lignans and Cognitive-Dysfunction

Dementia and its first or transitional stage, mild cognitive impairment (MCI), is a major concern for the aging Japanese society. Thus, the use of dietary supplements to improve or maintain cognitive function has become a topic of public interest.. In this study, we evaluated the effects of a composite supplement containing food-derived antioxidants, specifically astaxanthin and sesamin (AS), on cognitive function in people with MCI.. Twenty-one healthy participants with MCI were recruited in our double-blind placebo-controlled pilot study. They were assigned to either an AS group, who received ingestible capsules containing AS, or a placebo group, who received identical placebo capsules. To assess cognitive functions, we performed the Japanese version of the Central Nervous System Vital Signs (CNSVS) test and the Alzheimer's Disease Assessment Scale-Cog test at baseline, after 6 weeks, and after 12 weeks of dietary supplementation.. The CNSVS test revealed significant improvements in psychomotor speed and processing speed in the AS group compared with the placebo group, suggesting that the daily supplementation of AS improved cognitive functions related to the ability to comprehend, and perform complex tasks quickly and accurately.. Our results provide support for the use of AS as a dietary supplementation for improving cognitive functions.

Topics: Aged; Cognitive Dysfunction; Dietary Supplements; Dioxoles; Double-Blind Method; Female; Humans; Lignans; Male; Middle Aged; Neuropsychological Tests; Pilot Projects; Treatment Outcome; Xanthophylls

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

Arctigenin (Arc) is a phenylpropanoid dibenzylbutyrolactone lignan in Arctium lappa L, which has been widely applied as a traditional Chinese herbal medicine for treating inflammation. In the present study, we explored the neuroprotective effect and the potential mechanisms of arctigenin against LPS-evoked neuroinflammation, neurodegeneration, and memory impairments in the mice hippocampus. Daily administration of arctigenin (50 mg/kg per day, i.g.) for 28 days revealed noticeable improvements in spatial learning and memory deficits after exposure to LPS treatment. Arctigenin prevented LPS-induced neuronal/synaptic injury and inhibited the increases in Abeta (Aβ) generation and the levels of amyloid precursor protein (APP) and β-site amyloid precursor protein cleavage enzyme 1 (BACE1). Moreover, arctigenin treatment also suppressed glial activation and reduced the production of proinflammatory cytokines. In LPS-treated BV-2 microglial cells and mice, activation of the TLR4 mediated NF-κB signaling pathway was significantly suppressed by arctigenin administration. Mechanistically, arctigenin reduced the LPS-induced interaction of adiponectin receptor 1 (AdipoR1) with TLR4 and its coreceptor CD14 and inhibited the TLR4-mediated downstream inflammatory response. The outcomes of the current study indicate that arctigenin mitigates LPS-induced apoptotic neurodegeneration, amyloidogenesis and neuroinflammation as well as cognitive impairments, and suggest that arctigenin may be a potential therapeutic candidate for neuroinflammation/neurodegeneration-related diseases.

Topics: Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Arctium; Aspartic Acid Endopeptidases; Cognitive Dysfunction; Furans; Inflammation; Lignans; Lipopolysaccharides; Memory Disorders; Mice; Microglia; Neuroinflammatory Diseases; NF-kappa B; Toll-Like Receptor 4

Oxidative stress and mitochondrial dysfunction contribute greatly to fluoride-induced cognitive impairment and behavioural disorders. Honokiol, a natural biphenolic compound, possesses antioxidant and mitochondrial protective properties. The present study investigated the protective actions of honokiol on NaF-elicited cognitive deficits and elucidated the possible mechanism of honokiol-mediated protection. The results demonstrated that honokiol administration markedly attenuated fluoride-induced cognitive impairments and neural/synaptic injury in mice. Moreover, honokiol elevated the activity and expression of SOD2 and promoted mtROS scavenging through Sirt3 activation in NaF-treated mice and SH-SY5Y cell lines. Meanwhile, honokiol substantially lowered mtROS production by enhancing Sirt3-mediated mitochondrial DNA (mtDNA) transcription, thereby leading to significant increases in ATP synthesis and complex I activity. Further studies revealed that honokiol activated AMPK and upregulated the PGC-1α and Sirt3 protein expression in vivo and in vitro. Intriguingly, the protective actions of honokiol on oxidative stress and mitochondrial dysfunction were abolished by AMPK shRNA or Sirt3 shRNA. Notably, AMPK knockdown prevented the increase in PGC-1α and Sirt3 expression induced by honokiol, while Sirt3 shRNA suppressed Sirt3 signaling without significant effects on p-AMPK and PGC-1α expression. In conclusion, our findings indicate that honokiol mitigates NaF-induced oxidative stress and mitochondrial dysfunction by regulating mtROS homeostasis, partly via the AMPK/PGC-1α/Sirt3 pathway, which ultimately contributes to neuronal/synaptic injury and cognitive deficits.

Topics: AMP-Activated Protein Kinases; Animals; Biphenyl Compounds; Cognition; Cognitive Dysfunction; DNA, Mitochondrial; Fluorides; Humans; Lignans; Mice; Mitochondria; Neuroblastoma; Oxidative Stress; RNA, Small Interfering; Sirtuin 3

Topics: Animals; Cognitive Dysfunction; Dietary Supplements; Gastrointestinal Microbiome; Glucosides; Lignans; Mice

Alzheimer's disease (AD) is a neurodegenerative disease, characterized by memory loss and cognitive deficits accompanied by neuronal damage and cholinergic disorders. Sesamol, a lignan component in sesame oil, has been proven to have neuroprotective effects. This research aimed to investigate the preventive effects of sesamol on scopolamine (SCOP)-induced cholinergic disorders in C57BL/6 mice. The mice were pretreated with sesamol (100 mg/kg/d, p.o.) for 30 days. Behavioral tests indicated that sesamol supplement prevented SCOP-induced cognitive deficits. Sesamol enhanced the expression of neurotrophic factors and postsynaptic density (PSD) in SCOP-treated mice, reversing neuronal damage and synaptic dysfunction. Importantly, sesamol could balance the cholinergic system by suppressing the AChE activity and increasing the ChAT activity and

Topics: Animals; Antioxidants; Cholinergic Agents; Cognition; Cognitive Dysfunction; Humans; Lignans; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Nerve Growth Factors; Neuroblastoma; Neurodegenerative Diseases; Neuroinflammatory Diseases; Neuroprotective Agents; Oxidative Stress; Scopolamine; Sesame Oil

The global growing rates of cognitive decline and dementia, together with the absence of curative therapies for these conditions, support the interest in researching potential primary prevention interventions, with particular focus on dietary habits. The aim was to assess the association between polyphenol intake and 6-year change in cognitive function in the 'Seguimiento Universidad de Navarra' (SUN) Project, a Spanish prospective cohort study. Changes (final - initial) in cognitive function were evaluated in a subsample of 806 participants (mean age 66 (sd 5) years, 69·7 % male) of the SUN Project using the validated Spanish Telephone Interview for Cognitive Status-modified score. Polyphenol intake was derived from a validated semi-quantitative FFQ and matching food composition data from the Phenol-Explorer database. Multivariable linear regression models were used to evaluate the association between total polyphenol intake, polyphenol subclasses and cognitive changes. No significant association between total polyphenol intake and changes in cognitive function was found. However, a higher intake of lignans (βQuintile (Q) 5 v. Q1 0·81; 95 % CI 0·12, 1·51; Ptrend = 0·020) and stilbenes (βQ5 v. Q1 0·82; 95 % CI 0·15, 1·49; Ptrend = 0·028) was associated with more favourable changes in cognitive function over time, particularly with respect to immediate memory and language domains. Olive oil and nuts were the major sources of variability in lignan intake, and wine in stilbene intake. The results suggest that lignan and stilbene intake was associated with improvements in cognitive function.

Topics: Aged; Cognitive Dysfunction; Diet; Female; Humans; Lignans; Male; Middle Aged; Polyphenols; Prospective Studies; Spain; Stilbenes

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

Increasing evidence indicates that neuroinflammatory and oxidative stress play two pivotal roles in cognitive impairment after surgery. Honokiol (HNK), as an activator of Sirtuin3 (SIRT3), has potential multiple biological functions. The aim of these experiments is to evaluate the effects of HNK on surgery/anesthesia-induced cognitive decline in mice.. Adult C57BL/6 mice received a laparotomy under sevoflurane anesthesia and HNK or SIRT3 inhibitor (3-TYP) treatment. Cognitive function and locomotor activity of mice were evaluated using fear conditioning test and open field test on postoperative 1 and 3 days. Neuronal apoptosis in CA1 and CA3 area of hippocampus was examined using TUNEL assay. And Western blot was applied to measure the expression of pro-inflammatory cytokines and SIRT3/SOD2 signaling-associated proteins in hippocampus. Meanwhile, SIRT3 positive cells were calculated by immunohistochemistry. The mitochondrial membrane potential, malondialdehyde (MDA), and mitochondrial radical oxygen species (mtROS) were detected using standard methods.. Honokiol attenuated surgery-induced memory loss and neuronal apoptosis, decreased neuroinflammatory response, and ameliorated oxidative damage in hippocampus. Notably, surgery/anesthesia induced an obviously decrease in hippocampal SIRT3 expression, whereas the HNK increased SIRT3 expression and thus decreased the acetylation of superoxide dismutase 2 (SOD2). However, 3-TYP treatment inhibited the HNK's rescuing effects.. These results suggested that activation of SIRT3 by honokiol may attenuate surgery/anesthesia-induced cognitive impairment in mice through regulation of oxidative stress and neuroinflammatory in hippocampus.

Topics: Anesthesia; Anesthetics, Inhalation; Animals; Anti-Inflammatory Agents; Biphenyl Compounds; Cognitive Dysfunction; Female; Hippocampus; Inflammation; Laparotomy; Lignans; Mice, Inbred C57BL; Nootropic Agents; Oxidative Stress; Postoperative Complications; Random Allocation; Sevoflurane; Sirtuin 3

There is growing evidence that cognitive dysfunction induced by anesthetics is adversely affecting a large number of elderly surgical patients. Eleutheroside E (EE), a principal component of Eleutherococcus senticosus, exerts obvious protective effects on cognition. The aim of this study was to investigate the neuroprotective effect of EE on isoflurane (ISO)-induced cognitive dysfunction and explore the possible mechanisms. Learning and memory are assessed in novel object recognition and Morris water maze. We found that with ISO exposure, aged rats had a lower preference for the new object and spent less time in the target quarter. However, the amnesia can be alleviated by EE (50 mg/kg, intraperitoneally). Further research focused on the possible protective molecules associated with learning and memory, such as acetylcholine (ACh) and choline acetyltransferase (ChAT), nicotinic acetylcholine receptors (α7-nAChR), and NR2B, is required. The ACh in the hippocampus and serum was decreased after ISO exposure; meanwhile, the expression of ChAT, α7-nAChRs, and NR2B was downregulated. This abnormal state can be reversed by the administration of EE. Here, our results suggested that EE may be a potential therapeutic agent against ISO-induced cognitive dysfunction. The possible mechanism can be attributed to its neuroprotection through enhancing ChAT, which promotes the synthesis of ACh, further influencing the expression of the α7-nAChR-NR2B complex.

Topics: Acetylcholine; Animals; Cognition; Cognitive Dysfunction; Glucosides; Hippocampus; Isoflurane; Lignans; Male; Memory; Neuroprotective Agents; Nicotinic Agonists; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Receptors, Nicotinic

The potential mechanism of postoperative cognitive impairment is still largely unclear. The activation of NLRP3 inflammasome had been reported to be involved in neurodegenerative diseases, including postoperative cognitive change, and is closely related to mitochondrial ROS and mitophagy. Honokiol (HNK) owns multiple organic protective effects. This study is aimed at observing the neuroprotective effect of HNK in postoperative cognitive change and examining the role of HNK in the regulation of mitophagy and the relationship between these effects and NLRP3 inflammasome activation in mice induced by surgery/anesthesia.. In this study, mice were divided into several groups: control group, surgery group, surgery+HNK group, and surgery+HNK+3-methyladenine (3-MA) group. Hippocampal tissue samples were harvested and used for proinflammatory cytokines, mitochondrial ROS, and malondialdehyde (MDA) assay. The process of mitophagy and the activation of NLRP3 inflammasome were observed by Western blot, immunohistochemistry, and transmission electron microscopy.. The results showed that HNK treatment obviously recovered the postoperative decline and enhanced the expressions of LC3-II, Beclin-1, Parkin, and PINK1 at protein levels after surgery/sevoflurane treatment, which are both an autophagy marker and a mitophagy marker. In addition, HNK attenuated mitochondrial structure damage and reduced mtROS and MDA generation, which are closely associated with NLRP3 inflammasome activation. Honokiol-mediated mitophagy inhibited the activation of NLRP3 inflammasome and neuroinflammation in the hippocampus. Using 3-MA, an autophagy inhibitor, the neuroprotective effects of HNK on mitophagy and NLRP3 inflammasome activation were eliminated.. These results indicated that HNK-mediated mitophagy ameliorates postoperative cognitive impairment induced by surgery/sevoflurane. This neuroprotective effect may be involved in inhibiting the activation of NLRP3 inflammasome and suppressing inflammatory responses in the hippocampus.

Topics: Animals; Apoptosis; Autophagy; Biphenyl Compounds; Cognitive Dysfunction; Dentate Gyrus; Female; Hippocampus; Inflammasomes; Lignans; Mice, Inbred C57BL; Microglia; Mitochondria; Mitophagy; Neurons; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative Stress; Postoperative Complications; Reactive Oxygen Species; Sevoflurane

Hippocampal oxidative stress and apoptosis of CA1 neurons play significant roles in the pathophysiology of diabetes-associated cognitive decline (DACD). The present study was aimed to elucidate the putative effects of sesamin, a major lignan of sesame seed, against DACD, and possible involvement of anti-oxidative and anti-apoptotic mechanisms.. Fifty adult male Wistar rats were randomly divided into control, control-sesamin (30 mg/kg/day), diabetic, diabetic-sesamin (30 mg/kg/day), and diabetic-insulin (6 IU/rat/day) groups. Diabetic rats were treated with sesamin (P.O.) or insulin (S.C.) for eight consecutive weeks. Cognitive performance was evaluated in a Morris Water Maze (MWM) test; in addition, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and malondialdehyde (MDA) concentrations were assayed in the hippocampus using assay kits. Moreover, hematoxylin-eosin (HE), TUNEL, and immunohistochemistry (IHC) stainings were conducted to evaluate histological changes, the apoptosis status and expression of pro- and anti-apoptotic proteins in the hippocampal CA1 neurons, respectively.. The results showed that diabetes reduced the spatial cognitive ability in MWM, which was accompanied by decrease in SOD, CAT, and GPx activities and increase in MDA level in the hippocampus. Additionally, diabetes resulted in neuronal loss, enhanced apoptotic index, elevated the expression of pro-apoptotic Bax protein, and decreased the expression of anti-apoptotic Bcl-2 protein in the hippocampal CA1 neurons. Interestingly, sesamin treatment improved all the above-mentioned deficits of diabetes at a comparable level with insulin therapy.. The results suggest that sesamin could be a promising potential therapeutic agent against DACD, possibly through its intertwined anti-hyperglycemic, anti-oxidative, and anti-apoptotic properties.

Topics: Animals; Antioxidants; Apoptosis; Cognitive Dysfunction; Diabetes Complications; Diabetes Mellitus, Experimental; Dioxoles; Glutathione Peroxidase; Hippocampus; Insulin; Lignans; Male; Malondialdehyde; Oxidative Stress; Protective Agents; Rats; Rats, Wistar; Reactive Oxygen Species; Superoxide Dismutase

Sesame lignans, which are biologically active compounds present in sesame seeds and oil, are known to have neuroprotective effects in several models of brain dysfunction. However, the effects of sesame lignans on age-related brain dysfunction are not clear and were thus investigated in the present study using a senescence-accelerated mouse (SAMP10). Two-month-old male SAMP10 mice were administrated a basal diet with 0% or 0.05% sesame lignans for two months, or with 0%, 0.02%, or 0.05% sesame lignans for 10 months and subjected to step-through passive avoidance tasks and forced swim tests. Reactive carbonyl species (RCs) were evaluated as markers of oxidative stress using a recently developed comprehensive analytical method. Both learning time in passive avoidance tasks and immobile time in forced swim tests became longer with aging (

Topics: Aging; Animals; Body Weight; Brain; Cognitive Dysfunction; Humans; Lignans; Male; Mice; Mice, Inbred Strains; Organ Size; Sesamum; Survival Analysis

Five new lignan racemates, (±)-tatarinoid D-H (1-5), and three known analogues (6-8) were isolated from the rhizomes of Acorus tatarinowii. Their structures were established by 1D, 2D-NMR, HR-MS, IR and optical spectral data. Among them, 1 and 6-8 can alleviate the cognitive deterioration of Aβ transgenic flies.

Topics: Acorus; Amyloid beta-Peptides; Animals; Animals, Genetically Modified; Cognitive Dysfunction; Drosophila melanogaster; Lignans; Nootropic Agents; Peptide Fragments; Rhizome; Stereoisomerism

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