Objective: To assess the effect and safety of Huannao Yicong Formula (还脑益聪方, HYF) in the treatment of patients with mild-to-moderate Alzheimer's disease (AD). Methods: Sixty patients with mild-to moderate AD ...Objective: To assess the effect and safety of Huannao Yicong Formula (还脑益聪方, HYF) in the treatment of patients with mild-to-moderate Alzheimer's disease (AD). Methods: Sixty patients with mild-to moderate AD were evenly randomized into HYF group and donepezil group with the random number method. Patients in the HYF group took 5 g of HYF granules twice daily and 5 mg placebo of donepezil once daily. Patients in the donepezil group took 5 mg donepezil once daily and 5 g placebo of HYF granules twice daily. The intervention lasted for 6 months. Clinical researchers, participants and statisticians were blinded to the treatment assignment throughout the study. The primary outcomes were scores of Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and Chinese Medicine Symptom Scale (CM-SS). The secondary outcomes were scores of Montreal Cognitive Assessment (MoCA) test and Mini-Mental State Exam (MMSE). The serum levels of acetylcholinesterase (AchE) and amyloid-β protein 42 (Aβ 42) were detected with enzyme linked immunosorbent assay kits. The scale assessments were conducted at baseline, the 3rd and 6th months of treatment, respectively. Biochemistry tests were conducted at baseline and the 6th month of treatment. Results: A total of 52 patients completed the trial, 28 in HYF group and 24 in donepezil group. Compared with the baseline, HYF and donepezil significantly decreased the total scores of ADAS-Cog and CM-SS, and significantly increased the scores of MoCA and MMSE after 6-month treatment (all P<0.01). Both treatments remarkably reduced the serum levels of AchE and Aβ 42 (both P<0.05). The CM-SS total effective rate of HYF was significantly higher than donepezil [75.00%(21/28) vs. 54.17%(13/24), P<0.05]. No severe adverse events were observed in both groups. Conclusion: HYF is effective and safe for improving the cognitive function in mild to-moderate AD patients.[Trial registration: Chinese Clinical Trial Registry (Reg No. ChiCTR-IOR-17011746)].展开更多
Objective： Huannao Yicong Decoction （还脑益聪方, HYD）, an effective herbal formula against Alzheimer＇s disease （AD）, has been proven to have neuroprotective action in amyloid β-protein1.42 （Aβ1-42）-induced r...Objective： Huannao Yicong Decoction （还脑益聪方, HYD）, an effective herbal formula against Alzheimer＇s disease （AD）, has been proven to have neuroprotective action in amyloid β-protein1.42 （Aβ1-42）-induced rat model. This study was designed to characterize mechanisms by which HYD leads to suppression of inflammation and apoptosis in the brains of Aβ1-42-induced rat. Methods： A total of 72 rats were divided into 6 groups, which were referred to as： sham operation group, model group, donepezil-treated group, HYD low-dose group （HYDL）, HYD middle-dose group （HYDM） and HYD high-dose group （HYDH）. Rats in HYDL, HYDM and HYDH were injected with Aβ1-42 at the CA1 region of hippocampus to form AD model and were fed the HYD extract at different dose of 3.78, 7.56 and 18.90 g crude drug/kg. The behavioral changes of rats were evaluated by Morris water maze （MWM） before sacrifice. Pathological changes of the brain tissue were evaluated using hematoxylin eosin （HE） staining. The levels of intedeukin-1 （IL-1） and tumor necrosis factor-α （TNF-α ） were measured by radioimmunoassay. The levels of A 13 and proteins that are associated with apoptosis such as B-ceil lymphoma-2 protein （Bcl-2）, Bcl-2-associated X protein （Bax）, cysteine-aspartic protease （caspase）-3, -8, -9 and -12 in serum were measured by immunohistochemistry. Results： Compared with the sham operation group, the spatial learning and memory abilities of AD rats were significantly decreased （P〈0.05 or P〈0.01; Expressions of IL-1, TNF-α, Aβ and apoptosis-signaling proteins caspase-3, -8, -9, -12 were significantly up-regulated （P〈0.05 or P〈0.01）. The ratio of Bcl-2 to Bax were significantly decreased in the model group （P〈0.01）. When treated with HYD extract, the spatial learning and memory abilities of AD-model rats were significantly increased （P〈0.05 or P〈0.01）, IL-1, TNF- α, Aβ, caspase-3, -8, -9 and -12 were down-regulated （P〈0.05 or P〈0.01）, and the 展开更多
Objective： To observe the effect of Huannao Yicong Prescription （还脑益聪方, HNYC, a Chinese medical compound） extract on β-amyloid precursor protein （APP） metabolic signal transductionrelated protein kinase C ...Objective： To observe the effect of Huannao Yicong Prescription （还脑益聪方, HNYC, a Chinese medical compound） extract on β-amyloid precursor protein （APP） metabolic signal transductionrelated protein kinase C （PKC）, tyrosine amyloid protein kinase （TrKA）, and glycogen synthase kinase-3 （GSK-3） in brain tissue of transgenic mouse dementia model induced by APP. Methods： Sixty dementia model transgenic 3-month-old mice induced by APP695V7171 were randomly allocated in four groups： the model group （A）, the Donepezil （0.65×10^-3 g.kg-1.d-1）-treated group （B）, and the two HNYC-treated groups （C and D） with high dosage （2.8 g.kg^-1.d^-1） and low dosage （1.4 g.kg^-1.d^-1） of HNYC extract, respectively, 15 mice in each group. Besides, a normal control group was set up with 15 C57BL/6J mice with the same age and genetic background as the model mice. The drugs for treatment were administered once a day by dissolving in equal-volume distilled water through gastric infusion, continued for 6 months, to mice in group A and to normal control group equal-volume distilled water was administered instead. Spatial learning and memory capacity of mice were observed by Morris water maze; their one-time escape response memory capacity was tested by diving platform; and changes of PKC, TrkA, and GSK-3 levels in hippocampus and cortex of brain were detected by Western blotting. Results： HNYC extract showed significant effects on increasing the time of model mice for swimming through the flat roof and the swimming time and path in the fourth quadrant （P〈0.05 or P〈0.01）. Diving platform test showed that the latent times in Groups B and C were longer than that in Group A significantly （P〈0.05 and P〈0.01）. Compared with the normal control group, PKC and TrkA protein expression levels in hippocampus and cortex of model mice＇s brain lowered significantly （P〈0.01）, while GSK-3 protein expression increased significantly （P〈0.01）; compared with Group A （the展开更多
Objective To observe the effects of Huannao Yicong Formula (还脑益聪方, HYF) on learning and memory and it’s regulating effect on γ-secretase related anterior pharynx defective 1 (APH-1), presenilin enhancer-2 (PEN-...Objective To observe the effects of Huannao Yicong Formula (还脑益聪方, HYF) on learning and memory and it’s regulating effect on γ-secretase related anterior pharynx defective 1 (APH-1), presenilin enhancer-2 (PEN-2) signaling pathway, so as to discuss and further clarify the mechanism of HYF on Alzheimer’s disease. Methods Sixty APP/PS1 transgenic mice, randomly allocated into 4 groups, the model group, the donepezil group (0.65 mg/kg), HYF low-dose group (HYF-L, 5.46 g/kg) and HYF high-dose group (HYF-H, 10.92 g/kg), 15 for each group. Another 15 C57BL/6J mice with the same age and same genetic background were allocated into the control group, proper dosage of drugs or distilled water were given by intragastric administration once daily for 12 weeks. After 12 weeks of administration, the learning and memory abilities of mice in each group was evaluated by the morris water maze test, amyloid precursor protein (APP), Aβ<sub>1-40</sub> and Aβ<sub>1-42</sub> levels in hippocampus were detected by enzyme-linked immunosorbent assay, γ-secretase was detected by dual luciferase assaying, the levels of APH-1a, hypoxia-inducible factor 1α (HIF-1α), cAMP response element-binding protein (CREB) and PEN-2 and their mRNA expression was measured by Western blot and real-time polymerase chain reaction. Results HYF can ameliorate learning and memory deficits in APP/PS1 transgenic mice by decreasing the escape latency, improving the number of platform crossing and swimming speed (P<0.01, P<0.05). HYF can decrease the levels of APP, Aβ<sub>1-40</sub>, Aβ<sub>1-42</sub> and the activity of γ-secretase in hippocampus of Alzheimer’s disease model mice. HYF can down-regulate the levels of CREB and PEN-2 and the expression of their mRNA. Conclusion HYF can improve the learning and memory ability by inhibiting the activity of γ-secretase through the CREB/PEN-2 signaling pathway, and this may be one of the therapeutic mechanisms of HYF in Alzheimer’s disease.展开更多
Objective：To observe the effect of early intervention using extract of Huannao Yicong Decoction （还脑益聪方,HYD） on the pathological picture of hippocampus,neurocyte apoptosis,and associated regulatory genes inβ-a...Objective：To observe the effect of early intervention using extract of Huannao Yicong Decoction （还脑益聪方,HYD） on the pathological picture of hippocampus,neurocyte apoptosis,and associated regulatory genes inβ-amyloid precursor protein（APP） transgenic mice model of dementia.Methods：Sixty APP695^（V7171） transgenic mice were randomly divided into four groups of 15.The model group was treated with distilled water, the positive control group was treated with donepezil（0.65 mg/kg）,and the two HYD groups were treated with high dose（2.8 g/kg） and low dose（1.4 g/kg） HYD,respectively.All testing drugs were administered through gastrogavage by dissolving in equal volume of distilled water,once a day for six successive months.In addition, a normal control group with 15 healthy C57BL/6J mice of the same age and genetic background was set up with distilled water treatment.The pathologic picture of brain tissue was observed by microscopy with HE stain;the amount of apoptosis cells in the hippocampal CA1 area was detected by TUNEL;and expressions of associated genes,Bcl-2,and Bax were determined by immunohistochemical method.Results：Pathologic pictures of hippocampus showed that in the model group,cells messily arranged,neurons markedly decreased, and the surrounding tissue of some cells was loosened with edema,necrosis,and widened gap with glia cells proliferation.Compared with those in the normal group,the amount of apoptosis cells in the CA1 area was increased,Bcl-2 expression decreased,and Bax expression increased significantly,with markedly reduced Bcl-2/Bax ratio in the model group.Compared to the model group,the pathological changes were significantly milder in the HYD-treated groups,showing rather regularly arranged cells,significantly increased neurons, only few denatured necrotic cells with milder edema,less proliferation of glia cells,and obviously reduced cell apoptosis in CA1 area（P0.05 or P0.01）.Besides,Bcl-2 expression was up-regulated and Bax expression down-regulated,an展开更多
基金Supported by the National Science and Technology Projects for Significant Major New Drug Creation(No.2009ZX09103-391)the National Natural Science Foundation of China(No.81573819)the Self-determined Project of China Academy of Chinese Medical Sciences(No.ZZ0808003)
文摘Objective: To assess the effect and safety of Huannao Yicong Formula (还脑益聪方, HYF) in the treatment of patients with mild-to-moderate Alzheimer's disease (AD). Methods: Sixty patients with mild-to moderate AD were evenly randomized into HYF group and donepezil group with the random number method. Patients in the HYF group took 5 g of HYF granules twice daily and 5 mg placebo of donepezil once daily. Patients in the donepezil group took 5 mg donepezil once daily and 5 g placebo of HYF granules twice daily. The intervention lasted for 6 months. Clinical researchers, participants and statisticians were blinded to the treatment assignment throughout the study. The primary outcomes were scores of Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and Chinese Medicine Symptom Scale (CM-SS). The secondary outcomes were scores of Montreal Cognitive Assessment (MoCA) test and Mini-Mental State Exam (MMSE). The serum levels of acetylcholinesterase (AchE) and amyloid-β protein 42 (Aβ 42) were detected with enzyme linked immunosorbent assay kits. The scale assessments were conducted at baseline, the 3rd and 6th months of treatment, respectively. Biochemistry tests were conducted at baseline and the 6th month of treatment. Results: A total of 52 patients completed the trial, 28 in HYF group and 24 in donepezil group. Compared with the baseline, HYF and donepezil significantly decreased the total scores of ADAS-Cog and CM-SS, and significantly increased the scores of MoCA and MMSE after 6-month treatment (all P<0.01). Both treatments remarkably reduced the serum levels of AchE and Aβ 42 (both P<0.05). The CM-SS total effective rate of HYF was significantly higher than donepezil [75.00%(21/28) vs. 54.17%(13/24), P<0.05]. No severe adverse events were observed in both groups. Conclusion: HYF is effective and safe for improving the cognitive function in mild to-moderate AD patients.[Trial registration: Chinese Clinical Trial Registry (Reg No. ChiCTR-IOR-17011746)].
基金Supported by the National Natural Science Foundation of China(No.81173383)Beijing Municipal Science and Technology Plan(No.Z141100002214003)
文摘Objective： Huannao Yicong Decoction （还脑益聪方, HYD）, an effective herbal formula against Alzheimer＇s disease （AD）, has been proven to have neuroprotective action in amyloid β-protein1.42 （Aβ1-42）-induced rat model. This study was designed to characterize mechanisms by which HYD leads to suppression of inflammation and apoptosis in the brains of Aβ1-42-induced rat. Methods： A total of 72 rats were divided into 6 groups, which were referred to as： sham operation group, model group, donepezil-treated group, HYD low-dose group （HYDL）, HYD middle-dose group （HYDM） and HYD high-dose group （HYDH）. Rats in HYDL, HYDM and HYDH were injected with Aβ1-42 at the CA1 region of hippocampus to form AD model and were fed the HYD extract at different dose of 3.78, 7.56 and 18.90 g crude drug/kg. The behavioral changes of rats were evaluated by Morris water maze （MWM） before sacrifice. Pathological changes of the brain tissue were evaluated using hematoxylin eosin （HE） staining. The levels of intedeukin-1 （IL-1） and tumor necrosis factor-α （TNF-α ） were measured by radioimmunoassay. The levels of A 13 and proteins that are associated with apoptosis such as B-ceil lymphoma-2 protein （Bcl-2）, Bcl-2-associated X protein （Bax）, cysteine-aspartic protease （caspase）-3, -8, -9 and -12 in serum were measured by immunohistochemistry. Results： Compared with the sham operation group, the spatial learning and memory abilities of AD rats were significantly decreased （P〈0.05 or P〈0.01; Expressions of IL-1, TNF-α, Aβ and apoptosis-signaling proteins caspase-3, -8, -9, -12 were significantly up-regulated （P〈0.05 or P〈0.01）. The ratio of Bcl-2 to Bax were significantly decreased in the model group （P〈0.01）. When treated with HYD extract, the spatial learning and memory abilities of AD-model rats were significantly increased （P〈0.05 or P〈0.01）, IL-1, TNF- α, Aβ, caspase-3, -8, -9 and -12 were down-regulated （P〈0.05 or P〈0.01）, and the
基金Supported by the National Natural Science Foundation of China(No.30873338)the Major New Drug Projects of the Ministry of Science and Technology of P.R China(No 2009ZX09103-391)
文摘Objective： To observe the effect of Huannao Yicong Prescription （还脑益聪方, HNYC, a Chinese medical compound） extract on β-amyloid precursor protein （APP） metabolic signal transductionrelated protein kinase C （PKC）, tyrosine amyloid protein kinase （TrKA）, and glycogen synthase kinase-3 （GSK-3） in brain tissue of transgenic mouse dementia model induced by APP. Methods： Sixty dementia model transgenic 3-month-old mice induced by APP695V7171 were randomly allocated in four groups： the model group （A）, the Donepezil （0.65×10^-3 g.kg-1.d-1）-treated group （B）, and the two HNYC-treated groups （C and D） with high dosage （2.8 g.kg^-1.d^-1） and low dosage （1.4 g.kg^-1.d^-1） of HNYC extract, respectively, 15 mice in each group. Besides, a normal control group was set up with 15 C57BL/6J mice with the same age and genetic background as the model mice. The drugs for treatment were administered once a day by dissolving in equal-volume distilled water through gastric infusion, continued for 6 months, to mice in group A and to normal control group equal-volume distilled water was administered instead. Spatial learning and memory capacity of mice were observed by Morris water maze; their one-time escape response memory capacity was tested by diving platform; and changes of PKC, TrkA, and GSK-3 levels in hippocampus and cortex of brain were detected by Western blotting. Results： HNYC extract showed significant effects on increasing the time of model mice for swimming through the flat roof and the swimming time and path in the fourth quadrant （P〈0.05 or P〈0.01）. Diving platform test showed that the latent times in Groups B and C were longer than that in Group A significantly （P〈0.05 and P〈0.01）. Compared with the normal control group, PKC and TrkA protein expression levels in hippocampus and cortex of model mice＇s brain lowered significantly （P〈0.01）, while GSK-3 protein expression increased significantly （P〈0.01）; compared with Group A （the
基金Supported by the National Natural Science Foundation of China(No.81173383 and No.81573819)Beijing Municipal Science and Technology Plan "Ten Disease and Ten Medicine"(No.Z141100002214003)
文摘Objective To observe the effects of Huannao Yicong Formula (还脑益聪方, HYF) on learning and memory and it’s regulating effect on γ-secretase related anterior pharynx defective 1 (APH-1), presenilin enhancer-2 (PEN-2) signaling pathway, so as to discuss and further clarify the mechanism of HYF on Alzheimer’s disease. Methods Sixty APP/PS1 transgenic mice, randomly allocated into 4 groups, the model group, the donepezil group (0.65 mg/kg), HYF low-dose group (HYF-L, 5.46 g/kg) and HYF high-dose group (HYF-H, 10.92 g/kg), 15 for each group. Another 15 C57BL/6J mice with the same age and same genetic background were allocated into the control group, proper dosage of drugs or distilled water were given by intragastric administration once daily for 12 weeks. After 12 weeks of administration, the learning and memory abilities of mice in each group was evaluated by the morris water maze test, amyloid precursor protein (APP), Aβ<sub>1-40</sub> and Aβ<sub>1-42</sub> levels in hippocampus were detected by enzyme-linked immunosorbent assay, γ-secretase was detected by dual luciferase assaying, the levels of APH-1a, hypoxia-inducible factor 1α (HIF-1α), cAMP response element-binding protein (CREB) and PEN-2 and their mRNA expression was measured by Western blot and real-time polymerase chain reaction. Results HYF can ameliorate learning and memory deficits in APP/PS1 transgenic mice by decreasing the escape latency, improving the number of platform crossing and swimming speed (P<0.01, P<0.05). HYF can decrease the levels of APP, Aβ<sub>1-40</sub>, Aβ<sub>1-42</sub> and the activity of γ-secretase in hippocampus of Alzheimer’s disease model mice. HYF can down-regulate the levels of CREB and PEN-2 and the expression of their mRNA. Conclusion HYF can improve the learning and memory ability by inhibiting the activity of γ-secretase through the CREB/PEN-2 signaling pathway, and this may be one of the therapeutic mechanisms of HYF in Alzheimer’s disease.
基金Supported by the National Natural Science Foundation of China (No.30873338)the National Major Special Project of Science and Technology(No.2009ZX09103-391)
文摘Objective：To observe the effect of early intervention using extract of Huannao Yicong Decoction （还脑益聪方,HYD） on the pathological picture of hippocampus,neurocyte apoptosis,and associated regulatory genes inβ-amyloid precursor protein（APP） transgenic mice model of dementia.Methods：Sixty APP695^（V7171） transgenic mice were randomly divided into four groups of 15.The model group was treated with distilled water, the positive control group was treated with donepezil（0.65 mg/kg）,and the two HYD groups were treated with high dose（2.8 g/kg） and low dose（1.4 g/kg） HYD,respectively.All testing drugs were administered through gastrogavage by dissolving in equal volume of distilled water,once a day for six successive months.In addition, a normal control group with 15 healthy C57BL/6J mice of the same age and genetic background was set up with distilled water treatment.The pathologic picture of brain tissue was observed by microscopy with HE stain;the amount of apoptosis cells in the hippocampal CA1 area was detected by TUNEL;and expressions of associated genes,Bcl-2,and Bax were determined by immunohistochemical method.Results：Pathologic pictures of hippocampus showed that in the model group,cells messily arranged,neurons markedly decreased, and the surrounding tissue of some cells was loosened with edema,necrosis,and widened gap with glia cells proliferation.Compared with those in the normal group,the amount of apoptosis cells in the CA1 area was increased,Bcl-2 expression decreased,and Bax expression increased significantly,with markedly reduced Bcl-2/Bax ratio in the model group.Compared to the model group,the pathological changes were significantly milder in the HYD-treated groups,showing rather regularly arranged cells,significantly increased neurons, only few denatured necrotic cells with milder edema,less proliferation of glia cells,and obviously reduced cell apoptosis in CA1 area（P0.05 or P0.01）.Besides,Bcl-2 expression was up-regulated and Bax expression down-regulated,an
