phytoestrogens and Alzheimer-Disease

Alzheimer's disease (AD) is the most common form of dementia with a growing incidence rate primarily among the elderly. It is a neurodegenerative, progressive disorder leading to significant cognitive loss. Despite numerous pieces of research, no cure for halting the disease has been discovered yet. Phytoestrogens are nonestradiol compounds classified as one of the endocrine-disrupting chemicals (EDCs), meaning that they can potentially disrupt hormonal balance and result in developmental and reproductive abnormalities. Importantly, phytoestrogens are structurally, chemically, and functionally akin to estrogens, which undoubtedly has the potential to be detrimental to the organism. What is intriguing, although classified as EDCs, phytoestrogens seem to have a beneficial influence on Alzheimer's disease symptoms and neuropathologies. They have been observed to act as antioxidants, improve visual-spatial memory, lower amyloid-beta production, and increase the growth, survival, and plasticity of brain cells. This review article is aimed at contributing to the collective understanding of the role of phytoestrogens in the prevention and treatment of Alzheimer's disease. Importantly, it underlines the fact that despite being EDCs, phytoestrogens and their use can be beneficial in the prevention of Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Endocrine Disruptors; Flavonoids; Hormone Replacement Therapy; Humans; Nervous System; Phytoestrogens

Alzheimer's disease (AD) is the most common form of dementia affecting people mainly in their sixth decade of life and at a higher age. It is an extensively studied neurodegenerative disorder yet incurable to date. While its main postmortem brain hallmarks are the presence of amyloid-

Topics: Alzheimer Disease; Animals; Antioxidants; Clinical Trials as Topic; Cognitive Dysfunction; Drug Evaluation, Preclinical; Energy Metabolism; Evidence-Based Medicine; Ginkgo biloba; Humans; Mitochondria; Oxidative Stress; Phytoestrogens; Plant Extracts; Pregnanolone; Resveratrol

Alzheimer's disease (AD) is a major dementia disease worldwide with an increasing incidence rate among the elderly. It is a neurodegenerative disease with symptoms starting slowly and then progressing over time. There has been extensive research on AD prevention and treatment; however, there is no cure as of yet. Several drugs are being researched for the treatment and prevention of AD, with a rising interest in specific dietary compounds as potential interventions with lower side effects. One such dietary compound being tested is phytoestrogen. Phytoestrogens are chemically, structurally, and functionally similar to estrogen, which has numerous functions as a cognition-promoting agent; although, as a supplement it can be damaging. Phytoestrogens have the unique ability to substitute for estrogen in elderly individuals with Alzheimer's disease and depleted estrogen levels. This paper aims to contribute to the collective understanding of phytoestrogen's role in the treatment and prevention of Alzheimer's disease by describing its various mechanisms, including its ability to decrease amyloid beta peptide production, promote calcium outflow and acetylcholine release, and reduce Tau protein phosphorylation. The paper also addresses phytoestrogen's role as an anti-inflammatory and antioxidant agent for the cholinergic neurons associated with Alzheimer's disease.

Topics: Acetylcholine; Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Calcium; Humans; Neurons; Phosphorylation; Phytoestrogens; tau Proteins

Neuroprotective effects of phytoestrogen compounds (found in soy) have been demonstrated in animal research and cell culture studies. In particular, phytoestrogens have been shown to reduce Alzheimer's Disease (AD) related pathology, potentially alleviating risk of AD progression. In addition to their antioxidant properties, soy products also have the ability to affect cognition via interaction with estrogen receptors. However, observational studies and randomised controlled trials in humans have resulted in inconclusive findings within this domain. There are several possible reasons for these discrepant data. Studies which report no effect of phytoestrogens on cognition have mainly been carried out in European cohorts, with an average low dietary consumption. In contrast, investigation of Asian populations, with a higher general intake of tofu (a non-fermented soy product) have shown negative associations with cognitive function in those over the age of 65. Consideration of type of soy product is important, as in the latter sample, protective effects of tempe (fermented soy) were also observed. Limited data provide evidence that effects of phytoestrogens on cognition may be modified by dosage, duration of consumption and cognitive test used. Additionally, characteristics of the study population including age, gender, ethnicity and menopausal status appear to be mediating variables. Phytoestrogen treatment interventions have also shown time-limited positive effects on cognition. These findings are consistent with estrogen treatment studies, where initial positive short-term cognitive effects may occur, which reverse with long-term continuous use in elderly women. Well controlled, large scale studies are needed to assess the effects of phytoestrogens on the aging brain and provide further understanding of this association.

Topics: Alzheimer Disease; Brain; Cognition; Cognition Disorders; Female; Glycine max; Humans; Isoflavones; Male; Memory; Neuroprotective Agents; Phytoestrogens

Estrogen-containing hormone therapy initiated during late postmenopause does not improve episodic memory (an important early symptom of Alzheimer's disease), and it increases dementia risk. Cognitive consequences of exogenous estrogen exposures during midlife are less certain. Observational evidence implies that use of hormone therapy at a younger age close to the time of menopause may reduce risk of Alzheimer's disease later in life. However, there are concerns that observational findings may be systematically biased. Partial insight on this critical issue may be gleaned from results of ongoing clinical trials involving midlife postmenopausal women (Early versus Late Intervention Trial with Estrogen; Kronos Early Estrogen Prevention Study). The effects of exogenous midlife estrogen exposures and Alzheimer risk can also be approached through better animal models, through carefully designed cohort studies, and through use of surrogate outcomes in randomized controlled trials in midlife women. Selective estrogen receptor modulators have the potential to affect cognitive outcomes and also merit additional study.

Topics: Alzheimer Disease; Animals; Brain; Cognition; Drug Administration Schedule; Estrogen Replacement Therapy; Estrogens; Female; Humans; Memory; Middle Aged; Neuroprotective Agents; Phytoestrogens; Postmenopause; Risk Assessment; Selective Estrogen Receptor Modulators; Treatment Outcome

Interest in the physiologic and pharmacologic role of bioactive compounds present in plants has increased dramatically over the last decade. Of particular interest in relation to human health are the classes of compounds known as the phytoestrogens, which embody several groups of non-steroidal estrogens, including isoflavones and lignans that are widely distributed within nature. The impact of dietary phytoestrogens on normal biologic processes was first recognized in sheep. Observations of sheep grazing on fields rich in clover and cheetahs fed high soy diets in zoos suggested that flavonoids and related phytochemicals can affect mammalian health. Endogenous estrogens have an important role not only in the hypothalamic-pituitary-gonadal axis, but also in various non-gonadal systems, such as cardiovascular systems, bone, and central nervous systems, and lipid metabolism. There have been several clinical studies of hormone replacement therapy (HRT) in post-menopausal women to examine whether HRT has beneficial effects on the cardiovascular system, bone fractures, lipid metabolism, and Alzheimer's disease. In addition, estrogen contributes to the development of some estrogen-dependent cancers, such as breast cancer and prostate cancer and the number of patients with these cancers is increasing in developed countries. Although recent mega-studies showed negative results for classical HRT in the prevention of some of these diseases, the molecules that interact with estrogen receptors are candidate drugs for various diseases, including hormone-dependent cancers. This review focuses on the molecular properties and pharmaceutical potential of phytoestrogens.

Topics: Alzheimer Disease; Animals; Breast Neoplasms; Cardiovascular Diseases; Dietary Supplements; Female; Glucose Metabolism Disorders; Hormone Replacement Therapy; Humans; Isoflavones; Osteoporosis; Phytoestrogens; Postmenopause; Receptors, Estrogen; Sheep

Estrogens are pleiotropic hormones having an influence not only on reproductive system and sexual functions. These hormones are synthesized not only by ovaries, but also by glia in central nervous system (CNS) and Schwann cells in peripheral nervous system. Therefore they create microenvironment having a wide spectrum of effects such as neuroprotective and antiapoptotic or supporting neurogenesis and regeneration. Mechanisms of estrogens activity are both genomic and quick non-genomic transmitted through second intracellular messengers. There is evidence for protective action of estrogens in neurodegenerative diseases and other diseases of CNS. Nevertheless there are still secrets in estrogens nature. This fact pushes us to ask more questions and continue scientific research to look for the answer.

Topics: Alzheimer Disease; Animals; Central Nervous System; Estradiol; Estrogens; Female; Fertility; Gene Expression Regulation, Enzymologic; Humans; Male; Mood Disorders; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Phytoestrogens; Rats; Receptors, Estrogen

In traditional practices of medicine, numerous plants have been used to treat cognitive disorders, including neurodegenerative diseases such as Alzheimer's disease (AD) and other memory related disorders. An ethnopharmacological approach has provided leads to identifying potential new drugs from plant sources, including those for memory disorders. There are numerous drugs available in Western medicine that have been directly isolated from plants, or are derived from templates of compounds from plant sources. For example, some alkaloids from plant sources have been investigated for their potential in AD therapy, and are now in clinical use (e.g. galantamine from Galanthus nivalis L. is used in the United Kingdom). Various other plant species have shown favourable effects in AD, or pharmacological activities indicating the potential for use in AD therapy. This article reviews some of the plants and their active constituents that have been used in traditional medicine, including Ayurvedic, Chinese, European and Japanese medicine, for their reputed cognitive-enhancing and antidementia effects. Plants and their constituents with pharmacological activities that may be relevant to the treatment of cognitive disorders, including enhancement of cholinergic function in the central nervous system, anti-cholinesterase (anti-ChE), antiinflammatory, antioxidant and oestrogenic effects, are discussed.

Topics: Alkaloids; Alzheimer Disease; Estrogens, Non-Steroidal; Galantamine; Humans; Isoflavones; Physostigmine; Phytoestrogens; Phytotherapy; Plant Extracts; Plant Preparations; Plants, Medicinal; Sesquiterpenes

Topics: Adult; Aged; Alzheimer Disease; Breast Neoplasms; Cardiovascular Diseases; Cohort Studies; Diet; Double-Blind Method; Embryonal Carcinoma Stem Cells; Estrogens; Estrogens, Non-Steroidal; Female; Follow-Up Studies; Gonadal Steroid Hormones; Hormone Replacement Therapy; Hot Flashes; Humans; Isoflavones; Longevity; Menopause; Menopause, Premature; Middle Aged; Neoplasm Recurrence, Local; Neoplasms, Hormone-Dependent; Neoplasms, Second Primary; Neoplastic Stem Cells; Obesity; Osteoporosis, Postmenopausal; Phytoestrogens; Plant Preparations; Randomized Controlled Trials as Topic; Safety; Selective Estrogen Receptor Modulators; Survivors; Weight Gain

Probable developments in HRT and non-HRT treatments for menopausal and post-menopausal problems have been reviewed. More information is required on potential benefits and side-effects of HRT. The major potential benefit is prevention against stroke amelioration of Alzheimer's disease: the major potential side-effect discussed in this chapter is ovarian cancer. At present, techniques for delivering oestrogens are more varied and advanced than those for progestogens. Non-oral delivery systems for progestogens which minimize side-effects will be introduced during the next decade. It is not clear whether benefits expected with new progestational agents will be realized. Preliminary data suggest that SERMs and phytoestrogens are worthy of further evaluation. Their development will provoke intense interest over the next 10 years.

Topics: Aged; Alzheimer Disease; Estrogen Antagonists; Estrogen Replacement Therapy; Estrogens; Estrogens, Non-Steroidal; Female; Humans; Isoflavones; Menopause; Middle Aged; Phytoestrogens; Plant Preparations; Postmenopause; Progestins; Tamoxifen

Topics: Alzheimer Disease; Amyloid beta-Peptides; Coumestrol; Flavin-Adenine Dinucleotide; Flavonoids; Humans; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Phytoestrogens; Structure-Activity Relationship

β-amyloid formation in the brain is one of the characteristics of Alzheimer's disease. Exposure to this peptide may result in reentry into the cell cycle leading to cell death. The phytoestrogen equol has similar biological effects as estrogen without the side effects. This study investigated the possible mechanism of the neuron cell-protecting effect of equol during treatment with Aβ. SH-SY5Y neuroblastoma cells were treated with either 1 μM S-equol or 10 nM 17β-estradiol for 24 h prior to 1 μM Aβ (25-35) exposure. After 24 h exposure to Aβ (25-35), a significant reduction in cell survival and a reentry into the cell cycle process accompanied by increased levels of cyclin D1 were observed. The expressions of estrogen receptor alpha (ERα) and its coactivator, steroid receptor coactivator-1 (SRC-1), were also significantly downregulated by Aβ (25-35) in parallel with activated extracellular signal-regulated kinase (ERK)1/2. However, pretreatment of cells with S-equol or 17β-estradiol reversed these effects. Treatment with the ER antagonist, ICI-182,780 (1 μM), completely blocked the effects of S-equol and 17β-estradiol on cell viability, ERα, and ERK1/2 after Aβ (25-35) exposure. These data suggest that S-equol possesses a neuroprotective potential as it effectively antagonizes Aβ (25-35)-induced cell cytotoxicity and prevents cell cycle reentry in SH-SY5Y cells. The mechanism underlying S-equol neuroprotection might involve ERα-mediated pathways.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cell Cycle; Cell Line, Tumor; Cell Survival; Cyclin D1; Equol; Estradiol; Estrogen Receptor alpha; Gene Expression; Humans; Neuroblastoma; Neurons; Neuroprotective Agents; Peptide Fragments; Phytoestrogens

Recently, the significantly higher incidence of Alzheimer's disease (AD) in women than in men has been attributed to the loss of neuroprotective estrogen after menopause. Does phytoestrogen have the ability to protect against amyloid-β (Aβ) toxicity? The aim of this study was to evaluate hypothesis that β-ecdysterone (β-Ecd) protects SH-SY5Y cells from Aβ-induced apoptosis by separate signaling pathways involving protein kinase B (Akt) and c-Jun N-terminal kinase (JNK). Here, we demonstrate that phytoestrogen β-Ecd inhibits Aβ-triggered mitochondrial apoptotic pathway, as indicated by Bcl-2/Bax ratio elevation, cytochrome c (cyt c) release reduction, and caspase-9 inactivation. Interestingly, β-Ecd upregulates Bcl-2 expression in SH-SY5Y cells under both basal and Aβ-challenged conditions, but downregulates Bax expression only in Aβ-challenged conditions. Subsequently, Akt-dependent NF-κB activation is required for Bcl-2 upregulation, but not Bax downregulation, in response to β-Ecd, which was validated by the use of LY294002 and Bay11-7082. Notably, β-Ecd attenuates the Aβ-evoked reactive oxygen species (ROS) production, apoptosis signal-regulating kinase 1 (ASK1) phosphorylation and JNK activation without altering the basal ASK1 phosphorylation and JNK activation. ROS-scavenging by diphenyleneiodonium (DPI) abrogated the ability of β-Ecd to alter the activation of ASK1. Simultaneously, inhibition of JNK by SP600125 abolished β-Ecd-induced Bax downregulation in Aβ-challenged SH-SY5Y cells, whereas LY294002 failed to do so. Consequently, β-Ecd possesses neuroprotection by different and complementary pathways, which together promote a Bcl-2/Bax ratio. These data support our hypothesis and suggest that β-Ecd is a promising candidate for the treatment of AD.

Topics: Achyranthes; Alzheimer Disease; Apoptosis; Caspase 9; Cell Line, Tumor; Cytochromes c; Drug Evaluation, Preclinical; Humans; MAP Kinase Kinase Kinase 5; MAP Kinase Signaling System; NF-kappa B; Phytoestrogens; Phytotherapy; Plant Extracts; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2

Reductions in bioenergetic fluxes, mitochondrial enzyme activities, and mitochondrial number are observed in Alzheimer's disease (AD). Preclinical work indicates estrogen pathway signaling by either estrogen or selective β estrogen receptor (ERβ) agonists benefits these parameters. To assess whether an ERβ agonist could improve mitochondrial function in actual AD subjects, we administered S-equol (10 mg twice daily) to 15 women with AD and determined the platelet mitochondria cytochrome oxidase (COX) activity before initiating S-equol (lead-in), after two weeks of S-equol (active treatment), and two weeks after stopping S-equol (wash-out). Because the intra-individual variation of this enzyme across samples taken at different times was unknown we used a nonparametric, single-arm, dichotomous endpoint that classified subjects whose active treatment COX activity exceeded the average of their lead-in and wash-out measures as positive responders. Eleven positive responses were observed (p < 0.06). The implications of this finding on our null hypothesis (that S-equol does not influence platelet mitochondria COX activity) are discussed. To our knowledge, this is the first time a direct mitochondrial target engagement biomarker has been utilized in an AD clinical study.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Apolipoprotein E4; Electron Transport Complex IV; Equol; Female; Follow-Up Studies; Humans; Middle Aged; Mitochondria; Phytoestrogens; Pilot Projects; Treatment Outcome

Our recent developments have yielded a novel phytoestrogenic formulation, referred to as the phyto-β-SERM formulation, which exhibits an 83-fold binding selectivity for the estrogen receptor subtype β (ERβ) over ERα. Earlier studies indicate that the phyto-β-SERM formulation is neuroprotective and promotes estrogenic mechanisms in the brain while devoid of feminizing activity in the periphery. Further investigation in a mouse model of human menopause indicates that chronic exposure to the phyto-β-SERM formulation at a clinically relevant dosage prevents/alleviates menopause-related climacteric symptoms. This study assessed the efficacy, in an early intervention paradigm, of the phyto-β-SERM formulation in the regulation of early stages of physical and neurological changes associated with Alzheimer's disease (AD) in a female triple transgenic mouse model of AD. Results demonstrated that, when initiated prior to the appearance of AD pathology, a 9-month dietary supplementation with the phyto-β-SERM formulation promoted physical health, prolonged survival, improved spatial recognition memory, and attenuated amyloid-β deposition and plaque formation in the brains of treated AD mice. In comparison, dietary supplementation of a commercial soy extract preparation showed no effect on cognitive measures, although it appeared to have a positive impact on amyloid pathology. In overall agreement with the behavioral and histological outcomes, results from a gene expression profiling analysis offered insights on the underlying molecular mechanisms associated with the two dietary treatments. In particular, the data suggests that there may be a crosstalk between ERβ and glycogen synthase kinase 3 signaling pathways that could play a role in conferring ERβ-mediated neuroprotection against AD. Taken together, these results support the therapeutic potential of the phyto-β-SERM formulation for prevention and/or early intervention of AD, and warrants further investigations in human studies.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Estrogen Receptor beta; Female; Humans; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Mutation; Ovariectomy; Peptide Fragments; Phytoestrogens; Plaque, Amyloid; Presenilin-1; Recognition, Psychology; tau Proteins

The aim of this study was to evaluate the effect of a novel phytoestrogen, α-Zearalanol, on Alzheimer's disease-related memory impairment and neuronal oxidation in ovariectomized mice.. Female C57/BL6 mice were ovariectomized or received sham operations and treatment with equivalent doses of 17β-estradiol or α-Zearalanol for 8 weeks. Their spatial learning and memory were analyzed using the Morris water maze test. The antioxidant enzyme activities and reactive oxygen species generation, neuronal DNA oxidation, and MutT homolog 1 expression in the hippocampus were measured.. Treatment with 17β-estradiol or α-Zearalanol significantly improved spatial learning and memory performance in ovariectomized mice. In addition, 17β-estradiol and α-Zearalanol attenuated the decrease in antioxidant enzyme activities and increased reactive oxygen species production in ovariectomized mice. The findings indicated a significant elevation in hippocampi neuronal DNA oxidation and reduction in MutT homolog 1 expression in estrogen-deficient mice, but supplementation with 17β-estradiol or α-Zearalanol efficaciously ameliorated this situation.. These results demonstrate that α-Zearalanol is potentially beneficial for improving memory impairments and neuronal oxidation damage in a manner similar to that of 17β-estradiol. Therefore, the compound may be a potential therapeutic agent that can ameliorate neurodegenerative disorders related to estrogen deficiency.

Topics: Alzheimer Disease; Animals; Blotting, Western; DNA Damage; DNA Repair Enzymes; Estradiol; Female; Hippocampus; Immunohistochemistry; Memory Disorders; Mice; Mice, Inbred C57BL; Ovariectomy; Oxidative Stress; Phosphoric Monoester Hydrolases; Phytoestrogens; Reproducibility of Results; Time Factors; Treatment Outcome; Zeranol

Brains from ovariectomised (ovx) rats can display features similar to those observed in menopausal women with Alzheimer's disease (AD), and oestrogen seems to play a key role. Preliminary studies on young coconut juice (YCJ) have reported the presence of oestrogen-like components in it. The aim of the study was to investigate the effects of YCJ on the AD pathological changes in the brains of ovx rats. Rat groups included sham-operated, ovx, ovx+oestradiol benzoate (EB) and ovx+YCJ. Brain sections (4 μm) were taken and were immunostained with β-amyloid (Aβ) 1-42, glial fibrillary acidic protein (GFAP) (an intermediate neurofilament of astrocytes) and Tau-1 antibodies. Aβ 1-42, GFAP and Tau-1 are considered as reliable biomarkers of amyloidosis, astrogliosis and tauopathy (neurofibrillary tangles), respectively, which in turn are characteristic features associated with AD. The serum oestradiol (E2) level was measured using a chemiluminescent immunoassay technique. YCJ restored the serum E2 to levels significantly (P < 0·001) higher than that of the ovx group, and even that of the sham group. Aβ deposition was significantly (P < 0·0001) reduced in the cerebral cortex of the YCJ group, as compared with the ovx group and with the sham and ovx+EB groups (P < 0·01). A similar trend was observed in relation to GFAP expression in the cerebral cortex and to Tau-1 expression in the hippocampus. This is a novel study demonstrating that YCJ could have positive future implications in the prevention and treatment of AD in menopausal women.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Biomarkers; Brain; Cocos; Estradiol; Female; Glial Fibrillary Acidic Protein; Neurofibrillary Tangles; Nuts; Ovariectomy; Phytoestrogens; Phytotherapy; Plant Preparations; Rats; Rats, Wistar; tau Proteins

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by increased β-amyloid (Aβ) deposition and neuronal dysfunction leading to impaired learning and recall. Ageing, heredity, and induced oxidative stress are among proposed risk factors. The increased frequency of the disease in women also suggests a role for estrogen in development of AD. In the present study, effects of the phytoestrogen genistein (10mg/kg) on learning and memory impairments was assessed in intrahippocampal Aβ(1-40)-injected rats. The estrogen receptor antagonist fulvestrant was injected intracerebroventricularly in a group of Aβ-lesioned rats. The Aβ-injected animals exhibited the following: lower spontaneous alternation score in Y-maze tasks, impaired retention and recall capability in the passive avoidance test, and fewer correct choices and more errors in the RAM task. Genistein, but not genistein and fulvestrant, significantly improved most of these parameters. Measurements of oxidative stress markers in hippocampal tissue of Aβ-injected rats showed an elevation of malondialdehyde (MDA) and nitrite content, and a reduction of superoxide dismutase (SOD) activity. Genistein significantly attenuated the increased MDA content but did not affect the nitrite content or SOD activity. These results indicate that genistein pretreatment ameliorates Aβ-induced impairment of short-term spatial memory in rats through an estrogenic pathway and by inducing attenuation of oxidative stress.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Animals; Avoidance Learning; Disease Models, Animal; Estradiol; Estrogen Antagonists; Fulvestrant; Genistein; Hippocampus; Infusions, Intraventricular; Male; Malondialdehyde; Maze Learning; Memory, Short-Term; Mental Recall; Microinjections; Neuroprotective Agents; Oxidative Stress; Peptide Fragments; Phytoestrogens; Random Allocation; Rats; Rats, Wistar; Retention, Psychology; Statistics, Nonparametric; Thiobarbituric Acid Reactive Substances

Elevated levels of β-amyloid (Aβ) in the brains being a hallmark of Alzheimer's disease have been believed to play a critical role in the cognitive dysfunction that occurs in Alzheimer's disease. Recent evidence suggests that Aβ induces neuronal apoptosis in the brain and in primary neuronal cultures. In this study, we investigated the effects of puerarin, a phytoestrogen isolated from Pueraria lobata, on cognitive function and neuronal apoptosis in the intrahippocampal injection of Aβ rats and its mechanism of action. The results show the intrahippocampal injection of Aβ induced a spatial memory deficit, apoptosis, and caspase-9 activation in hippocampal neurons. Puerarin treatment ameliorated Aβ(1-42)-induced cognitive impairment and reversed the increase of apoptosis in the hippocampus. The attenuation is associated with the activation of Akt and phosphorylation of Bad. These results suggest that puerarin may be an anti-Alzheimer's disease candidate drug to suppress both Alzheimer's disease-related neuronal cell apoptosis and dysfunction of the memory system.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Apoptosis Regulatory Proteins; Cells, Cultured; Cognition Disorders; Dose-Response Relationship, Drug; Enzyme Activation; Gene Expression Regulation; Hippocampus; Isoflavones; Male; Maze Learning; Memory Disorders; Nerve Tissue Proteins; Neurons; Neuroprotective Agents; Phosphorylation; Phytoestrogens; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; RNA, Messenger

Besides the classical hormonal effect, estrogen possesses neuroprotective effects in the brain, which leads to the searching of novel treatments for neurodegenerative diseases such as Alzheimer's disease. Scutellarin is a major flavone derived from Herba Erigerontis, a Chinese medicine derived from Erigeron breviscapus, which has been shown here to possess both estrogenic and neuroprotective properties. Scutellarin showed the estrogenic effects by activating the estrogen responsive elements and phosphorylation of estrogen receptor alpha in cultured MCF-7 cells: the activation was in a dose-dependent manner. On the other hand, scutellarin inhibited the aggregation of beta-amyloid in vitro, and prevented the cell death mediated by beta-amyloid when applied to cultured neuronal PC12 cells. These results therefore suggested that Herba Erigerontis and its component scutellarin might have therapeutic effects against postmenopausal symptoms and Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apigenin; Cell Death; Cell Line, Tumor; Dose-Response Relationship, Drug; Erigeron; Estrogen Receptor alpha; Glucuronates; Humans; Neuroprotective Agents; PC12 Cells; Phosphorylation; Phytoestrogens; Phytotherapy; Plant Extracts; Postmenopause; Rats

The neuroprotective action of oestrogens and oestrogen-like compounds is in the focus of basic and clinical research. Although such action has been shown to be associated with neuronal plasma membranes, the implication of G-proteins remains to be elucidated. This study revealed that micromolar concentrations (microM) of 17beta-oestradiol and phytoestrogens, genistein and daidzein, significantly (P < 0.05) stimulate G-proteins ([(35)S]GTP gamma S binding) in the post-mortem hippocampal membranes of age-matched control women with the respective maximum effects of 28, 20 and 15% at 10 microM. In the frontocortical membranes, the stimulation of G-proteins did not differ significantly from that in hippocampal membranes. Although in the hippocampus and frontal cortex of the Alzheimer's disease (AD) women's brain, 10 microM 17beta-oestradiol produced significantly (P < 0.05) lower stimulation of G-proteins than in the control regions, stimulation by phytoestrogens revealed no remarkable decline. 17beta-Oestradiol, genistein and daidzein revealed a selective effect on various G-proteins (G(alphas), G(alpha o), G(alpha i1) or G(alpha 11) plus G(beta 1 gamma 2)) expressed in Sf9 cells. At a concentration of 10 microM, 17beta-oestradiol suppressed the H(2)O(2) and homocysteine stimulated G-proteins in the frontocortical membranes of control women to a greater extent than phytoestrogens. In AD, the suppressing effect of each compound was lower than in the controls. In the cell-free systems, micromolar concentrations of phytoestrogens scavenged OH(*) and the 2.2-diphenyl-1-picrylhydrazyl free radical (DPPH(*)) more than 17beta-oestradiol did. In the frontocortical membranes of control women, the 20 microM 17beta-oestradiol stimulated adenylate cyclase with 20% maximal effect, whereas, in AD, the effect was insignificant. Genistein did not stimulate enzyme either in control or AD frontocortical membranes. Our data confirm that the agents stimulate G-proteins in control and AD women's brains, although 17beta-oestradiol and phytoestrogens have similarities and differences in this respect. We suggest that, besides the ER-dependent one, the ER-independent antioxidant mechanism is responsible for the oestrogen stimulation of G-proteins in the brain membranes. Both of these mechanisms could be involved in the neuroprotective signalling of oestrogens that contributes to their preventive/therapeutic action against postmenopausal neurological disorders.

Topics: Adenylyl Cyclases; Aged; Aged, 80 and over; Alzheimer Disease; Brain; Case-Control Studies; Cell Membrane; Cytoprotection; Estradiol; Female; Free Radical Scavengers; Genistein; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Humans; Isoflavones; Male; Models, Biological; Phytoestrogens; Protein Binding

Extensive research suggests that a number of plant-derived chemicals and traditional Oriental herbal remedies possess cognition-enhancing properties. Widely used current treatments for dementia include extracts of Ginkgo biloba and several alkaloidal, and therefore toxic, plant-derived cholinergic agents. Several non-toxic, European herbal species have pan-cultural traditions as treatments for cognitive deficits, including those associated with ageing. To date they have not received research interest commensurate with their potential utility. Particularly promising candidate species include sage (Salvia lavandulaefolia/officinalis), Lemon balm (Melissa officinalis) and rosemary (Rosmarinus officinalis). In the case of sage, extracts possess anti-oxidant, estrogenic, and anti-inflammatory properties, and specifically inhibit butyryl- and acetyl-cholinesterase. Acute administration has also been found to reliably improve mnemonic performance in healthy young and elderly cohorts, whilst a chronic regime has been shown to attenuate cognitive declines in sufferers from Alzheimer's disease. In the case of Melissa officinalis, extracts have, most notably, been shown to bind directly to both nicotinic and muscarinic receptors in human brain tissue. This property has been shown to vary with extraction method and strain. Robust anxiolytic effects have also been demonstrated following acute administration to healthy humans, with mnemonic enhancement restricted to an extract with high cholinergic binding properties. Chronic regimes of aromatherapy and essential oil respectively have also been shown to reduce agitation and attenuate cognitive declines in sufferers from dementia. Given the side effect profile of prescribed cholinesterase inhibitors, and a current lack of a well tolerated nicotinic receptor agonist, these herbal treatments may well provide effective and well-tolerated treatments for dementia, either alone, in combination, or as an adjunct to conventional treatments.

Topics: Alzheimer Disease; Animals; Anti-Inflammatory Agents; Antioxidants; Aromatherapy; Behavior; Behavior, Animal; Cholinesterase Inhibitors; Cognition; Europe; Humans; Melissa; Nootropic Agents; Phytoestrogens; Plant Extracts; Plants, Medicinal; Randomized Controlled Trials as Topic; Receptors, Cholinergic; Rosmarinus; Salvia officinalis

Topics: Alzheimer Disease; Breast Neoplasms; Cardiovascular Diseases; Colorectal Neoplasms; Dehydration; Estrogen Replacement Therapy; Estrogens; Female; Hot Flashes; Humans; Menopause; Osteoporosis; Phytoestrogens; Progesterone; Urination Disorders; Vaginal Diseases

Topics: Aluminum; Alzheimer Disease; Breast Neoplasms; Child; Chronic Kidney Disease-Mineral and Bone Disorder; Estrogens, Non-Steroidal; Female; Food Contamination; Glycine max; Humans; Infertility, Male; Isoflavones; Male; Menarche; Phytoestrogens; Plant Preparations; Sperm Count

Salvia lavandulaefolia Vahl. (Spanish sage) essential oil and individual monoterpenoid constituents have been shown to inhibit the enzyme acetylcholinesterase in-vitro and in-vivo. This activity is relevant to the treatment of Alzheimer's disease, since anticholinesterase drugs are currently the only drugs available to treat Alzheimer's disease. Other activities relevant to Alzheimer's disease include antioxidant, anti-inflammatory and estrogenic effects. Results of in-vitro tests for these activities are reported here for S. lavandulaefolia extracts, the essential oil and its major constituents. Antioxidant activity (inhibition of bovine brain liposome peroxidation) was found in the EtOH extract of the dried herb (5 mg mL(-1)) and the monoterpenoids (0.1 M) alpha- and beta-pinene and 1,8-cineole. Thujone and geraniol had lower antioxidant effects, while camphor had no antioxidant effects. Possible anti-inflammatory activity (eicosanoid inhibition in rat leucocytes) was found in the EtOH extract (50 microg mL(-1)) and was shown by the monoterpenoids alpha-pinene and geraniol (0.2 mM), but not 1,8-cineole, thujone or camphor. Possible estrogenic activity (via induction of beta-galactosidase activity in yeast cells) was found in the essential oil (0.01 mg mL(-1)) and the monoterpenoid geraniol (0.1-2 mM). 1,8-Cineole, alpha- and beta-pinene and thujone did not exhibit estrogenic activity in this analysis. These results demonstrate that S. lavandulaefolia, its essential oil and some chemical constituents have properties relevant to the treatment of Alzheimer's disease and provide further data supporting the value of carrying out clinical studies in patients with Alzheimer's disease using this plant species.

Topics: Alzheimer Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Cattle; Cells, Cultured; Eicosanoids; Estrogens, Non-Steroidal; Humans; In Vitro Techniques; Isoflavones; Lipid Peroxidation; Oils, Volatile; Phytoestrogens; Phytotherapy; Plant Preparations; Receptors, Estrogen; Saccharomyces cerevisiae; Salvia