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
WANG QiLI HaoWANG Fei-xueGAO LeiQIN Ji-changLIU Jian-gangWEI YunLIU Mei-xia
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), Aβ1-40 and Aβ1-42 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, Aβ1-40, Aβ1-42 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.
WANG Zhi-yongLIU Jian-gangWEI YunLIU Mei-xiaWANG QiLIANG LinYANG Hui-minLI Hao
