OBJECTIVETo research Angelica tenuissima Nakai (ATN) for use in novel Alzheimer's disease (AD) therapeutics.

METHODSThe effect of a 30% ethanol extract of ATN (KH032) on AD-like cognitive impairment and neuropathological and neuroinflammatory changes induced by bilateral intracerebroventricular injections of β-amyloid (Aβ) peptide (Aβ) was investigated. Male C57Bl/6 mice were randomly divided into 4 groups, 10 in each group. KH032-treated groups were administrated with a low or high dose of KH032 (50 and 200 mg/kg, respectively), intragastrically for 16 days; distilled water was applied in the sham and negative groups. Open fifield test, Y maze and Morris water maze test were used for behavior test and cognitive ability. In addition, the neuroprotective effects of KH032 in Aβ-infused mice on the histopathological markers [neuronspecific nuclear protein (NeuN), Aβ] of neurodegeneration were examined. The levels of glial fibrillary acidic protein (GFAP), NeuN, phosphorylation extracellular signal-regulated kinase (ERK)/ERK, brain-derived neurotrophic factor (BDNF), phosphorylation cAMP response element-binding (CREB)/CREB protein expression were measured by Western blot.

RESULTSKH032 treatment ameliorated cognitive impairments, reduced the overexpression of Aβ, and inhibited neuronal loss and neuroinflammatory response in the Aβ-infused mice. Moreover, KH032 treatment enhanced BDNF expression levels in the hippocampus. Finally, KH032 treatment increased phosphorylation of ERK1/2 and CREB, vital for ERK-CREB signaling.

CONCLUSIONSKH032 attenuated cognitive defificits in the Aβ-infused mice by increasing BDNF expression and ERK1/2 and CREB phosphorylation and inhibiting neuronal loss and neuroinflflammatory response, suggesting that KH032 has therapeutic potential in neurodegenerative disorders such as AD.

Alzheimer Disease ; drug therapy ; pathology ; physiopathology ; Amyloid beta-Peptides ; Angelica ; chemistry ; Animals ; Brain ; pathology ; Brain-Derived Neurotrophic Factor ; metabolism ; Cognitive Dysfunction ; complications ; drug therapy ; physiopathology ; Cyclic AMP Response Element-Binding Protein ; metabolism ; Disease Models, Animal ; Male ; Maze Learning ; drug effects ; Memory, Short-Term ; drug effects ; Mice, Inbred C57BL ; Neurogenesis ; drug effects ; Neuroglia ; drug effects ; metabolism ; pathology ; Neurons ; drug effects ; metabolism ; pathology ; Neuroprotective Agents ; pharmacology ; therapeutic use ; Phosphorylation ; drug effects ; Phytotherapy ; Plant Extracts ; pharmacology ; therapeutic use ; Plaque, Amyloid ; drug therapy ; pathology ; physiopathology ; Signal Transduction ; drug effects

BACKGROUNDHyperbaric oxygen (HBO) and Ginkgo biloba extract (e.g., EGB 761) were shown to ameliorate cognitive and memory impairment in Alzheimer's disease (AD). However, the exact mechanism remains elusive. The aim of the present study was to investigate the possible mechanisms of HBO and EGB 761 via the function of nuclear factor kappa-B (NF-κB) pathway.

METHODSAD rats were induced by injecting β-amyloid 25-35 into the hippocampus. All animals were divided into six groups: Normal, sham, AD model, HBO (2 atmosphere absolute; 60 min/d), EGB 761 (20 mg·kg-1·d-1 ), and HBO/EGB 761 groups. Morris water maze tests were used to assess cognitive, and memory capacities of rats; TdT-mediated dUTP Nick-End Labeling staining and Western blotting were used to analyze apoptosis and NF-κB pathway-related proteins in hippocampus tissues.

RESULTSMorris water maze tests revealed that EGB 761 and HBO significantly improved the cognitive and memory ability of AD rats. In addition, the protective effect of combinational therapy (HBO/EGB 761) was superior to either HBO or EGB 761 alone. In line, reduced apoptosis with NF-κB pathway activation was observed in hippocampus neurons treated by HBO and EGB 761.

CONCLUSIONSOur results suggested that HBO and EGB 761 improve cognitive and memory capacity in a rat model of AD. The protective effects are associated with the reduced apoptosis with NF-κB pathway activation in hippocampus neurons.

Alzheimer Disease ; chemically induced ; drug therapy ; physiopathology ; therapy ; Amyloid beta-Peptides ; toxicity ; Animals ; Disease Models, Animal ; Ginkgo biloba ; chemistry ; Hyperbaric Oxygenation ; Male ; Maze Learning ; drug effects ; Memory Disorders ; drug therapy ; therapy ; NF-kappa B ; metabolism ; Plant Extracts ; therapeutic use ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo study the effects of Dipsacus total saponins on the ability of learning and memory and its mechanism of action.

METHODSForty rats were randomly divided into blank control group, model group, Dipsacus group and positive control group (n = 10), general situation of rats were observed, the ability of learning and memory of rats was tested by Square water maze, the activities of acetylcholinesterase (AChE)and choline acetyltransferase (ChAT) of hippocampus in rats were measured using double antibody sandwich method.

RESULTSDuring the period of treatment, general situation had no obvious change in model group, but general situation and the ability of activity were gradually improved in Dipsacus group and positive control group. Compared with blank control group, the swimming time was obviously prolonged and the number of mistakes was obviously increased at different time, the activity of AChE was significantly enhanced and the activity of ChAT was significantly decreased in model group. Compared with model group, the swimming time was obviously shortened and the number of mistakes was obviously reduced at different time, the activities of AChE were significantly decreased and the activities of ChAT were significantly enhanced in Dipsacus group and positive control group; Compared with positive control group, the swimming time and the number of mistakes at different time and the activities of AChE and ChAT had no significant difference in Dipsacus group.

CONCLUSIONDipsacus total saponins can improve the ability of learning and memory in Alzheimer' s disease(AD) rats, its mechanism of 'action may be related to regulating ACh metabolism of hippocampus.

Acetylcholine ; metabolism ; Acetylcholinesterase ; metabolism ; Alzheimer Disease ; drug therapy ; physiopathology ; Animals ; Choline O-Acetyltransferase ; metabolism ; Dipsacaceae ; chemistry ; Disease Models, Animal ; Hippocampus ; drug effects ; Learning ; drug effects ; Memory ; drug effects ; Rats ; Saponins ; pharmacology

OBJECTIVETo study the role of PI3K/Akt pathway in the neuroprotective effect of paeoniflorin on PC12 cells.

METHODThe paeoniflorin group (5, 10, 20 μmol · L(-1)) was pretreated for 30 min, and then added with Aβ25-35 (20 μmol · L(-1)) for interaction for 24 h. Inhibitor LY294002 (10 μmol · L(-1)) was pretreated for 30 min before the action of paeoniflorin (10 μmol · L(-1)). The MTT colorimetric method was used to detect the cell viability. The apoptosis rate was tested by the FITC-Annexin V/PI staining. The protein expression of p-AKT, Bax, Bcl-2 and cleaved caspase-3 protein were detected by Western blot analysis.

RESULTPaeoniflorin could significantly inhibit the Aβ25-35-induced PC12 cell toxicity and apoptosis. Its protection effect may be achieved by up- regulating AKT phosphorylation level, increasing Bcl-2 protein expression, reducing Bax protein expression, inhibiting the activation of caspase-3. Inhibitor LY294002 could weaken the above protective effects of paeoniflorin.

CONCLUSIONPaeoniflorin could activate PI3K/Akt signaling pathway to protect the PC12 cell injury induced by Aβ25-35.

Alzheimer Disease ; drug therapy ; genetics ; metabolism ; physiopathology ; Amyloid beta-Peptides ; toxicity ; Animals ; Apoptosis ; drug effects ; Cell Survival ; drug effects ; Drugs, Chinese Herbal ; pharmacology ; Glucosides ; pharmacology ; Humans ; Monoterpenes ; pharmacology ; Neurons ; cytology ; drug effects ; metabolism ; Neuroprotective Agents ; pharmacology ; PC12 Cells ; Peptide Fragments ; toxicity ; Phosphatidylinositol 3-Kinases ; genetics ; metabolism ; Proto-Oncogene Proteins c-akt ; genetics ; metabolism ; Proto-Oncogene Proteins c-bcl-2 ; genetics ; metabolism ; Rats ; Signal Transduction ; drug effects

Qifu-Yin (QFY), a widely used formula of traditional Chinese medicine (TCM) derived from "Jingyue Quanshu", is one of the most commonly used TCM prescriptions for the clinical treatment of Alzheimer disease. The role of advanced glycation end products (AGEs) and its receptor RAGE have attracted increasing attention as the pivotal role of Aβ has been questioned. The present study was designed to test the neuroprotective effects of QFY, and the possible mechanism in AGE-induced Alzheimer model rats. After injection of AGE in the CA3 area of the hippocampus, QFY (8.6, 4.3, and 2.15 g·kg(-1)), and a positive control drug donepezil (2 mg·kg(-1)) were administrated through gastric intubation to rats once daily for thirty consecutive days. Another positive control group was the AGE + anti-RAGE group, which was simultaneously injected with anti-RAGE antibody before AGE treatment. The control group, sham-operated group, as well as the AGE + anti-RAGE group received saline at the same dosage. The Morris water maze test and the step-down passive avoidance test were conducted to evaluate the cognitive function of the rats. The expression of RAGE and NF-κB were assayed by immunohistochemical staining. The levels of Aβ, TNF-α, and IL-1β in the hippocampus were measured by enzyme-linked immunosorbent assay (ELISA). The results showed that QFY could significantly attenuate the memory impairment induced by AGE, decrease the expressions of RAGE and NF-κB, and reduce the levels of Aβ, TNF-α, and IL-1β in the hippocampus in a dose-dependent manner. Also, the blockage of RAGE could significantly reduce the impairments caused by AGEs. In conclusion, QFY could attenuate AGEs-induced, Alzheimer-like pathophysiological changes. These neuroprotective effects might be related to the RAGE/NF-κB pathway and its anti-inflammatory activity.
Alzheimer Disease ; drug therapy ; metabolism ; physiopathology ; Amyloid beta-Peptides ; metabolism ; Animals ; Anti-Inflammatory Agents ; pharmacology ; therapeutic use ; Brain ; drug effects ; metabolism ; Dose-Response Relationship, Drug ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Glycation End Products, Advanced ; adverse effects ; Interleukin-1beta ; metabolism ; Learning ; drug effects ; Magnoliopsida ; Male ; Memory Disorders ; drug therapy ; metabolism ; NF-kappa B ; metabolism ; Phytotherapy ; Plants, Medicinal ; Rats, Sprague-Dawley ; Receptor for Advanced Glycation End Products ; Receptors, Immunologic ; metabolism ; Signal Transduction ; Tumor Necrosis Factor-alpha ; metabolism

OBJECTIVETo investigate the protective effect of paeonol on amyloid beta1-42 (Abeta1-42)-induced neurotoxicity and its mechanism.

METHODHippocampal neurons of well-grown newborn SD rats and differentiated SH-SY5Y cell lines were cultured with various concentrations of paeonol (1, 5, 10 micromol x L(-1), respectively) for 6 hours and then incubated with Abeta1-42 oligomer (30 micromol x L(-1)) for 24 hours and 48 hours, respectively. The neuron apoptosis was observed by Heochst33258. Annexin V/PI double stain flow cytometry assay was adopted for determining SH-SY5Y cell apoptosis rate. And the expression of BDNF and Bcl-2 mRNA was detected by RT-PCR.

RESULTCompared with the model group, various concentrations of paeonol (1, 5, 10 micromol x L(-1)) significantly reduced the hippocampal neurons karyopycnosis, decreased the rate of SH-SY5Y cell apoptosis to 22.4%, 18.1% and 16.4%, respectively, and improved the expressions of BDNF and Bcl-2 mRNA.

CONCLUSIONPaeonol relieves Abeta1-42 oligomer-induced neuron injury by increasing BDNF and Bcl-2 expressions.

Acetophenones ; pharmacology ; Alzheimer Disease ; drug therapy ; genetics ; metabolism ; physiopathology ; Amyloid beta-Peptides ; toxicity ; Animals ; Apoptosis ; drug effects ; Cell Line ; Cells, Cultured ; Hippocampus ; cytology ; drug effects ; Humans ; Neurons ; drug effects ; Neuroprotective Agents ; pharmacology ; Peptide Fragments ; toxicity ; Proto-Oncogene Proteins c-bcl-2 ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo observe the effect of a Chinese medicine compound, Naoerkang (NEK), on amyloid-beta peptide (1-42; Aβ(1-42)) and matrix metalloproteinase-9 (MMP-9) expressions in the hippocampus of Alzheimer's disease (AD) model rats.

METHODSA total of 48 male Sprague Dawley (SD) rats were randomly divided into normal control, untreated, and piracetam groups, and low-dose, medium-dose, and high-dose NEK groups, with 8 rats in each group. The 5-μL aggregated Aβ(1-42) (2 μg/μL) were injected into both CA1 areas of the hippocampus in the rats to establish an AD model, whereas the normal control was treated with the same dose of normal saline. The rats in the NEK groups were treated with a high, medium, or low dose of NEK [60 g/(kg·d), 30 g/(kg·d), and 15 g/(kg·d)], respectively, intragastrically for 28 days; piracetam (0.375 g/kg, intragastrically) was consecutively administered in the piracetam group; and normal saline was applied in the normal control and untreated groups. A Y-maze test was used for behavioral study to test the learning and memory abilities. Aβ(1-42) and MMP-9 expressions in the hippocampus was determined immunohistochemically, and the results were analyzed by image acquisition and an analysis system.

RESULTSAggregated Aβ(1-42) induced obvious learning and memory dysfunction, as well as up-regulation of Aβ(1-42) expression in the hippocampus. Compared with those in the normal control group, the learning and memory abilities of rats in the untreated group significantly decreased (P<0.01), and the expression of Aβ(1-42) was significantly increased (P<0.01). Twenty-eight days after different treatments, compared with those in the untreated group, the learning and memory abilities of AD model rats in the piracetam, low-dose, medium-dose and high-dose NEK groups were significantly improved (P<0.01 or P<0.05), and the expression of Aβ(1-42) in the hippocampus decreased (P<0.01 or P<0.05), and MMP-9 increased (P<0.01 or P<0.05), especially in the high-dose NEK group.

CONCLUSIONNEK might play a role of anti-dementia by increasing the expression of MMP-9 in the hippocampus of AD model rats, resulting in the reduction of the quantity of Aβ(1-42) and improvement in learning and memory ability in AD model rats.

Alzheimer Disease ; drug therapy ; metabolism ; pathology ; physiopathology ; Amyloid beta-Peptides ; metabolism ; Animals ; CA1 Region, Hippocampal ; drug effects ; enzymology ; pathology ; physiopathology ; Disease Models, Animal ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Hippocampus ; drug effects ; metabolism ; pathology ; physiopathology ; Immunohistochemistry ; Male ; Matrix Metalloproteinase 9 ; metabolism ; Memory ; drug effects ; Rats ; Rats, Sprague-Dawley

There is a close correlation between type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) in the course of pathophysiological processes. The neuroprotective action of glucagon-like peptide 1 (GLP-1), a latest drug for clinical treatment of T2DM, is being more deeply investigated at present, and a novel therapeutic strategy for AD with GLP-1 has been proposed boldly. This review mainly discussed the correlation of pathogenesis between T2DM and AD, the synthesis and secretion of GLP-1, the distribution and physiological effects of GLP-1 receptor in the brain, and the progresses on the study of GLP-1 in the treatment of AD.
Alzheimer Disease ; drug therapy ; physiopathology ; Amyloid beta-Peptides ; drug effects ; metabolism ; Animals ; Brain ; metabolism ; Diabetes Mellitus, Type 2 ; physiopathology ; Glucagon-Like Peptide 1 ; pharmacology ; therapeutic use ; Glucagon-Like Peptide-1 Receptor ; Humans ; Neuroprotective Agents ; pharmacology ; therapeutic use ; Receptors, Glucagon ; metabolism

OBJECTIVETo investigate the influence of Qingkailing (QKL) on learning and memory abilities, global neurotransmitter and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway of senescence accelerated mouse-prone/8 (SAMP8) mice with Alzheimer's dementia (AD).

METHODSSAMP mice were modeled and divided into the model group, the QKL group and the doneppezil hydrochloride group, all treated for 90 days. And a control group was set up with senescence accelerated mouse-resistance/1 (SAMR1) mice. Morris water maze was used to test the learning and memory abilities of mice; contents of acetylcholine (Ach) and monoamine neurotransmitters in brain were measured by HPLC; levels of Grb2-associated binder-1 (Gab1), AKT and phospho-serine/threonine protein kinase B (PAKT473) were evaluated by Western-blot.

RESULTSCompared with the control group, in the model group, the average escape latency detected by hidden platform trial and reverse trial on the 3rd day was higher (P < 0.01); levels of Ach, 5-hydroxytryptamine (5-HT) and Gab1 were lower (P < 0.01, P < 0.05 and P < 0.01), respectively. As compared with the model group, the escape latency (within the 2nd to 5th day) decreased (P < 0.01), levels of Ach and 5-HT increased (P < 0.05), and Gab1 protein expression increased (P < 0.01) in the QKL treated group after treatment, in addition, the level of phosphorylated AKT protein significantly increased (P < 0.05).

CONCLUSIONQKL could improve the learning and memory ability of AD model mice, which is probably related to its function in increasing cerebral Ach, 5-HT and activating PI3K/AKT pathway.

Alzheimer Disease ; drug therapy ; physiopathology ; Animals ; Disease Models, Animal ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Female ; Learning ; drug effects ; Male ; Memory ; drug effects ; Mice ; Mice, Mutant Strains ; Phosphatidylinositol 3-Kinases ; metabolism ; Phytotherapy ; Proto-Oncogene Proteins ; metabolism ; Receptor Protein-Tyrosine Kinases ; metabolism ; Signal Transduction ; drug effects

OBJECTIVETo explore the effect of the total flavonoids of Jiawei Wuzi Yanzong prescription on the Voltage-gated calcium channel of the CA1 pyramidal cell of rat hippocampus.

METHODThe inward calcium current was recorded by the whole-cell patch clamp and the amplitude of it was thought to observe the effect of Abeta25-35 and the total flavonoids. The hippocampus of rat was separated and cut into slices. Active pyramidal cells of slices were chosen for the whole-cell patch clamp recording. After exposure to Abeta25-35, voltage steps (500 ms) were used to depolarize stepwise in a range from 50 to +50 mV (increment: 5 mV). An inward Ca2+ current which was suggested to be survey was evoked. Application of the total flavonoids was to be observed if it had effect on this voltage-depended inward current.

RESULTAbeta25-35 could enhance the calcium current to induce intracellular calcium overload. The amplitude of the control group was--(157.1 +/- 19.9) pA, but after application of Abeta25-35 the current enhanced to--(323.2 +/- 23.4) pA. When the total flavonoids at concentration of 125, 250, 500 g x L(-1) were added, the current declined to--(257.9 +/- 31.6), - (196.4 +/- 29.8) and--(169.3 +/- 34.0) pA, respectively.

CONCLUSIONAbeta-induced intracellular calcium overload may be one of neurotoxic of beta-amyloid peptide. The total flavonoids of Jiawei Wuzi Yanzong prescription can suppress inward calcium current to protect neurons.

Alzheimer Disease ; drug therapy ; metabolism ; physiopathology ; Amyloid beta-Peptides ; metabolism ; Animals ; CA1 Region, Hippocampal ; cytology ; drug effects ; physiology ; Calcium Channels ; genetics ; physiology ; Disease Models, Animal ; Drugs, Chinese Herbal ; chemistry ; pharmacology ; Electrophysiology ; Female ; Flavonoids ; chemistry ; pharmacology ; Humans ; Male ; Peptide Fragments ; metabolism ; Prescription Drugs ; chemistry ; pharmacology ; Pyramidal Cells ; drug effects ; physiology ; Rats ; Rats, Sprague-Dawley