Amyloid beta-Peptides ; metabolism ; Animals ; ErbB Receptors ; antagonists & inhibitors ; Humans ; Memory Disorders ; prevention & control ; Protein Kinase Inhibitors ; pharmacology

OBJECTIVETo investigate the effects and underlying mechanism of notoginsenoside R1 on amyloid-β (1-42) (Aβ(1-42)) induced mitochondrial apoptotic death in SH-SY5Y cells.

METHODCell viability was assayed by MTT, apoptotic rates were analyzed with PI/Annexin V flow cytometry, Bax and Bcl-2 expression were detected with Western blotting, enzymatic activity of caspase-3, caspase-8 and caspase-9 were measured by ELISA assay.

RESULTThe 6.25-100 nmol x L(-1) of notoginsenoside R1 attenuate Aβ(1-42) induced apoptotic death of SH-SY5Y in dose dependent manner. The ratio of Bcl-2/Bax was elevated in SH-SY5Y with notoginsenoside R1 treatment. Caspase-3 and caspase-9 were activated with notoginsenoside R1 treatment while caspase-8 was not affected.

CONCLUSIONNotoginsenoside R1 could protect SH-SY5Y cells from Aβ(1-42) induced apoptosis via mitochondria related apoptotic pathway.

Amyloid beta-Peptides ; antagonists & inhibitors ; Apoptosis ; drug effects ; Caspases ; metabolism ; Cell Line, Tumor ; Cell Survival ; drug effects ; Cytoprotection ; Ginsenosides ; pharmacology ; Humans ; Mitochondria ; drug effects ; Peptide Fragments ; antagonists & inhibitors

AIMTo investigate the inhibition of amyloid beta-protein 42 (Abeta42) production in M146L cells by gamma-schisandrin.

METHODSM146L cells which can produce considerable Abeta42 in vitro were treated with gamma-schisandrin (1.67, 5.00 and 15.00 microg x mL(-1)), beta-secretase inhibitor (S4562, 100.00 microg x mL(-1)) and gamma-secretase inhibitor (S2188, 13.68 microg x mL(-1)), separately. Cell counting kit-8 (CCK-8) was used to assess cell viability. Enzyme-linked immunosorbent assay (ELISA) was carried out to determine the amount of Abeta42. Western blotting was used to examine C99, an intermediary product of APP cleaved by beta-secretase. beta-Secretase and gamma-secretase activities were assayed by commercial kits.

RESULTSThe CCK-8 assay indicated that different concentrations of gamma-schisandrin had no neurotoxicity on the cultured M146L. And the ELISA test showed that the amount of Abeta42 secreted by M146L cells treated with gamma-schisandrin (5.00 and 15.00 microg x mL(-1)) decreased obviously as compared with solvent control. The results of Western blotting test indicated that there was no change of C99 contents and beta-secretase activity in gamma-schisandrin treated cells, while gamma-secretase activity decreased obviously.

CONCLUSIONgamma-Schisandrin inhibited production of Abeta42 in M146L cells through inhibiting gamma-secretase.

Alzheimer Disease ; drug therapy ; Amyloid Precursor Protein Secretases ; antagonists & inhibitors ; metabolism ; Amyloid beta-Peptides ; antagonists & inhibitors ; biosynthesis ; Animals ; CHO Cells ; Cricetinae ; Cricetulus ; Cyclooctanes ; Dose-Response Relationship, Drug ; Humans ; Lignans ; Peptide Fragments ; antagonists & inhibitors ; biosynthesis ; Polycyclic Compounds ; pharmacology

Alzheimer Disease ; immunology ; therapy ; Amyloid beta-Peptides ; antagonists & inhibitors ; immunology ; metabolism ; Animals ; Antibodies, Monoclonal ; therapeutic use ; Blood-Brain Barrier ; Brain ; drug effects ; immunology ; Enzyme Inhibitors ; therapeutic use ; Humans

OBJECTIVETo study the effect of the active fraction of Tiaoxin recipe (TXR-A), in inhibiting long-term potentiation (LTP) induced by beta amyloid protein (beta-AP) in CA1 area of rats' hippocampal slices.

METHODSThe population spike (PS) in CA1 area of hippocampal slices incubated in different medium was recorded before and after LTP was evoked by a 100 Hz, 100 trains high frequency stimulation (HFS), using extracellular microelectrode recording techniques.

RESULTSThe amplitude of PS significantly decreased after HFS in hippocampal slices incubated in medium containing 0.2 micromol/L beta-AP for more than 1.5 hour, as compared with that incubated in normal cerebrospinal fluid, the difference was significant, suggesting that beta-AP could inhibit LTP in hippocampal slices. The average amplitude of PS in slices incubated in beta-AP containing medium could be significantly enhanced by adding high-concentration TXR-A or TXR into the medium, and TXR-A showed a better effect of enhancing than that of TXR, indicating that TXR-A could increase the amplitude of LTP.

CONCLUSIONTXR-A may be the chief ingredient extracted from TXR for improving beta-AP induced LTP in CA1 area of rats' hippocampus, to antagonise the inhibition of beta-AP on LTP is possibly one of the mechanisms for its intelligence benefiting action.

Alzheimer Disease ; drug therapy ; physiopathology ; Amyloid beta-Peptides ; antagonists & inhibitors ; Animals ; Drugs, Chinese Herbal ; pharmacology ; Female ; Hippocampus ; physiopathology ; Long-Term Potentiation ; drug effects ; Phytotherapy ; Rats ; Rats, Wistar

MTT analysis and intracellular calcium measurement by using confocal laser scanning microscopy were used to study the possible mechanism of protective effect of pituitary adenylate cyclase activating polypeptide 27 (PACAP27) from beta amyloid protein (Abeta)-induced neurotoxicity. The results showed that treatment with PACAP (less than 0.1 micromol/L) increased the survival and reproductive ability of neuro-2a cells and protected the neuro-2a cells from being injured by Abeta. The protective effect of PACAP27 was reversed by the competitive PACAP receptor antagonist PACAP6-27. An increase in intracellular calcium was observed when the cells were challenged with Abeta and PACAP. But the calcium increase induced by Abeta kept stable for a long time while PACAP caused a transient rise in intracellular calcium. The intracellular calcium increase induced by Abeta was blocked by pretreatment with PACAP for 10 min. It is suggested that the neuroprotective effect of PACAP against neuronal damage induced by Abeta may result from its role in inhibiting the sustained rise in intracellular calcium.
Amyloid beta-Peptides ; antagonists & inhibitors ; toxicity ; Calcium ; metabolism ; Calcium Channels ; metabolism ; Cell Line, Tumor ; Humans ; Neuroblastoma ; pathology ; Neuroprotective Agents ; pharmacology ; Pituitary Adenylate Cyclase-Activating Polypeptide ; pharmacology

A novel series of bis-nicotine derivatives (3a-3i) were designed, synthesized and evaluated as bivalent anti-Alzheimer's disease agents. The pharmacological results indicated that compounds 3e-3i inhibited both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in the micromolar range (IC50, 2.28-117.86 micromol x L(-1) for AChE and 1.67-125 micromol x L(-1) for BChE), which was at the same potency as rivastigmine. A Lineweaver-Burk plot and molecular modeling study showed that these derivatives targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds could significantly inhibit the self-induced Abeta aggregation with inhibition activity (11.85%-62.14%) at the concentration of 20 micromol x L(-1).
Acetylcholinesterase ; metabolism ; Amyloid beta-Peptides ; antagonists & inhibitors ; metabolism ; Binding Sites ; Butyrylcholinesterase ; metabolism ; Cholinesterase Inhibitors ; chemical synthesis ; chemistry ; pharmacology ; Nicotine ; analogs & derivatives ; chemical synthesis ; chemistry ; pharmacology

Amyloid β protein (Aβ) is closely involved in the pathogenesis of Alzheimer's disease (AD), and one of the main strategies for AD treatment is antagonizing the neurotoxicity of Aβ or even clearing the Aβ deposited in the brain. The present study was aimed to observe the effects of intrahippocampal injection of Aβ₃₁₋₃₅ on the spatial learning and memory of rats by using Morris water maze technique, and explore the neuroprotective effects and possible mechanism of [Gly14]-humanin (HNG) against Aβ-induced deficits in learning behavior. The results showed that bilateral intrahippocampal injection of 2.0 nmol Aβ₃₁₋₃₅ significantly increased the mean traveled distance of rats in searching for the hidden underwater platform and decreased the distance percentage in the target quadrant in probe test after withdrawal of platform, whereas pretreatment with HNG (0.2 nmol and 2.0 nmol) suppressed Aβ₃₁₋₃₅-induced increase in the traveled distance and decrease in swimming distance percentage. Application of Genistein (40 nmol), a specific tyrosine kinase inhibitor, almost completely blocked the antagonistic effects of HNG against Aβ₃₁₋₃₅. These results indicate that HNG can dose-dependently prevent against Aβ₃₁₋₃₅-induced impairment in spatial learning and memory of rats, and the neuroprotective effects of HNG might involve the activation of endogenous tyrosine kinase pathway, suggesting that up-regulation of the tyrosine kinase signaling by using HNG might be of great significance for the improvement of cognitive function in AD.
Alzheimer Disease ; physiopathology ; Amyloid beta-Peptides ; adverse effects ; antagonists & inhibitors ; Animals ; Brain ; drug effects ; Genistein ; pharmacology ; Memory ; drug effects ; Neuroprotective Agents ; pharmacology ; Peptide Fragments ; adverse effects ; antagonists & inhibitors ; Peptides ; pharmacology ; Rats ; Spatial Learning ; drug effects

This study is to screen the Chinese herbal compounds which could inhibit the production of Abeta and investigate the underlying mechanism. Ten types of compounds which have potential value in the treatment of AD were selected as initial screening trial. The cell models which used could overexpress Abeta and beta-secretases or Abeta and gamma-secretases. Extracellular Abeta was determined by ELISA after the cell models treated with different concentrations of compounds (0.5-100 micromol x L(-1)), separately. Then the compounds were selected which could inhibit extracellular Abeta and their best concentration ranges were decided, too. Furthermore, the cell viability and apoptosis rate, the level of intracellular Abeta, beta and gamma-secretases were determined after the cell models treated with different concentrations of selected compounds. The results showed that 4 of the 10 compounds could reduce the level of extracellular Abeta; they were cryptotanshinone, astragalosides, gastrodin and paeoniflorin, and their best concentration ranges were 0.5-5.0, 0.5-5.0, 5.0-50, 1.0-25 micromol x L(-1), respectively. Further study indicated that the 4 selected compounds were nontoxic to the cellular models and lowering intracellular Abeta were more effective compared with extracellular; of which astragalosides and gastrodin showed dose-dependent inhibition to the activities of beta and gamma-secretases, with the maximum inhibiting rates of 78.2% and 80.3%, respectively. In conclusion, cryptotanshinone, astragalosides, gastrodin and paeoniflorin could inhibit the expression and secretion of Abeta, and the underlying inhibiting mechanism of astragalosides and gastrodin were related with the reduction of the beta and gamma-secretase activities, respectively.
Amyloid Precursor Protein Secretases ; metabolism ; Amyloid beta-Peptides ; antagonists & inhibitors ; Apoptosis ; Benzyl Alcohols ; pharmacology ; Cell Line ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Drugs, Chinese Herbal ; pharmacology ; Glucosides ; pharmacology ; Humans ; Monoterpenes ; pharmacology ; Phenanthrenes ; pharmacology ; Saponins ; pharmacology

Alzheimer's disease (AD) is the most common form of dementia caused by neurodegenerative process and is tightly related to amyloid beta (Abeta) and neurofibrillary tangles. The lack of early diagnostic biomarker and therapeutic remedy hinders the prevention of increasing population of AD patients every year. In spite of accumulated scientific information, numerous clinical trials for candidate drug targets have failed to be preceded into therapeutic development, therefore, AD-related sufferers including patients and caregivers, are desperate to seek the solution. Also, effective AD intervention is desperately needed to reduce AD-related societal threats to public health. In this review, we summarize various drug targets and strategies in recent preclinical studies and clinical trials for AD therapy: Allopathic treatment, immunotherapy, Abeta production/aggregation modulator, tau-targeting therapy and metabolic targeting. Some has already failed in their clinical trials and the others are still in various stages of investigations, both of which give us valuable information for future research in AD therapeutic development.
Alzheimer Disease/immunology/pathology/*therapy ; Amyloid beta-Peptides/antagonists & inhibitors/immunology/metabolism ; Antibodies, Monoclonal/therapeutic use ; Brain/metabolism/pathology ; Humans ; Immunotherapy ; N-Methylaspartate/therapeutic use ; tau Proteins/antagonists & inhibitors/metabolism