lignans and Cognition-Disorders

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

The primary objective of our study is to investigate the neuroprotective efficacy of honokiol and imipramine against restraint stress (RS)-induced cognitive impairment and depressive-like behaviour in mice. We examined whether the neuroprotective activity of honokiol and imipramine mediates through the inhibition of endoplasmic reticulum stress. Adult Swiss albino mice were restrained for 6h/day for 28 days. Honokiol (3 and 10mg/kg) and Imipramine (10 and 30mg/kg) were administered for last 7 days to the different groups. Cognitive function was assessed by Morris water maze and novel object recognition test. Forced swimming test and tail suspension test were performed to evaluate the restraint stress-induced depressive-like behaviour. Proinflammatory cytokines, brain-derived neurotrophic factor, and ER stress markers i.e. 78-kDa glucose-regulated protein (GRP78) and C/EBP homologous protein (CHOP) were quantified in the hippocampus. We observed cognitive impairment and depressive-like behaviour in RS-exposed animals. Honokiol (10mg/kg) treated group depicted marked reduction in cognitive impairment and depressive-like behaviour. However, imipramine (10 and 30mg/kg) prevented the depressive-like behaviour but failed to prevent RS-induced cognitive impairment. Moreover, proinflammatory cytokines, GRP78 and CHOP were elevated in the hippocampus of stressed mice as compared to unstressed mice. Honokiol (10mg/kg) significantly prevented the RS-induced elevated levels of proinflammatory cytokines and endoplasmic reticulum stress markers. Our results clearly suggest the beneficial potential of honokiol in restraint stress through inhibition of proinflammatory cytokines and endoplasmic reticulum stress. Honokiol could be an intriguing therapeutic approach in endoplasmic reticulum stress related neuro-pathophysiological conditions.

Topics: Animals; Behavior, Animal; Biphenyl Compounds; Brain-Derived Neurotrophic Factor; Cognition Disorders; Cytokines; Depression; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Gene Expression Regulation; Heat-Shock Proteins; Hippocampus; Imipramine; Lignans; Male; Mice; Restraint, Physical; Stress, Psychological; Transcription Factor CHOP

Lignan compounds extracted from Schisandra chinensis (Turcz.) Baill. have been reported to possess various biological activities, and have potential in the treatment of Alzheimer's disease. This study was designed to investigate the effects of total lignans of Schisandra chinensis (TLS) on cognitive function and neurodegeneration in the model of AD induced by Aβ1-42 in vivo and in vitro. It was found that intragastric infusion with TLS (50 and 200 mg/kg) to Aβ1-42-induced mice significantly increased the number of avoidances in the shuttle-box test and swimming time in the target quadrant in the Morris water maze test. TLS at dose of 200 mg/kg significantly restored the activities of total antioxidant capacity (T-AOC), as well as the level of malondialdehyde (MDA) both in the hippocampus and cerebral cortex in mice. Results of histopathological examination indicated that TLS noticeably ameliorated the neurodegeneration in the hippocampus in mice. On the other hand, TLS (100 μM) could protect the Aβ1-42-induced primary mouse neuronal cells by blocking the decrease of mitochondrial membrane potential (MMP), change the expressions of Bcl-2 (important regulator in the mitochondria apoptosis pathway). Moreover, TLS also decreased the activity of β-secretase 1 (BACE1), crucial protease contributes to the hydrolysis of amyloid precursor protein (APP), and inhibited the expression of JKN/p38, which involved in the MAPKs signaling pathways in both mice and primary mouse neuronal cells. In summary, TLS might protect against cognitive deficits and neurodegeneration by releasing the damage of oxidative stress, inhibiting the expression of BACE1 and the MAPKs inflammatory signaling pathways.

Topics: Amyloid beta-Peptides; Animals; Cognition Disorders; Lignans; Mice; Neurodegenerative Diseases; Neurons; Peptide Fragments; Schisandra

To assess the relationship between dietary intake of antioxidants (vitamin C, vitamin E, β-carotene, lutein, flavonoids and lignans) and cognitive decline at middle age, analyses were performed on data from the population based Doetinchem Cohort Study. Habitual diet and cognitive function were assessed twice with a 5-year interval in 2613 persons aged 43-70 year at baseline (1995-2002). Diet was assessed with a validated 178-item semi-quantitative FFQ. Cognitive function was assessed with a neuropsychological test battery, consisting of the 15 Words Learning Test, the Stroop Test, the Word Fluency test, and the Letter Digit Substitution Test. Scores on global cognitive function, memory, processing speed, and cognitive flexibility were calculated. In regression analyses, quintiles of antioxidant intake were associated with change in cognitive domain scores. Results showed that higher lignan intake was linearly associated with less decline in global cognitive function (P= 0.01), memory (P< 0.01) and processing speed (P= 0.04), with about two times less declines in the highest v. the lowest quintile. In the lowest quintile of vitamin E intake, decline in memory was twice as fast as in all higher quintiles (P< 0.01). Global cognitive decline in the highest lutein intake group was greater than in the lowest intake group (P< 0.05). Higher flavonoid intake was associated with greater decline in cognitive flexibility (P for trend = 0.04). Intakes of other antioxidants were not associated with cognitive decline. We conclude that within the range of a habitual dietary intake, higher intake of lignans is associated with less cognitive decline at middle age.

Topics: Adult; Aged; Antioxidants; Ascorbic Acid; beta Carotene; Cognition; Cognition Disorders; Cohort Studies; Diet; Dietary Supplements; Feeding Behavior; Female; Flavonoids; Humans; Lignans; Lutein; Male; Middle Aged; Neuropsychological Tests; Surveys and Questionnaires; Vitamin E

Schisantherin A (STA) is a main bioactive lignan isolated from Schisandra chinensis (Turcz.) Baill., which has been widely used as a tonic in traditional Chinese medicine for many years. Lots of studies have reported that STA exhibited anti-inflammatory and antioxidant effects. This paper was designed to investigate the effects of STA on cognitive function and neurodegeneration in the mouse control of Alzheimer's disease (AD) induced by Aβ1-42. It was found that successive intracerebroventricular (ICV) administration of STA (0.01 and 0.1mg/kg) for 5days significantly attenuated Aβ1-42-induced learning and memory impairment as measured by the Y-maze test, shuttle-box test and Morris water maze test. Furthermore, STA at a dose of 0.1mg/kg restored the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) as well as the levels of Aβ1-42, malondialdehyde (MDA) and glutathione (GSH) to some extent in the hippocampus and cerebral cortex. It also noticeably improved the histopathological changes in the hippocampus. The results suggested that STA might protect against cognitive deficits, oxidative stress and neurodegeneration induced by Aβ1-42, and serve as a potential agent in treatment of AD.

Topics: Amyloid beta-Peptides; Analysis of Variance; Animals; Antioxidants; Brain; Cognition Disorders; Cyclooctanes; Dioxoles; Disease Models, Animal; Glutathione; Glutathione Peroxidase; Injections, Intraventricular; Lignans; Male; Malondialdehyde; Maze Learning; Mice; Mice, Inbred Strains; Neurodegenerative Diseases; Peptide Fragments; Superoxide Dismutase

The fruits of Schisandra chinensis (Trucz.) Baill. (Schisandraceae) which have been used as a tonic especially for kidney yin deficiency in Chinese traditional medicine are recently receiving attention for its preventive activity on age-related neurodegenerative diseases. A variety of studies demonstrated the cognitive-enhancing effects of Schisandra chinensis through animal tests and also in clinical trials.. In this study, we attempted to investigate the effects of the lignan-riched extract of Schisandra chinensis fruits (ESP-806) on neurotoxicity and memory impairment induced by Aβ1-42 injection in mice.. The fruits of Schisandra chinensis were extracted with the mixture of n-hexane:ethanol (9:1), which is riched with bioactive dibenzocyclooctadiene lignans, schizandrin, gomisin N, wuweigisu C. After oral treatment of ESP-806 (100 mg/kg body weight) followed by injection of Aβ1-42 (2 μg/mouse, i.c.v.), novel object recognition and passive avoidance tests were evaluated. To verify the cognition enhancing effects of ESP-806, we examined the effects of ESP-806 on the activities of β-secretase and acetylcholinesterase, and the contents of Aβ and the reduced glutathione within the cortex and hippocampus of Aβ-injected mice.. Oral treatment of ESP-806 (100 mg/kg body weight) significantly attenuated Aβ1-42-induced memory impairment evaluated by behavioral tests. Furthermore, the treatment of ESP-806 attenuated the elevation of β-secretase activity accompanying the reduced level of Aβ1-42 in the cortex and hippocampus of the brain. ESP-806 also significantly inhibited the acetylcholinesterase activity in the hippocampus and increased the content of the reduced glutathione in the cortex and hippocampus of mouse brain.. These data suggested that the extract of Schisandra chinensis fruits riched with dibenzocyclooctadiene lignans may be useful in the prevention and treatment of Alzheimer's disease.

Topics: Acetylcholinesterase; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Avoidance Learning; Cerebral Cortex; Cognition Disorders; Fruit; Glutathione; Hippocampus; Lignans; Male; Memory Disorders; Mice; Mice, Inbred ICR; Neuroprotective Agents; Peptide Fragments; Phytotherapy; Plant Extracts; Recognition, Psychology; Schisandra

To model glucocorticoid-induced cognitive impairment and evaluate the neuroprotection by schizandrin (Sch) against dexamethasone (Dex)-induced neurotoxicity in vivo and in vitro.. Cerebral cortical cells from neonatal Sprague-Dawley rats (within 24 hours after birth) were cultured for 9 days, and then treated with Dex (10(-4), 10(-5), 10(-6) or 10(-7) mol/L) for 24 h or pretreated with 10(-4) mol/L Dex for 24 h followed by 10, 20, 40, or 80 μmol/L Sch for 48 h. Cell viability was assessed using the MTT assay. Immunofluorescence and real-time PCR for MAP2 were performed to confirm the effects of Dex on neurite outgrowth. In vivo, kunming mice were randomly divided into six groups: control [(intragastric (i.g.) vehicle for 42 days]; Dex group I (5 mg/kg · d(-1) Dex i.g. treatment for 28 days followed by i.g. vehicle for 14 days); Dex group II (Dex i.g. for 42 days); Dex + Sch (Dex i.g. for 28 days followed by 5, 15, or 45 mg/kg · d(-1) Sch i.g. for 14 days). Learning and memory were assessed by Morris water maze test. Histological examination was used to assess pathology and apoptosis in neurons.. Compared to the Dex groups, Sch increased cell viability in a dose-dependent manner, improved performance in the Morris water maze and ameliorated the morphological changes.. Sch has neuroprotective effects against insults induced by glucocorticoid.

Topics: Animals; Animals, Newborn; Cell Survival; Cells, Cultured; Cerebral Cortex; Cognition Disorders; Cyclooctanes; Dexamethasone; Dose-Response Relationship, Drug; Lignans; Male; Mice; Neuroprotective Agents; Polycyclic Compounds; Random Allocation; Rats; Rats, Sprague-Dawley; Schisandra

The effects of (-)clausenamide (clau) on spatial cognitive functions and hippocampal long-term potentiation (LTP) after transient focal cerebral ischemia in rats were investigated. Four weeks after middle cerebral artery occlusion, Morris water maze tasks demonstrated that 2 h of transient forebrain ischemia resulted in a significant decrease in spatial discrimination performance. The escape latency at 4 and 5 days of acquisition trial was lower in the ischemic rats than in sham-operated rats (33.8+/-6.7 sec and 26.8+/-5 sec versus 12.2+/-4.0 sec and 10.4+/-3.6 sec), chronic treatment with clau (10 mg kg(-1) p.o. once daily) significantly improved the impairment (12.4+/-4.1 sec and 15.2+/-3.1 sec). After Morris water maze, the changes in population spike (PS) amplitude were recorded as an index of LTP in the perforant path-dentate gyrus synapses. There was no difference in PS amplitude between the sham-operated and vehicle-treated animals, whereas the fractional increase of PS 20-50 min after tetanus was significantly larger in clau-treated group. Histopathological analysis revealed that clau could protect against neuron loss in the regions of cortex and striatum. In conclusion, these data indicate a beneficial effect of clau for synaptic plasticity and cognitive function impaired by transient focal cerebral ischemia.

Topics: Action Potentials; Animals; Brain; Brain Ischemia; Cognition Disorders; Drugs, Chinese Herbal; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Lactams; Lignans; Male; Maze Learning; Nerve Degeneration; Neurons; Rats; Rats, Wistar; Recovery of Function; Reperfusion Injury; Treatment Outcome