lignans and Alzheimer-Disease

Neurodegenerative Diseases (NDs) are characterized by progressive neuronal deterioration as a result of several pathogenesis mechanisms. Phytochemicals, including sesamin with multitarget activities, have been studied widely.. In this review, we aim to survey the neuroprotective effects of sesamin on NDs and its mechanisms of action.. Searching GoogleScholar, PubMed, and Science Direct databases, we reviewed original English language articles on sesamin effects against NDs, specifically Alzheimer's Disease (AD) and Parkinson's Disease (PD), either in vivo or in vitro settings, with no time limitation.. Sesamin has been reported to interfere with NDs progression through its antioxidative, antiinflammatory, and antiapoptotic actions in most of the retrieved studies. Sesamin also can prevent amyloid-β aggregation in AD models and elevate dopamine levels in PD-induced models.. The results of this study revealed the beneficial effects of sesamin in the prevention and management of NDs, including AD and PD; however, no clinical data supporting these effects in humans is available, which highlights the need for designing clinical trials to evaluate the efficacy, proper dosage, pharmacokinetics aspects, and possible side effects of sesamin in humans.

Topics: Alzheimer Disease; Dioxoles; Humans; Lignans; Parkinson Disease

Arctium lappa L. is a common specie of Asteraceae. Its main active ingredient, Arctigenin (AG), in mature seeds exerts pharmacological effects on the Central Nervous System (CNS).. To review studies on the specific effects of the AG mechanism on various CNS diseases and elucidate signal transduction mechanisms and their pharmacological actions.. This investigation reviewed the essential role of AG in treating neurological disorders. Basic information on Arctium lappa L. was retrieved from the Pharmacopoeia of the People's Republic of China. The related articles from 1981 to 2022 on the network database (including CNKI, PubMed, and Wan Fang and so on) were reviewed using AG and CNS diseases-related terms such as Arctigenin and Epilepsy.. It was confirmed that AG has a therapeutic effect on Alzheimer's disease, Glioma, infectious CNS diseases (such as Toxoplasma and Japanese Encephalitis Virus), Parkinson's disease, Epilepsy, etc. In these diseases, related experiments such as a Western blot analysis revealed that AG could alter the content of some key factors (such as the reduction of Aβ in Alzheimer's disease). However, in-vivo AG's metabolic process and possible metabolites are still undetermined.. Based on this review, the existing pharmacological research has indeed made objective progress to elucidate how AG prevents and treats CNS diseases, especially senile degenerative disease such as Alzheimer's diseases. It was revealed that AG could be used as a potential nervous system drug as it has a wide range of effects in theory with markedly high application value, especially in the elder group. However, the existing studies are limited to in-vitro experiments; therefore, little is known about how AG metabolizes and functions in-vivo, limiting its clinical application and requiring further research.

Topics: Alzheimer Disease; Arctium; Furans; Humans; Lignans; Signal Transduction

Alzheimer's disease (AD) is the most common neurodegenerative disease, and its incidence is increasing worldwide with increased lifespan. Currently, there is no effective treatment to cure or prevent the progression of AD, which indicates the need to develop novel therapeutic targets and agents. Sirtuins, especially SIRT3, a mitochondrial deacetylase, are NAD-dependent histone deacetylases involved in aging and longevity. Accumulating evidence indicates that SIRT3 dysfunction is strongly associated with pathologies of AD, hence, therapeutic modulation of SIRT3 activity may be a novel application to ameliorate the pathologies of AD. Natural products commonly used in traditional medicine have wide utility and appear to have therapeutic benefits for the treatment of neurodegenerative diseases such as AD. The present review summarizes the currently available natural SIRT3 activators and their potentially neuroprotective molecular mechanisms of action that make them a promising agent in the treatment and management of neurodegenerative diseases such as AD.

Topics: Aging; Alzheimer Disease; Animals; Biphenyl Compounds; Dietary Supplements; Drug Delivery Systems; Enzyme Inhibitors; Glucosides; Humans; Hydrazines; Indazoles; Lignans; Neuroprotection; Phenols; Sirtuin 3

Developed regions, including Japan, have become "aged societies," and the number of adults with senile dementias, such as Alzheimer's disease (AD), Parkinson's disease, and Huntington's disease, has also increased in such regions. Neurotrophins (NTs) may play a role in the treatment of AD because endogenous neurotrophic factors (NFs) prevent neuronal death. However, peptidyl compounds have been unable to cross the blood-brain barrier in clinical studies. Thus, small molecules, which can mimic the functions of NFs, might be promising alternatives for the treatment of neurodegenerative diseases. Natural products, such as or nutraceuticals or those used in traditional medicine, can potentially be used to develop new therapeutic agents against neurodegenerative diseases. In this review, we introduced the neurotrophic activities of polyphenols honokiol and magnolol, which are the main constituents of Magnolia obovata Thunb, and methanol extracts from Zingiber purpureum (BANGLE), which may have potential therapeutic applications in various neurodegenerative disorders.

Topics: Alzheimer Disease; Animals; Biphenyl Compounds; Cells, Cultured; Dietary Supplements; Hippocampus; Humans; Lignans; Magnolia; Mice; Molecular Weight; Nerve Growth Factors; Neurodegenerative Diseases; Neurogenesis; Phytotherapy; Polyphenols; Rats; Structure-Activity Relationship; Zingiberales

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and memory loss. One of the hallmarks in AD is amyloid-β peptide (Aβ) accumulation, where the soluble oligomers of Aβ (AβOs) are the most toxic species, deteriorating the synaptic function, membrane integrity, and neuronal structures, which ultimately lead to apoptosis. Currently, there are no drugs to arrest AD progression, and current scientific efforts are focused on searching for novel leads to control this disease. Lignans are compounds extracted from conifers and have several medicinal properties. Eudesmin (Eu) is an extractable lignan from the wood of Araucaria araucana, a native tree from Chile. This metabolite has shown a range of biological properties, including the ability to control inflammation and antibacterial effects.. In this study, the neuroprotective abilities of Eu on synaptic failure induced by AβOs were analyzed.. Using neuronal models, PC12 cells, and in silico simulations we evaluated the neuroprotective effect of Eu (30 nM) against the toxicity induced by AβOs.. In primary cultures from mouse hippocampus, Eu preserved the synaptic structure against AβOs toxicity, maintaining stable levels of the presynaptic protein SV2 at the same concentration. Eu also averted synapsis failure from the AβOs toxicity by sustaining the frequencies of cytosolic Ca2+ transients. Finally, we found that Eu (30 nM) interacts with the Aβ aggregation process inducing a decrease in AβOs toxicity, suggesting an alternative mechanism to explain the neuroprotective activity of Eu.. We believe that Eu represents a novel lead that reduces the Aβ toxicity, opening new research venues for lignans as neuroprotective agents.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Lignans; Mice; Neuroprotective Agents; PC12 Cells; Rats

Alzheimer's disease (AD) is a common neurodegenerative disease characterized by neuronal degeneration and hyperphosphorylated Tau. Magnolol is an active component isolated from Magnolia officinalis with potential neuroprotection activity. However, the function and mechanism of magnolol in AD progression is largely uncertain. In present study, the biomarkers related to AD and magnolol were predicted by bioinformatics analyses. The key biomarker levels were predicted by GSE5281 and GSE36980 using AlzData. Cell viability was detected by CCK-8 assay. mRNA and protein levels were examined by qRT-PCR and western blotting assays. Cell apoptosis was investigated by caspase-3 activity and flow cytometry analyses. The cAMP/PKA/CREB signaling was evaluated by ELISA and western blotting analyses. The results showed that CHRM1 was a key biomarker for magnolol against AD progression. Magnolol attenuated Aβ-induced viability inhibition, Tau hyperphosphorylation and apoptosis in SH-SY5Y cells by upregulating CHRM1. In addition, the cAMP signaling might be a potential pathway of CHRM1 in AD. Magnolol contributed to activation of the cAMP/PKA/CREB pathway through enhancing CHRM1 level. Inactivation of the cAMP/PKA/CREB signaling reversed the suppressive effect of magnolol on Tau hyperphosphorylation and apoptosis in Aβ-treated SH-SY5Y cells. As a conclusion, magnolol mitigated Aβ-induced Tau hyperphosphorylation and neuron apoptosis by upregulating CHRM1 and activating the cAMP/PKA/CREB pathway.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Apoptosis; Biphenyl Compounds; Humans; Lignans; Neurodegenerative Diseases; Neurons; Receptor, Muscarinic M1

In this study, we aimed to investigate the effect of Magnolol on Alzheimer's disease (AD). After the model of streptozotocin-induced AD mice with brain insulin resistance was established, the mice were treated with Magnolol or miR-200c antagomiR. The abilities of ambulations, rearings, discrimination, spatial learning, and memory were evaluated by open-field test (OFT), novel object recognition (NOR), and morris water maze (MWM) tests. The levels of malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), and miR-200c in the mice hippocampus were evaluated by enzyme-linked immunosorbent assay, Western blot, or Quantitative real-time Polymerase Chain Reaction. In AD mice model, streptozotocin induced the locomotor impairment and cognitive deficit, up-regulated levels of MDA, TNF-α, IL-6, and CRP, while down-regulated levels of GSH, SOD, and miR-200c. Magnolol increased the rearings numbers and discrimination index of AD mice in OFT and NOR tests. Magnolol increased the number of entries in the target quadrant and time spent in the target quadrant and decreased the escape latency of AD mice in the MWM test. Magnolol also down-regulated the levels of MDA, TNF-α, IL-6, and CRP, and up-regulated the levels of GSH, SOD, and miR-200c in the hippocampus tissues of AD mice. However, miR-200c antagomiR did the opposite and further offset the effects of the Magnolol on AD mice. Magnolol attenuated the locomotor impairment, cognitive deficit, and neuroinflammatory in AD mice with brain insulin resistance via up-regulating miR-200c.

Topics: Alzheimer Disease; Animals; Antagomirs; Biphenyl Compounds; Brain; Disease Models, Animal; Insulin Resistance; Lignans; Locomotion; Male; Malondialdehyde; Mice; Morris Water Maze Test; Spatial Learning; Streptozocin

Honokiol (HO) exerts neuroprotective effects in several animal models of Alzheimer's disease (AD), but the poor dissolution hampers its bioavailability and therapeutic efficacy.. A novel honokiol nanoscale drug delivery system (Nano-HO) with smaller size and excellent stability was developed in this study to improve the solubility and bioavailability of HO. The anti-AD effects of Nano-HO was determined.. Male TgCRND8 mice were daily orally administered Nano-HO or HO at the same dosage (20 mg/kg) for 17 consecutive weeks, followed by assessment of the spatial learning and memory functions using the Morris Water Maze test (MWMT).. Our pharmacokinetic study indicated that the oral bioavailability was greatly improved by Nano-HO. In addition, Nano-HO significantly improved cognitive deficits and inhibited neuroinflammation via suppressing the levels of TNF-α, IL-6 and IL-1β in the brain, preventing the activation of microglia (IBA-1) and astrocyte (GFAP), and reducing β-amyloid (Aβ) deposition in the cortex and hippocampus of TgCRND8 mice. Moreover, Nano-HO was more effective than HO in modulating amyloid precursor protein (APP) processing via suppressing β-secretase, as well as enhancing Aβ-degrading enzymes like neprilysin (NEP). Furthermore, Nano-HO more markedly inhibited tau hyperphosphorylation via decreasing the ratio of p-Tau (Thr 205)/tau and regulating tau-related apoptosis proteins (caspase-3 and Bcl-2). In addition, Nano-HO more markedly attenuated the ratios of p-JNK/JNK and p-35/CDK5, while enhancing the ratio of p-GSK-3β (Ser9)/GSK-3β. Finally, Nano-HO prevented the gut microflora dysbiosis in TgCRND8 mice in a more potent manner than free HO.. Nano-HO was more potent than free HO in improving cognitive impairments in TgCRND8 mice via inhibiting Aβ deposition, tau hyperphosphorylation and neuroinflammation through suppressing the activation of JNK/CDK5/GSK-3β signaling pathway. Nano-HO also more potently modulated the gut microbiota community to protect its stability than free HO. These results suggest that Nano-HO has good potential for further development into therapeutic agent for AD treatment.

Topics: Alzheimer Disease; Animals; Biphenyl Compounds; Cognition; Cognitive Dysfunction; Gastrointestinal Microbiome; Glycogen Synthase Kinase 3 beta; Lignans; Male; Mice; Neuroinflammatory Diseases

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders characterized by memory deficits. Although no drug has given promising results, synaptic dysfunction-modulating agents might be considered potential candidates for alleviating this disorder. Pinoresinol, a lignan found in Forsythia suspensa, is a memory-enhancing agent with excitatory synaptic activation. In the present study, we tested whether pinoresinol reduces learning and memory and excitatory synaptic deficits in an amyloid β (Aβ)-induced AD-like mouse model. Pinoresinol enhanced hippocampal long-term potentiation (LTP) through calcium-permeable AMPA receptor, which was mediated by Akt activation. Moreover, pinoresinol ameliorated LTP deficits in amyloid β (Aβ)-treated hippocampal slices via Akt signaling. Oral administration of pinoresinol ameliorated Aβ-induced memory deficits without sensory dysfunction. Moreover, AD-like pathology, including neuroinflammation and synaptic deficit, were ameliorated by pinoresinol administration. Collectively, pinoresinol may be a good candidate for AD therapy by modulating synaptic functions.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Furans; Hippocampus; Lignans; Long-Term Potentiation; Male; Memory Disorders; Mice, Inbred Strains; Neuronal Plasticity; Peptide Fragments; Proto-Oncogene Proteins c-akt; Receptors, AMPA

For Alzheimer's disease (AD), there is still no effective treatment strategy. Pinoresinol diglucoside (PDG) is one of the major lignans isolated from Eucommia ulmoides. It is endowed with multiple pharmacological activities, including anti-inflammatory, antioxidant and anticancer activities. In this study, we investigated the potential neuroprotective functions of PDG in AD. Mice model with AD was established adopting stereotactic hippocampal injection of Aβ1-42 (410 pmol/mouse), and 3 days later, mice were administrated with 5 and 10 mg/kg PDG by intragastric administration every day for 3 weeks. Morris water maze and Y-maze tests demonstrated that PDG treatment could markedly reverse Aβ1-42-induced memory impairment in mice. It is found that PDG restrained the release of proinflammatory cytokines (tumor necrosis factor α and interleukin 1β), reactive oxygen species and malondialdehyde, and promoted the activity of the antioxidant enzyme (superoxide dismutase and catalase) by quantitative real-time-PCR, colorimetric method and ELISA assay. Western blot assay results have shown that PDG could also upregulate the ratio of Bcl-2/Bax and downregulate cytochrome c and cleaved caspase-3 expressions, thereby inhibiting neuronal apoptosis. Furthermore, PDG also significantly reduced the expression of Toll-like receptor 4 (TLR4) and the activation of nuclear factor-κB (NF-κB) p65, and promoted nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) expressions. In conclusion, PDG can attenuate neuroinflammation, neuronal apoptosis and oxidative stress through the TLR4/NF-κB and Nrf2/HO-1 pathways, and ameliorate memory dysfunction induced by Aβ1-42 in mice.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Catalase; Disease Models, Animal; Hippocampus; Inflammation; Injections; Interleukin-1beta; Lignans; Malondialdehyde; Mice; Morris Water Maze Test; Oxidative Stress; Peptide Fragments; Reactive Oxygen Species; Stereotaxic Techniques; Superoxide Dismutase; Toll-Like Receptor 4; Transcription Factor RelA; Tumor Necrosis Factor-alpha

Schisandrin which is derived from Schisandra chinensis has shown multiple pharmacological effects on various diseases including Alzheimer's disease (AD). It is demonstrated that mitochondrial dysfunction plays an essential role in the pathogenesis of neurodegenerative disorders.. Our study aims to investigate the effects of schisandrin on mitochondrial functions and metabolisms in primary hippocampal neurons.. In our study, rat primary hippocampal neurons were isolated and treated with indicated dose of amyloid β1-42 (Aβ1-42) oligomer to establish a cell model of AD in vitro. Schisandrin (2 μg/mL) was further subjected to test its effects on mitochondrial function, energy metabolism, mitochondrial biogenesis, and dynamics in the Aβ1-42 oligomer-treated neurons.. Our findings indicated that schisandrin significantly alleviated the Aβ1-42 oligomer-induced loss of mitochondrial membrane potential and impaired cytochrome c oxidase activity. Additionally, the opening of mitochondrial permeability transition pore and release of cytochrome c were highly restricted with schisandrin treatment. Alterations in cell viability, ATP production, citrate synthase activity, and the expressions of glycolysis-related enzymes demonstrated the relief of defective energy metabolism in Aβ-treated neurons after the treatment of schisandrin. For mitochondrial biogenesis, elevated expression of peroxisome proliferator-activated receptor γ coactivator along with promoted mitochondrial mass was found in schisandrin-treated cells. The imbalance in the cycle of fusion and fission was also remarkably restored by schisandrin. In summary, this study provides novel mechanisms for the protective effect of schisandrin on mitochondria-related functions.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Animals, Newborn; Cyclooctanes; Cytochromes c; Energy Metabolism; Hippocampus; Lignans; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Dynamics; Models, Biological; Neurons; Neuroprotective Agents; Organelle Biogenesis; Peptide Fragments; Polycyclic Compounds; Primary Cell Culture; Rats, Sprague-Dawley

Dysfunction of microglia has been increasingly recognized as a causative factor in Alzheimer's disease (AD); thus, developing medicines capable of restoring microglial functions is critically important and constitutes a promising therapeutic strategy. Honokiol is a natural neuroprotective compound extracted from Magnolia officinalis, which may play roles in AD therapy.. This study aimed to evaluate the role and the underlying mechanisms of honokiol in microglial phagocytosis.. MTT and flow cytometry were used to assess the cell viability and apoptosis, respectively. Phagocytic capacity, mitochondrial reactive oxygen species production, and membrane potential were evaluated using fluorescence microscopy. Seahorse XF24 extracellular flux analyzer was for cell glycolysis and oxidative phosphorylation detection. Mass spectrometry was applied for metabolites measurement. Quantitative real-time polymerase chain reaction and western blotting were performed to detect the mRNA and protein level of PPARγ and PGC1α, respectively.. Honokiol alleviated Aβ42-induced BV2 neurotoxicity. Honokiol promoted phagocytic efficiency of BV2 cells through reversing a metabolic switch from oxidative phosphorylation to anaerobic glycolysis and enhancing ATP production. Meanwhile, honokiol reduced mitochondrial reactive oxygen species production and elevated mitochondrial membrane potential. Moreover, honokiol increased the expression of PPARγ and PGC1α, which might play positive roles in energy metabolism and microglial phagocytosis.. In this study, honokiol was identified as an effect natural product capable of enhancing mitochondrial function thus promoting microglial phagocytic function.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Biphenyl Compounds; Cell Culture Techniques; Cell Survival; Humans; Lignans; Magnolia; Mice; Microglia; Phagocytosis; Reactive Oxygen Species

Lignans from Schisandra chinensis (Turcz.) Baill (LFS) has been proved to improve impaired cognitive ability thereby show potential in treating Alzheimer's disease (AD). In this study, UHPLC-Q-TOF-MS and UHPLC-QQQ-MS were adopted cooperatively to establish a method synchronously detecting 10 kinds of LFS monomers in rat plasma samples. And this method was further applied for pharmacokinetic study to compare the metabolism of LFS in normal and AD rats. The results indicated that AD rats showed an observably better absorption of LFS compared to normal rats. Based on time-varying plasma concentration of LFS, metabolomics was used to establish a plasma concentration-time-endogenous metabolite connection. In total 54 time-varying endogenous metabolites were screened and most of which were closely associated with AD. And LFS exerted a concentration dependent regulating effect to most of these metabolites. Through biomarker related pathways and biological function analysis, LFS might treat AD through neuroprotection, antioxidant damage and regulating the metabolism of unsaturated fatty acids. This is the first study connecting LFS absorbtion and endogenous metabolite changes with the time lapse. The pharmacokinetics and metabolic profile differences between normal and AD rats were firstly investigated as well. This study provides a novel perspective in exploring the effect and mechanism of LFS in treating AD.

Topics: Alzheimer Disease; Animals; Chromatography, High Pressure Liquid; Disease Models, Animal; Lignans; Male; Mass Spectrometry; Metabolome; Metabolomics; Plant Extracts; Rats; Rats, Wistar; Schisandra

The purpose of this study is to provide a complete metabolic profile of the hydroalcoholic extracts of the leaves and fruits of

Topics: Acetylcholine; Alzheimer Disease; Animals; Arecaceae; Brain; Cholinesterase Inhibitors; Disease Models, Animal; Fatty Acids; Flavonoids; Fruit; Lignans; Plant Extracts; Plant Leaves; Rats; Stilbenes

This study aims to investigate whether magnolol (MG), a natural neolignane compound, can prevent AD induced by beta-amyloid (Aβ) and the possible mechanisms involved. MG dose-dependently reduces Aβ deposition, toxicity and memory impairment caused by Aβ in transgenic C. elegans. More importantly, these effects are reversed by GW9662, a selective peroxisome proliferator-activated receptor-γ (PPAR-γ) antagonist. MG is more effective in enhancing PPAR-γ luciferase levels than honokiol (HK). Meanwhile, MG has the potential to bind with the ligand binding domain of PPAR-γ (PPAR-γ-LBD). As expected, MG inhibited the luciferase activity of NF-κB and its target genes of inflammatory cytokines, and this effect was blocked by GW9662. The luciferase activity of Nrf2-ARE expression can be activated by MG and decreased Aβ-induced reactive oxygen species (ROS). The target gene LXR of PPAR-γ is activated by MG, which upregulates ApoE and promotes microglia phagocytosis and the degradation of Aβ, and these effects were also reversed by GW9662. In summary, MG can attenuate Aβ-induced AD and the underlying mechanism is the reduction of inflammation and promotion of phagocytosis and degradation of Aβ, which is dependent on PPAR-γ.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Animals, Genetically Modified; Apolipoproteins E; Biphenyl Compounds; Caenorhabditis elegans; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Inflammation; Lignans; Microglia; NF-kappa B; Phagocytosis; PPAR gamma

Alzheimer's disease (AD) is a neurodegenerative disease that seriously threatens elderly health. Schisandrin (SCH) and nootkatone (NKT) are two core components derived from Alpinia oxyphylla-Schisandra chinensis herb pair (ASHP), a traditional Chinese medicine formulation. Previous studies demonstrated that the combination of NKT and SCH exerted a neuroprotective effect in AD mouse models. The present study was undertaken to investigate whether there was a synergistic effect between NKT and SCH and the possible mechanism in Aβ1-42 induced PC12 cells. SCH (50 μM) and NKT (10 μM) had the most notable inhibitory effect on the level of Aβ secreted by cells. Treatment with NKT + SCH activated the PI3K/AKT/Gsk-3β/mTOR pathway. Inflammation related proteins such as NF-κB, IKK, IL-1β, IL-6 and TNF-α were decreased. The levels of cleaved-Caspase3 and LC3-II were reduced, indicating that apoptosis and autophagy were inhibited. These results revealed that NKT + SCH exerted a neuroprotective effect via the PI3K/AKT pathway, inhibiting inflammation, apoptosis and autophagy.

Topics: Alzheimer Disease; Animals; Apoptosis; Autophagy; Cyclooctanes; Disease Models, Animal; Drug Synergism; Inflammation; Lignans; Mice; Neuroprotective Agents; PC12 Cells; Phosphatidylinositol 3-Kinases; Polycyclic Compounds; Polycyclic Sesquiterpenes; Proto-Oncogene Proteins c-akt; Rats; Signal Transduction; tau Proteins

Schisandrin, an active component extracted from Schisandra chinensis (Turcz.) Baill has been reported to alleviate the cognitive impairment in neurodegenerative disorder like Alzheimer's disease (AD). However, the mechanism by which schisandrin regulates the cognitive decline is still unclear. In our study, intracerebroventricular injection of streptozotocin (STZ) was employed to establish AD model in male Wistar rats, and indicated dose of schisandrin was further administered. The Morris water maze test was performed to evaluate the ability of learning and memory in rats with schisandrin treatment. The results indicated that schisandrin improved the capacity of cognition in STZ-induced rats. The contents of pro-inflammatory cytokines in brain tissue were determined by ELISA, and the expressions of these cytokines were assessed by western-blot and immunohistochemistry. The results showed that treatment of schisandrin significantly reduced the production of inflammation mediators including tumor necrosis factor-α, interleukin-1β and interleukin-6. Further study suggested a remarkable decrease in the expressions of ER stress maker proteins like C/EBP-homologous protein, glucose-regulated protein 78 and cleaved caspase-12 in the presence of schisandrin, meanwhile the up-regulation of sirtuin 1 (SIRT1) was also observed in the same group. Additionally, the results of western-blot and EMSA demonstrated that schisandrin inhibited NF-κB signaling in the brain of STZ-induced rats. In conclusion, schisandrin ameliorated STZ-induced cognitive dysfunction, ER stress and neuroinflammation which may be associated with up-regulation of SIRT1. Our study provides novel mechanisms for the neuroprotective effect of schisandrin in AD treatment.

Topics: Alzheimer Disease; Animals; Cognition; Cognitive Dysfunction; Cyclooctanes; Disease Models, Animal; Endoplasmic Reticulum Stress; Lignans; Male; Phytotherapy; Polycyclic Compounds; Rats, Wistar; Schisandra; Sirtuin 1; Streptozocin; Up-Regulation

Alzheimer's disease (AD) is characterized by the progressive disturbance in cognition and affects approximately 36 million people, worldwide. However, the drugs used to treat this disease are only moderately effective and do not alter the course of the neurodegenerative process. This is because the pathogenesis of AD is mainly associated with oxidative stress, and current drugs only target two enzymes involved in neurotransmission. Therefore, the present study sought to identify potential multitarget compounds for enzymes that are directly or indirectly involved in the oxidative pathway, with minimal side effects, for AD treatment. A set of 159 lignans were submitted to studies of QSAR and molecular docking. A combined analysis was performed, based on ligand and structure, followed by the prediction of absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. The results showed that the combined analysis was able to select 139 potentially active and multitarget lignans targeting two or more enzymes, among them are c-Jun N-terminal kinase 3 (JNK-3), protein tyrosine phosphatase 1B (PTP1B), nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1), NADPH quinone oxidoreductase 1 (NQO1), phosphodiesterase 5 (PDE5), nuclear factor erythroid 2-related factor 2 (Nrf2), cycloxygenase 2 (COX-2), and inducible nitric oxide synthase (

Topics: Algorithms; Alzheimer Disease; Cyclic Nucleotide Phosphodiesterases, Type 5; Databases, Chemical; Drug Evaluation, Preclinical; Humans; Hydrogen Bonding; Lignans; Molecular Docking Simulation; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Quantitative Structure-Activity Relationship; ROC Curve; Thermodynamics; User-Computer Interface

Topics: Alzheimer Disease; Animals; Cyclooctanes; Disease Models, Animal; Glutathione; Lignans; Malondialdehyde; Maze Learning; Mice; Neuroprotective Agents; Oxidative Stress; Plant Extracts; Polycyclic Compounds; Polycyclic Sesquiterpenes; Superoxide Dismutase

Schisandra chinensis (Turcz.) Baill (S. chinensis), a functional food, is used as a tonic and sedative agent in traditional Chinese medicine. Modern pharmacological research has proved that S. chinensis could prevent and treat age-related neurodegenerative diseases. The presence of bioactive lignans in S. chinensis is the main reason for its neuroprotective and cognitive enhancement effects. This study aimed to clarify the mechanism of lignans in S. chinensis in ameliorating learning and memory deficits in Alzheimer's disease (AD) animals. The step-down test and Morris water maze (MWM) test were used to verify the effects of lignans in S. chinensis on learning and memory in AD animals. Then, metabolomics approaches based on ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) were used to clarify the mechanism of lignans in S. chinensis in treating AD. Finally, quantitative analysis of AD-related neurotransmitters in the brain was conducted after treatment with lignans in S. chinensis. In the MWM and step-down tests, lignans in S. chinensis showed a clear ability to ameliorate the impaired learning and memory of AD animals. A total of 31 endogenous metabolites were identified after treatment with lignans in S. chinensis, which were associated with lignans ameliorating learning and memory. These biomarkers were mainly associated with polyunsaturated fatty acid metabolism and amino acid and vitamin metabolism. Moreover, lignans in S. chinensis upregulated the levels of γ-aminobutyric acid (GABA), 5-hydroxytryptamine (5-HT), acetylcholine (Ach), norepinephrine (NE) and glycine (Gly) and downregulate the level of aspartic acid (Asp). Lignans in S. chinensis might alleviate the neurotoxic effects of neurological inflammation and oxidative stress, Aβ deposition, and tau phosphorylation via the regulation of multiple endogenous metabolic pathways during pathological AD. The research might provide useful support for the further study of pharmacology and new drug development of lignans in S. chinensis.

Topics: Alzheimer Disease; Animals; Biomarkers; Chromatography, High Pressure Liquid; Cognition; Drugs, Chinese Herbal; Humans; Lignans; Male; Maze Learning; Memory; Metabolomics; Neurotransmitter Agents; Oxidative Stress; Plasma; Rats; Rats, Sprague-Dawley; Schisandra; Tandem Mass Spectrometry; Urine

Glycogen synthase kinase-3β (GSK-3β) is a key enzyme in hyperphosphorylation of tau proteins and is a promising therapeutic target in Alzheimer's disease (AD). Here, we reported, for the first time, that the stereoisomers of Schisandrin B (Sch B), (+)-1, (-)-1, (+)-2, and (-)-2, were potent GSK-3β inhibitors. They were demonstrated to selectively target GSK-3β in an orthosteric binding mode, with IC

Topics: Adenosine Triphosphate; Alzheimer Disease; Animals; Cell Line, Tumor; Cell Survival; Cyclooctanes; Enzyme Inhibitors; Glycogen Synthase Kinase 3 beta; Hippocampus; Humans; Lignans; Male; Mice; Mice, Inbred ICR; Molecular Docking Simulation; Neuroprotective Agents; Polycyclic Compounds; Stereoisomerism; Treatment Outcome

Lignans from

Topics: Alzheimer Disease; Animals; Biomarkers; Chromatography, High Pressure Liquid; Cyclooctanes; Lignans; Metabolic Networks and Pathways; Molecular Structure; Neurons; Neurotransmitter Agents; Plant Extracts; Polycyclic Compounds; Rats; Schisandra; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Topics: Acetylcholinesterase; Alzheimer Disease; Butyrylcholinesterase; Cholinesterase Inhibitors; Chromatography, High Pressure Liquid; Coumarins; Humans; Lignans; Plant Extracts; Quinolines; Rutaceae; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Turkey

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cerebral Cortex; Chromatography, Liquid; Cognitive Dysfunction; Cyclooctanes; Female; Hippocampus; Lignans; Male; Maze Learning; Memory Disorders; Mice, Inbred C57BL; Mice, Transgenic; Neurotransmitter Agents; Nootropic Agents; Polycyclic Compounds; Presenilin-1; Tandem Mass Spectrometry

Shengmai San (SMS), a Chinese classic herbal formula, has been widely used for the treatment of Qi-Yin deficiency syndrome in Asia. Modern pharmacological studies have shown that SMS improves the cognitive function. However, the quality markers (Q-markers) for SMS still need further research.. Using chinmedocmics strategy to systematically evaluate the efficacy of SMS in the treatment of APPswe/PS1dE9 (APP/PS1) transgenic model of Alzheimer's disease (AD) and to discover the efficacy-related Q-markers.. The effect of SMS on APP/PS1 mice was evaluated by behavioral test, immunohistochemistry and urine metabolic profile, and the urine marker metabolites associated with SMS treatment of AD were characterized using metabolomics method. In the premise of efficacy, Serum Pharmacochemistry of Traditional Chinese Medicine was applied to investigate the in vivo constituents of SMS. A correlation analysis between marker metabolites of therapeutic effects and serum constituents was completed by chinmedomics approach.. SMS had a therapeutic effect on APP/PS1 mice, and 34 potential urine biomarkers were reversed by SMS treatment. A total of 17 in vivo constituents were detected, including 14 prototype components and 3 metabolites. The correlation analysis showed that eight constituents were extremely correlated with protective effects of SMS in AD, and considered as potential Q-markers of SMS, including schisandrin, isoschisandrin, angeloylgomisin Q, gomisin D, angeloylgomisin H, gomisin M2, ginsenoside F1, 20(R)-ginsenoside Rg3.. This study has demonstrated that chinmedomics is novel strategy for discovering the potential effective constituents from herbal formula, which are recognized as Q-markers.

Topics: Alzheimer Disease; Animals; Biomarkers, Pharmacological; Cyclooctanes; Dioxoles; Disease Models, Animal; Drug Combinations; Drugs, Chinese Herbal; Ginsenosides; Lignans; Male; Medicine, Chinese Traditional; Metabolomics; Mice, Transgenic; Neuroprotective Agents; Polycyclic Compounds

Accumulating evidence has demonstrated that mitochondrial dysfunction is a prominent early event in the progression of Alzheimer's disease (AD). Whether protecting mitochondrial function can reduce amyloid-β oligomer (AβO)-induced neurotoxicity in PS1V97L transgenic mice remains unknown. In this study, we examined the possible protective effects of honokiol (HKL) on mitochondrial dysfunction induced by AβOs in neurons, and cognitive function in AD PS1V97Ltransgenic mice. We determined that HKL increased mitochondrial sirtuin 3 (SIRT3) expression levels and activity, which in turn markedly improved ATP production and weakened mitochondrial reactive oxygen species production. We demonstrated that the enhanced energy metabolism and attenuated oxidative stress of HKL restores AβO-mediated mitochondrial dysfunction in vitro and in vivo. Consequently, memory deficits in the PS1V97L transgenic mice were rescued by HKL in the early stages. These results suggest that HKL has therapeutic potential for delaying the onset of AD symptoms by alleviating mitochondrial impairment and increasing hyperactivation of SIRT3 in the pathogenesis of preclinical AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Biphenyl Compounds; Cells, Cultured; Cognition Disorders; Disease Models, Animal; Embryo, Mammalian; Enzyme Inhibitors; Female; Hippocampus; Lignans; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Neurons; Oligoribonucleotides; Oxidative Stress; Presenilin-1; Rats; Rats, Sprague-Dawley; Sirtuin 3

Increasing evidence indicates that amyloid β oligomer (AβO) is toxic to neurons in Alzheimer's disease (AD) brain. The aim of the present study is to evaluate the effects of honokiol on AβO-induced learning and memory dysfunction in mice.. AD mice model was established by AβO intrahippocampal injection. The cognitive function was evaluated using Morris water maze (MWM). Nissl staining was used to examine the hippocampal neuron damage. Primary hippocampal neurons were exposed to AβO. The apoptosis in the hippocampal tissues and primary neurons was assessed using terminal dexynucleotidyl transferase-mediated dUTP nick end labeling-neuronal nuclei (NeuN) and Hoechst staining, respectively. The mitochondrial membrane potential and radical oxygen species were detected using standard methods. Western blotting assay was used to check the expression levels of apoptotic and nuclear factor kappa-B (NF-κB) signaling-associated proteins and electrophoretic mobility shift assay was used to detect NF-κB-DNA binding.. Honokiol increased the time spend in the target zone of the AD mice in the MWM. In addition, honokiol dose-dependently attenuated AβO-induced hippocampal neuronal apoptosis, reactive oxygen species production and loss of mitochondrial membrane potential. Furthermore, AβO-induced NF-κB activation was inhibited by honokiol, as well as the upregulated amyloid precursor protein and β-secretase.. Honokiol attenuates AβO-induced learning and memory dysfunction in mice and it may be a potential candidate in AD therapy.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Apoptosis Regulatory Proteins; Biphenyl Compounds; Cells, Cultured; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Hippocampus; Lignans; Male; Maze Learning; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mitochondria; Neurons; NF-kappa B; Peptide Fragments; Reactive Oxygen Species; Signal Transduction

Nine new phenylpropanoids, one new coumarin, and 43 known polyphenols were isolated from wolfberry. Their structures were determined by spectroscopic analyses, chemical methods, and comparison of NMR data. Polyphenols, an important type of natural products, are notable constituents in wolfberry. 53 polyphenols, including 28 phenylpropanoids, four coumarins, eight lignans, five flavonoids, three isoflavonoids, two chlorogenic acid derivatives, and three other constituents, were identified from wolfberry. Lignans and isoflavonoids were firstly reported from wolfberry. 22 known polyphenols were the first isolates from the genus Lycium. This research presents a systematic study on wolfberry polyphenols, including their bioactivities. All these compounds exhibited oxygen radical absorbance capacity (ORAC), and some compounds displayed DPPH radical scavenging activity. One compound had acetylcholinesterase inhibitory activity. The discovery of new polyphenols and their bioactivities is beneficial for understanding the scientific basis of the effects of wolfberry.

Topics: Acetylcholinesterase; Alzheimer Disease; Benzothiazoles; Biphenyl Compounds; Chlorogenic Acid; Cholinesterase Inhibitors; Flavonoids; Food Analysis; Free Radical Scavengers; Free Radicals; Lignans; Lycium; Molecular Structure; Oxygen; Picrates; Plant Extracts; Polyphenols; Spectrophotometry, Ultraviolet; Structure-Activity Relationship; Thiazoles

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; CHO Cells; Cinnamomum zeylanicum; Cricetinae; Cricetulus; Enzyme Inhibitors; Inhibitory Concentration 50; Lignans; Plant Bark; Plant Extracts; Plant Stems

Disturbances in DNA methylation are postulated to result in various central nervous system diseases including Alzheimer's disease (AD). The SH-SY5Y neuronal cell line treated with Aβ1-40 (5 μmol/L) protein is considered to be a model of AD. Hence the aim of this study was to examine the influence of Schizandrol A, a plant extract, on DNA methylation in SH-SY5Y cells exposed to Aβ1-40. Aβ1-40 were incubated with varying concentrations of Sehizandrol A to a final concentration of 1 (low), 3 (intermediate) or 9 μg/ml (high). Exposure of SH-SY5Y with Aβ1-40 reduced viability, and altered cellular morphology and mRNA expression of DNA methyltransferase (DNMT3A) and DNMT3B. Treatment with 1 or 3 μg/ml Sehizandrol A resulted in normal cell morphology as well as elevated cell number, enhanced viability, and increased mRNA expression of DNMT3A and DNMT3B compared to saline. However, an increase in Sehizandrol A to 9 μg/ml produced a fall in cell viability, as well as a decrease in mRNA DNMT3A and DNMT3B expression to control levels. Data demonstrated that Schizandrol A at 1 or 3 μg/ml improved cell morphological appearance and viability of Aβ1-40 injured SH-SY5Y cells by an enhanced DNA methylation pathway.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cell Line; Cell Survival; Cyclooctanes; DNA Methylation; Gene Expression Regulation; Humans; Lignans; Neurons; Peptide Fragments; Polycyclic Compounds; Real-Time Polymerase Chain Reaction; RNA, Messenger

In previous study, we have screened the effective fraction against Alzheimer's disease (AD-EF) from the extracts of roots and rhizomes of Valeriana amurensis, based on which neuroprotective active constituents from AD-EF were investigated. Six new compounds 1-6, including four iridoids (xiecaoside A-C and xiecaoline A), one pinane-type monoterpeneglucoside (xiecaoside D), and one phenylpropanoid glycoside (xiecaoside E) were isolated together with 11 known compounds 7-17. The structures of 1-6 were elucidated by their spectroscopic data. The protective effects of compounds 1-17 on PC12 cells with neurotoxicity induced by amyloid-beta 1-42 (Aβ(1-42)) was also investigated, respectively. Consequently, compound 6 and lignans 11-17 were responsible for protecting against Aβ-induced toxicity in PC12 cells.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Survival; Iridoids; Lignans; Magnetic Resonance Spectroscopy; Molecular Structure; Neuroprotective Agents; PC12 Cells; Plant Extracts; Plant Roots; Plants, Medicinal; Rats; Reference Values; Rhizome; Valerian

Alzheimer's disease (AD) chiefly characterizes a progressively neurodegenerative disorder of the brain, and eventually leads to irreversible loss of intellectual abilities. The β-amyloid (Aβ)-induced neurodegeneration is believed to be the main pathological mechanism of AD, and Aβ production inhibition or its clearance promotion is one of the promising therapeutic strategies for anti-AD research. Here, we report that the natural product arctigenin from Arctium lappa (L.) can both inhibit Aβ production by suppressing β-site amyloid precursor protein cleavage enzyme 1 expression and promote Aβ clearance by enhancing autophagy through AKT/mTOR signaling inhibition and AMPK/Raptor pathway activation as investigated in cells and APP/PS1 transgenic AD model mice. Moreover, the results showing that treatment of arctigenin in mice highly decreased Aβ formation and senile plaques and efficiently ameliorated AD mouse memory impairment strongly highlight the potential of arctigenin in anti-AD drug discovery.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Cells, Cultured; Disease Models, Animal; eIF-2 Kinase; Embryo, Mammalian; Eukaryotic Initiation Factor-2; Furans; Gene Expression Regulation; Humans; Lignans; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Mutation; Neurons; Presenilin-1; Signal Transduction; TOR Serine-Threonine Kinases

A new lignan glucoside, (+)-(7S,8R,8'R)-lyoniresinol 9-O-β-D-(6″-O-trans-sinapoyl)glucopyranoside (1), and a new iridoid glucoside, 10-O-trans-sinapoylgeniposide (2), together with eight known compounds, were isolated from the fruits of Gardenia jasminoides Ellis. The structures of the isolates were elucidated by extensive spectroscopic studies, including UV, IR, 1D and 2D NMR, ESI-MS, HR-ESI-MS, and CD experiments. The short-term-memory-enhancement activities of some compounds were evaluated on an Aβ transgenic drosophila model.

Topics: Alzheimer Disease; Animals; Animals, Genetically Modified; Disease Models, Animal; Drosophila; Fruit; Gardenia; Glycosides; Humans; Iridoids; Lignans; Memory, Short-Term; Molecular Structure; Nootropic Agents; Phytotherapy; Plant Extracts

Alzheimer's disease (AD), the most common form of dementia, is characterized by memory deficits and deposition of amyloid-β (Aβ) in the brain. It has been known that neuroinflammation and oxidative stress are critical factors in the development of AD. 4-O-methylhonokiol, an extract from Magnolia officinalis, is known to have anti-inflammatory and anti-oxidative effects. Thus, we investigated the properties of 4-O-methylhonokiol against progression and development of AD in Tg2576 mice. Tg2576 mice models show memory impairment and AD-like pathological features including Aβ deposition. Oral administration of 4-O-methylhonokiol through drinking water (1 mg/kg in 0.0002% Tween 80) for 12 weeks not only prevented memory impairment but also inhibited Aβ deposition. In addition, 4-O-methylhonokiol decreased β-secretase activity, oxidative lipid and protein damage levels, activation of astrocytes and microglia cells, and generation of IL-1β and TNF-α with increase of glutathione level in the brain. Our results showed that 4-O-methylhonokiol effectively prevented memory impairment by down-regulating β-secretase activity through inhibition of oxidative stress and neuroinflammatory responses in Tg2576 transgenic mice.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Analysis of Variance; Animals; Anti-Inflammatory Agents; Avoidance Learning; Biphenyl Compounds; Brain; Disease Models, Animal; Exploratory Behavior; Gene Expression Regulation; Glutathione; Humans; Lignans; Lipid Peroxidation; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Mutation; Oxidative Stress; Peptide Fragments; Protein Carbonylation; Time Factors

The cannabinoid type-2 G protein-coupled (CB₂) receptor is an emerging therapeutic target for pain management and immune system modulation. In a mouse model of Alzheimer's disease (AD) the orally administered natural product 4'-O-methylhonokiol (MH) has been shown to prevent amyloidogenesis and progression of AD by inhibiting neuroinflammation. In this commentary we discuss an intriguing link between the recently found CB₂ receptor-mediated molecular mechanisms of MH and its anti-inflammatory and protective effects in AD animal models. We argue that the novel cannabimimetic MH may exert its beneficial effects via modulation of CB₂ receptors expressed in microglial cells and astrocytes. The recent findings provide further evidence for a potential role of CB₂ receptors in the pathophysiology of AD, spurring target validation and drug discovery.

Topics: Alzheimer Disease; Animals; Biphenyl Compounds; Humans; Inflammation; Lignans; Plants, Medicinal; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid

In the present study, we examined the effects of deoxyschisandrin (DS) from Schisandra chinensis on the amyloid-beta₁₋₄₂ (Aβ₁₋₄₂)-induced memory impairment in mice and investigated the possible antioxidative mechanism. Mice were given an intracerebroventricular (i. c. v.) injection with the aggregated Aβ₁₋₄₂ and then treated with DS (4, 12, and 36 mg/kg body weight) or donepezil (DPZ), a positive control drug (0.65 mg/kg), by intragastric infusion for 14 days. Non-cognitive disturbances and cognitive performance were evaluated by the locomotor activity, Y-maze, and water maze tests. Antioxidative enzyme activities including superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) and levels of malondialdehyde (MDA), glutathione (GSH), and oxidized glutathione (GSSG) within the cerebral cortex and hippocampus of mice were measured to investigate the mechanism. Our results showed that DS significantly improved Aβ₁₋₄₂-induced short-term and spatial memory impairments in the Y-maze and water maze tests. Furthermore, in the cerebral cortex and hippocampus of mice, the reduced activities of SOD and GSH-px, the GSH level, and the GSH/GSSG ratio were increased, and increased levels of MDA and GSSG were reduced following treatment with DS, although the improvement of GSH and the reduction of GSSG levels were not marked. These results suggest that DS is a potential cognitive enhancer in Alzheimer's disease through its antioxidative action.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Cerebral Cortex; Cyclooctanes; Drugs, Chinese Herbal; Fruit; Glutathione; Glutathione Peroxidase; Hippocampus; Lignans; Male; Malondialdehyde; Maze Learning; Memory Disorders; Mice; Polycyclic Compounds; Schisandra; Superoxide Dismutase

Three new germacrane-type sesquiterpenoids, heishuixiecaoline A-C (compounds 1-3), were isolated along with ten known compounds 4-13 from fraction of Valeriana amurensis roots and rhizomes effective against Alzheimer's disease (AD). The structures of 1-3 were elucidated on the basis of their spectroscopic data. We also investigated the protective effect of compounds 1-13 on the neurotoxicity of PC12 cells induced by amyloid-beta (Aβ(25-25)), respectively. As a result, germacrane-type sesquiterpenoids 1-4 and lignans 5-7 were seen to afford protection against Aβ-induced toxicity in PC 12 cells. This study will contribute to revealing the chemical basis for the therapeutic effect of V. amurensis against AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Lignans; Neuroprotective Agents; PC12 Cells; Plant Roots; Rats; Rhizome; Sesquiterpenes; Valerian

Oxidative stress induced neuronal cell death by accumulation of β-amyloid (Aβ) is a critical pathological mechanism of Alzheimer's disease (AD). Intracerebroventrical infusion of Aβ(1-42) (300 pmol/day per mouse) for 14 days induced neuronal cell death and memory impairment, but pre-treatment of 4-O-methylhonokiol (4-O-MH), a novel compound extracted from Magnolia officinalis for 3 weeks (0.2, 0.5 and 1.0 mg/kg) prior to the infusion of Aβ(1-42) and during the infusion dose dependently improved Aβ(1-42)-induced memory impairment and prevented neuronal cell death. Additionally, 4-O-MH reduced Aβ(1-42) infusion-induced oxidative damages of protein and lipid but reduced glutathione levels in the cortex and hippocampus. Aβ(1-42) infusion-induced activation of astrocytes and p38 mitogenic activated protein (MAP) kinase was also prevented by 4-O-MH in mice brains. In further study using culture cortical neurons, p38 MAP kinase inhibitor abolished the inhibitory effect of 4-O-MH (10 μM) on the Aβ(1-42) (5 μM)-induced reactive oxidative species generation and neuronal cell death. These results suggest that 4-O-MH might prevent the development and progression of AD through the reduction of oxidative stress and neuronal cell death via inactivation of p38 MAP kinase pathway.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Animals; Apoptosis; Astrocytes; Biphenyl Compounds; Cell Survival; Cells, Cultured; Disease Models, Animal; Hippocampus; Lignans; Lipid Peroxidation; Magnolia; Male; Memory Disorders; Mice; Mice, Inbred ICR; Neurons; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Peptide Fragments; Protein Carbonylation; Reactive Oxygen Species

Accumulations of amyloid-β (Aβ) and oxidative damage are critical pathological mechanisms in the development of Alzheimer's disease (AD). We previously found that 4-O-methylhonokiol, a compound extracted from Magnolia officinalis, improved memory dysfunction in Aβ-injected and presenilin 2 mutant mice through the reduction of accumulated Aβ. To investigate mechanisms of the reduced Aβ accumulation, we examined generation, degradation, efflux and aggregation of Aβ in Swedish AβPP AD model (AβPPsw) mice pre-treated with 4-O-methylhonokiol (1.0 mg/kg) for 3 months. 4-O-methylhonokiol treatment recovered memory impairment and prevented neuronal cell death. This memory improving activity was associated with 4-O-methylhonokiol-induced reduction of Aβ1-42 accumulation in the brains of AβPPsw mice. According to the reduction of Aβ1-42 accumulation, 4-O-methylhonkiol modulated oxidative damage sensitive enzymes. 4-O-methylhonkiol decreased expression and activity of brain beta-site AβPP cleaving enzyme (BACE1), but increased clearance of Aβ in the brain through an increase of expressions and activities of Aβ degradation enzymes; insulin degrading enzyme and neprilysin. 4-O-methylhonkiol also increased expression of Aβ transport molecule, low density lipoprotein receptor-related protein-1 in the brain and liver. 4-O-methylhonkiol decreased carbonyl protein and lipid peroxidation, but increased glutathione levels in the brains of AβPPsw mice suggesting that oxidative damage of protein and lipid is critical in the impairment of those enzyme activities. 4-O-methylhonokiol treatment also prevented neuronal cell death in the AβPPsw mousee brain through inactivation of caspase-3 and BAX. These results suggest that 4-O-methylhonokiol might prevent the development and progression of AD by reducing Aβ accumulation through an increase of clearance and decrease of Aβ generation via antioxidant mechanisms.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Analysis of Variance; Animals; Avoidance Learning; Biphenyl Compounds; Brain; Circular Dichroism; Disease Models, Animal; Exploratory Behavior; Humans; Lignans; Lipid Peroxidation; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Neprilysin; Presenilin-2; Protein Carbonylation; Reaction Time

To observe the protective and therapeutic effect of schisandrol A on the Abeta damaged PC12 cells.. PC12 cells were damaged by Abeta in vitro. Morphological changes were observed and the number of cells with neurite was analyzed by phase contrast microscope. The cell viability of PC12 cells was determined by the MTT method.. Many dispirited cells with atrophied or fragmented neurites in the Abeta damaged PC12 cells were observed under the microscope. More vital cells with longer neurites were observed in the schisandrol A treated PC12 cells and the number of cells with neurite increased. The difference of cell viability between the two groups was statistical significant.. Schisandrol A can antagonize the neurotoxicity of Abeta and has protective and therapeutic efficacy on Abeta damaged PC12 cells.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Differentiation; Cell Survival; Cyclooctanes; Dose-Response Relationship, Drug; Lignans; Neurites; Neurons; Neuroprotective Agents; PC12 Cells; Rats; Schisandra

Amyloid β peptide (Aβ) induced toxicity is a well-established pathway of neuronal cell death which might play a role in Alzheimer's disease. In this regard, the toxic effect of Aβ on a cultured Aβ-sensitive neuronal cell line was used as a primary screening tool for potential anti-Alzheimer's therapeutic agents. The effects of nine pure compounds (vitamin E, α-asarone, salidroside, baicolin, magnolol, gastrodin, bilobalide, honokiol and β-asarone) from selected Chinese herbs on neuronal cell death induced by Aβ in NGF-differentiated PC12 cells were examined. Only two of the studied compounds, honokiol and magnolol, significantly decreased Aβ-induced cell death. Further experiments indicated that their neuroprotective effects are possibly mediated through reduced ROS production as well as suppression of intracellular calcium elevation and inhibition of caspase-3 activity. The results provide for the first time a scientific rationale for the clinical use of honokiol and magnolol in the treatment of Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Biphenyl Compounds; Calcium; Caspase 3; Cell Survival; Drugs, Chinese Herbal; Lignans; Magnolia; Neuroprotective Agents; PC12 Cells; Rats; Reactive Oxygen Species

To investigate the inhibition of amyloid beta-protein 42 (Abeta42) production in M146L cells by gamma-schisandrin.. M146L 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.. The 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.. gamma-Schisandrin inhibited production of Abeta42 in M146L cells through inhibiting gamma-secretase.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; CHO Cells; Cricetinae; Cricetulus; Cyclooctanes; Dose-Response Relationship, Drug; Humans; Lignans; Peptide Fragments; Polycyclic Compounds