was established by β-amyloid protein 1-42 (Aβ1-42) injected into bilateral dentate convolution of hippocampus in the other groups. Fi days after establishment, no treatment was applied in the model and sham operation groups, and EA with corresponding frequencies at “Baihui (GV 20)” and “Shenshu (BL 23)” was used in the three EA groups for two sessions, once a day and seven times as one session. There was one day between the two sessions. The same acupoints were adopted in the acupuncture group, without electrical connection. The escape latency, the first spanning platform time, and the number of crossing platform were tested in the Morris water maze immediately after treatment. The expressions of GSK-3β and GAP-43 were examined by immunohistochemistry and Western blot. Results ① Morris water maze test showed that the escape latency and the first spanning platform time significantly increased in the model group compared with those in the normal group (both P < 0.01), and the number of crossing platform decreased (P < 0.01). Compared with the model group, the escape latency and the first spanning platform times decreased in the acupuncture and three EA groups (all P < 0.01), and the numbers of crossing platform increased (P < 0.01). Compared with the acupuncture and 2 Hz, 30 Hz EA groups, the escape latency decreased in the 50 Hz EA group (P < 0.01, P < 0.05); the first spanning platform time reduced (all P < 0.01); the number of crossing platform increased (P < 0.01, P < 0.05). ② The expressions of GSK-3β and GAP-43 of the model group increased compared with those of the normal group (both P < 0.01). The expressions of GSK-3β in the acupuncture and three EA groups decreased compared with that in the model group (all P < 0.01), and the expressions of GAP-43 increased (all P < 0.01). The expressions of GSK-3β decreased and GAP-43 increases in the 50 Hz EA group compared with those in the acupuncture group and 2 Hz, 30 Hz groups (all P < 0.01). Conclusion EA may promote synaptic damage rehabilitation by down regulating GSK-3β and up regulating GAP-43 to improve learning and memory ability of AD rats. The effect of 50 Hz EA is better than those of 30 Hz and 2 Hz EA and acupuncture.

System pharmacology-based study on mechanism of Radix Polygalae in the treatment of Alzheimer’s disease

WANG Hao;ZHAO Zhen-yu;SHEN Xia;HU Ben-xiang;CHEN Ying

Acta Pharmaceutica Sinica,2017,Vol 52,No. 10

【Abstract】 This study was designed to investigate the molecular mechanism and potential active constituents of Radix Polygalae in treatment of Alzheimer’s disease with multiple data bases combined with literature mining to build Radix Polygalae chemical composition database. A novel analysis tool Pharmmapper was used to obtain the main active ingredient and potential target of Radix Polygalae. By extensive data profiling, the Radix Polygalae was found to contain 111 chemical constituents. Among them, a total of 10 active molecules included 3 xanthones, 1 saponin, 3 oligosaccharide esters, and 3 other classes were related to 13 Alzheimer’s disease-related targets. Two of the core targets were beta-secretase 1 and glycogen synthase kinase-3 beta. GO analysis and KEGG were used to explore the molecular mechanism of Radix Polygalae in treatment of Alzheimer’s disease, which had 3 signaling pathways, and the most important signaling pathway was the cell death signaling pathway. The active constituents of Radix Polygalae could control the formation of Aβ and the apoptosis of cells through interaction with multiple targets, and control the treatment of Alzheimer’s disease.

Effects of Acupuncture Stimulation of Bilateral“Hegu” (LI 4) and “Taichong” (LR 3) on Learning-memory Ability, Hippocampal Aβ42 Expression and Inflammatory Cytokines in Rats with Alzheimer's Disease

JIANG Mei-chi;LIANG Jing;ZHANG Yu-jie;WANG Jing-rong;HAO Jin-dong;WANG Mei-kang;XU Jian-yang

Acupuncture Research,2016,Vol 41,No. 02

【Abstract】 Objective To observe the effect of acupuncture stimulation of bilateral "Hegu" (LI 4)and "Taichong" (LR 3, the so-called "Four Gate Points") on learning-memory ability, hippocampal interleukin-1 (IL-1) β and IL-2 and amyloid β (Aβ) 42 levels in Alzheimer’s disease (AD) rats, so as to reveal its underlying mechanism in improving AD. Methods Male SD rats were randomly divided into sham operation, model, medication and acupuncture groups (n=12 rats in each group).The AD model was created by microinjection of streptozotocin (10 μL, 3 mg/kg) into the lateral ventricle (repeated the microinjection once two days later). Bilateral LR 3 and LI 4 were punctured with filiform needles and stimulated manually, once a day, 6 days a week for 4 weeks.The rats of the medication group were intragastric perfusion of Donepezil HCl (0.45 mg/kg), once a day for 4weeks. The learning-memory ability was detected by Morris water maze swimming tests. The immunoactivity of hippocampal Aβ42 was detected by immunohistochemistry, and the contents of IL-1β and IL-2 in the hippocampus tissue were determined by ELISA. Results After modeling, the average escape latency of Morris water navigation task was significantly increased, and the target-platform crossing times of space probe trials were significantly reduced in the model group (P < 0.05), suggesting a lowering of learning-memory ability. After acupuncture intervention, the increased escape latency and the decreased target-platform crossing times were reversed, suggesting an improvement of the learning-memory. The hippocampal Aβ42 immunoactivity and IL-1β content were significantly higher in the model group than in the sham operation group (P < 0.05), but the hippocampal IL-2content was markedly decreased in the model group (P < 0.05). Following the interventions, the increased Aβ42 expression and IL-1β contents, and the decreased IL-2 contents in the hippocampus were also reversed in both the acupuncture and medication groups (P < 0.05). Conclusion Acupuncture may improve learning-memory ability in AD rats, which may be associated with its effects in reducing hippocampal Aβ42 expression and IL-1βcontent and in up-regulating IL-2 level.

Network pharmacology study of effective constituents of traditional Chinese medicine for Alzheimer's disease treatment

PANG Xiao-cong;WANG Zhe;FANG Jian-song;LIAN Wen-wen;ZHAO Ying;KANG De;LIU Ai-lin;DU Guan-hua

Acta Pharmaceutica Sinica,2016,Vol 51,No. 05

【Abstract】 This study aims to investigate the network pharmacology of Chinese medicinal formulae for treatment of Alzheimer's disease (AD). Machine learning algorithms were applied to construct classifiers in predicting the active molecules against 25 key targets toward AD. By extensive data profiling, we compiled 13 classical traditional Chinese medicine (TCM) formulae with clinical efficacy for AD. There were 7 Chinese herbs with a frequency of 5 or higher in our study. Based on the predicted results, we built constituent-target, and further construct target-target interaction network by STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) and target-disease network by DAVID (Database for Annotation, Visualization and Integrated Discovery) and gene disease database to study the synergistic mechanism of the herbal constituents in the Chinese traditional patent medicine. By prediction of blood-brain penetration and validation by TCMsp (traditional Chinese medicine systems pharmacology) and Drugbank, we found 7 typical multi-target constituents which have diverse structure. The mechanism uncovered by this study may offer a deep insight into the action mechanism of TCMs for AD. The predicted inhibitors for the AD-related targets may provide a good source of new lead constituents against AD.

Effect of Heixiaoyao Powder on Hippocampal Gene Expression Profile of Alzheimer's Disease Rats

WU Hong-yan;LI Hai-long;GU Jing;YANG Zhi-yuan;WANG Hu-ping;CHE Min;LAN Mei-hua

Chinese Journal of Integrated Traditional and Western Medicine,2016,Vol 36,No. 11

【Abstract】 Objective To observe the effect of Heixiaoyao Powder (HP) on gene microarray profile of hippocampus in Aβ25-35 fragments induced Alzheimer's disease rat model. Methods Female SD rats were chosen to establish AD model by injecting Aβ25-35 amyloid into hippocampus, and then they were divided into 6 groups, i.e., the sham-operation group, the model group, the Western medicine (WM) group, high, middle, and low dose HP groups, 14 in each group. After 7 days of modeling, all rats were administered with respective solution at the daily dose of 3 mL/kg by gastrogavage for 28 successive days. Normal saline was administered to rats in the sham-operation group and the model group. Huperzine A Tablets water solution was administered to rats in the WM group at the daily dose of 0.02 mL/kg. HP at the daily dose of 4.25, 8.50, and 17.00 g/kg was administered to rats in the low, middle, high HP groups. All rats were sacrificed after ending gastrogavage, and their hippocampal tissues were collected to extract tissue RNA. Rat gene microarray was used to screen differentially expressed genes, and then differentially expressed genes with partial dose-dependently changing obtained by microarry were verified by qRT-PCR. Results Compared with the sham-operation group, 538 genes were up-regulated, and 579 genes were down-regulated in the model group. mRNA expressions of wisp1, crebbp, igfbp-1, znf483, zfp37, and zic4 increased, while mRNA expressions of casq2and bcl-2 decreased in the model group (P < 0.05). Compared with the model group, 276 genes were up-regulated, and 170 genes were down-regulated in the 3 HP groups. Of them, 71 up-regulated genes dose-dependently and 70 down-regulated genes dose-dependently. mRNA expressions of igfbp-1, znf483, zfp37, and zic4decreased, while mRNA expressions of casq2 and bcl-2 increased in the WM group (P < 0.01). mRNA expressions of wisp1, crebbp, igfbp-1, znf483, zfp37, and zic4 decreased, while mRNA expressions of casq2 and bcl-2 increased in the high dose HP group (P < 0.01). mRNA expressions of crebbp, igfbp-1, znf483, zfp37, and zic4 decreased (P < 0.01, P < 0.05), while mRNA expressions of casq2 and bcl-2 increased in the middle dose HP group (P < 0.01, P < 0.05). mRNA expressions of igfbp-1, znf483, zfp37, and zic4 decreased in the low dose HP group (P < 0.01). Compared with the middle dose HP group, mRNA expressions of crebbp, zfp37, and zic4 increased (P < 0.01), mRNA expressions of igfbp-1 and bcl-2 decreased in the middle dose HP group (P < 0.01, P < 0.05); mRNA expressions of crebbp, znf483, and zfp37 increased (P < 0.01, P < 0.05), mRNA expressions of igfbp-1, zic4, and bcl-2 decreased in the low dose HP group (P < 0.01). Compared with the middle HP group, mRNA expressions of casq2, zic4, and bcl-2 decreased in the low dose HP group (P < 0.01, P < 0.05). Conclusion HP could affect the occurrence of AD by regulating mRNA expressions of zfp37, znf483, and zic4, and affect the metabolism of Aβ and abnormal phosphorylation of Tau protein by inhibiting wnt signal pathway related genes such as wisp-1, crebbp, igfbp-1, and casq2.

Effects of Total Ginsenosides and Volatile Oil of Acorus Tatarinowii Co-Administration on Ability of Learning and Memory and Apoptosis in Alzheimer's Disease Mice Model Induced By D-Galactose and Aluminium Chloride

DENG Min-zhen;HUANG Li-ping;FANG Yong-qi

Journal of Chinese Medicinal Materials,2015,Vol 38,No. 05

【Abstract】 Objective: To observe the effects of the co-administration of total ginsenosides and volatile oil of Acorus tatarinowii on the ability of learning and memory and apoptosis in Alzheimer's disease (AD) mice model induced by D-galactose and aluminium chloride. Methods: 50 Kunming (KM) mice were randomly divided into normal group, model group, Aricept group (1 mg/kg), Ding Zhi Wan group (10 g/kg) and co-administration of total ginsenosides and volatile oil of Acorus tatarinowii group (co-administration group, the doses of volatile oil of Acorus tatarinowii and total ginsenosides were 30 mg/kg and 150 mg/kg, respectively). In addition to normal group, mice in other groups were given D-galactose 150 mg /(kg·d), ip, and aluminium chloride 5 mg/kg, i.g., once daily for 40 days. At the same time, mice in the treatment groups were administrated with the corresponding drug from the 20th day after modeling, once daily for 40 days. Water maze and avoiding darkness experiments were conducted to test learning and memory abilities; Aβ1-42 and BCL-2 content in cortex and hippocampus were detected by ELISA; the vitalities of acetyl cholinesterase (AChE) and acetylcholine transferase (ChAT) were detected by ultraviolet spectrophotometry. Superoxide dismutase (SOD) vitalities were detected by a water-soluble tetrazolium salt (WST-1) method; the content of malondialdehyde (MDA) in cortex and hippocampus were detected by the thiobarbituric acid (TBA) method; senile plaque on Aβ1-42 precipitation were observed by immunohistochemistry; brain tissues were observed by hematoxylin-eosin staining (HE). Results: As compared with model group, in the co-administration group, the time of AD mice swimming, the numbers of blind area and electric shock reduced significantly (P < 0.05), and the latent period was prolonged (P < 0.05); AChE activity and levels of Aβ1-42 and MDA in cortex and hippocampus were decreased significantly (P < 0.05 or P < 0.01); ChAT and SOD activities as well as BCL-2 content were increased significantly (P < 0.05 or P < 0.01); the formation of senile plaque was decreased and brain tissue morphology was improved. Conclusion: Total ginsenosides and volatile oil of Acorus tatarinowii co-administration has an effect on improving the ability of learning and memory and inhibiting apoptosis.

Theoretic basis on the same therapeutic program for different degenerative brain diseases in terms of the Governor Vessel: Alzheimer’s disease and Parkinson’s disease

WU Junyan;WANG Jie;ZHANG Junlong

Chinese Acupuncture & Moxibustion,2015,Vol 35,No. 05

【Abstract】 Through the consultation of TCM ancient classical theory, the relationship of kidney essence, marrow and brain is analyzed. It is discovered that the degenerative brain diseases, represented by Alzheimer’s disease (AD) and Parkinson’s disease (PD) share the same etiological basis as “kidney essence deficiency and brain marrow emptiness” and have the mutual pathological outcomes as yang qi declining. The Governor Vessel gathers yang qi of the whole body and maintains the normal functional activity of zangfu organs in the human body through the storage, regulation and invigoration of yang qi. It is viewed that the theory of the governor vessel is applied to treat the different degenerative brain diseases, which provides the theoretic support and practice guide for the thought of TCM as the same therapeutic program for the different diseases. As a result, the degenerative brain diseases can be retarded and the approach is provided to the effective prevention and treatment of degenerative diseases in central nerve system.

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