phytoestrogens and Cognitive-Dysfunction

S-equol, a metabolite of soy isoflavone daidzein transformed by the gut microbiome, is the most biologically potent among all soy isoflavones and their metabolites. Soy isoflavones are phytoestrogens and exert their actions through estrogen receptor-β. Epidemiological studies in East Asia, where soy isoflavones are regularly consumed, show that dietary isoflavone intake is inversely associated with cognitive decline and dementia; however, randomized controlled trials of soy isoflavones in Western countries did not generally show their cognitive benefit. The discrepant results may be attributed to S-equol production capability; after consuming soy isoflavones, 40-70% of East Asians produce S-equol, whereas 20-30% of Westerners do. Recent observational and clinical studies in Japan show that S-equol but not soy isoflavones is inversely associated with multiple vascular pathologies, contributing to cognitive impairment and dementia, including arterial stiffness and white matter lesion volume. S-equol has better permeability to the blood-brain barrier than soy isoflavones, although their affinity to estrogen receptor-β is similar. S-equol is also the most potent antioxidant among all known soy isoflavones. Although S-equol is available as a dietary supplement, no long-term trials in humans have examined the effect of S-equol supplementation on arterial stiffness, cerebrovascular disease, cognitive decline, or dementia.

Topics: Antioxidants; Cognitive Dysfunction; Dementia; Equol; Estrogen Receptor beta; Gastrointestinal Microbiome; Humans; Isoflavones; Phytoestrogens; Receptors, Estrogen

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

Cognitive impairment results from a complex interplay of many factors. The most important independent predictor of cognitive decline is age but other contributing factors include demographic, genetic, socio-economic, and environmental parameters, including nutrition. The number of persons with cognitive decline and dementia will increase in the next decades in parallel with aging of the world population. Effective pharmaceutical treatments for age-related cognitive decline are lacking, emphasizing the importance of prevention strategies. There is extensive evidence supporting a relationship between diet and cognitive functions. Thus, nutritional approaches to prevent or slow cognitive decline could have a remarkable public health impact. Several dietary components and supplements have been examined in relation to their association with the development of cognitive decline. A number of studies have examined the role of dietary patterns on late-life cognition, with accumulating evidence that combinations of foods and nutrients may act synergistically to provide stronger benefit than those conferred by individual dietary components. Higher adherence to the Mediterranean dietary pattern has been associated with decreased cognitive decline and incident AD. Another dietary pattern with neuroprotective actions is the Dietary Approach to Stop Hypertension (DASH). The combination of these two dietary patterns has been associated with slower rates of cognitive decline and significant reduction in incident AD. This review evaluates the evidence for the effects of some dietary components, supplements, and dietary patterns as neuroprotective, with potential to delay cognitive decline and the onset of dementia.

Topics: Antioxidants; Autophagy; Caffeine; Catechin; Central Nervous System Stimulants; Chocolate; Cognitive Dysfunction; Curcumin; Dementia; Diet; Fatty Acids, Omega-3; Garlic; Ginkgo biloba; Healthy Aging; Humans; Inflammation; Magnesium; Oxidative Stress; Phytoestrogens; Phytotherapy; Resveratrol; Tea; Vitamins

Observational studies and treatment trials investigating nutrition and cognitive function, with a focus on folate and soya and dementia, were reviewed. Data suggested that effects of folic acid based interventions may only be shown before cognitive decline is evident and/or if people are folate deficient. In older people in Indonesia, Hawai'i and China, tofu, which can contain high levels of phytoestrogens, was found to increase dementia risk. This association was not mediated by a vegetarian diet, socioeconomic status, formaldehyde, thyroid function, or loss of teeth. On the other hand, human observational and animal treatment studies suggested that tempe, a fermented soya product containing phytoestrogens and folate, reduced dementia risk and improved memory. High oestrogen levels were found to increase dementia risk in older women. However, in women with adequate serum folate, high oestrogen levels did not confer additional dementia risk and may protect ageing neurons. In conclusion, reviews seem to suggest that folic acid interventions are only effective on cognitive outcomes in people who are folate deficient and do not have cognitive impairment. Frequent consumption of tofu may have detrimental effects on memory and increase dementia risk in older East Asian people, while tempe may reduce these risks. Possibly folate in tempe offsets the potential negative effects of oestrogenic compounds on ageing neurons.

Topics: Cognitive Dysfunction; Dementia; Female; Folic Acid; Folic Acid Deficiency; Glycine max; Humans; Male; Phytoestrogens; Plant Proteins, Dietary; Soy Foods

It is predicted that around 20% of the worlds population will be age 60 or above by 2050. Prevalence of cognitive decline and dementia is high in older adults and modifiable dietary factors may be able to reduce risk for these conditions. Phytoestrogens are bioactive plant chemicals found in soy, which have a similarity in structure to natural estradiol (the most abundant circulating estrogen). This structural likeness enables phytoestrogens to interact with estrogen receptors in the brain, potentially affecting cognition. However, findings in this domain are largely inconsistent, with approximately 50% of studies showing positive effects of phytoestrogens on cognition and the other half resulting in null/negative findings. This paper provides an updated review of the relationship between consumption of phytoestrogens and risk for cognitive decline and/or dementia. In particular, possible mediators were identified to explain discrepant findings and for consideration in future research. A case can be made for a link between phytoestrogen consumption, thyroid status and cognition in older age, although current findings in this area are very limited. Evidence suggests that inter-individual variants that can affect phytoestrogen bioavailability (and thus cognitive outcome) include age and ability to breakdown ingested phytoestrogens into their bioactive metabolites. Factors of the study design that must be taken into account are type of soy product, dosage, frequency of dietary intake and type of cognitive test used. Guidelines regarding optimal phytoestrogen dosage and frequency of intake are yet to be determined.

Topics: Aging; Animals; Cognition; Cognitive Dysfunction; Dementia; Diet; Functional Food; Glycine max; Humans; Phytoestrogens; Thyroid Gland

PhytoSERM is a selective estrogen receptor beta (ERβ) modulator comprised of three phytoestrogens: genistein, daidzein, and S-equol. The PhytoSERM formulation promotes estrogenic action in the brain while largely inactive or inhibitory in reproductive tissue. A phase Ib/IIa clinical trial (ClinicalTrial.gov ID: NCT01723917) of PhytoSERM demonstrated safety and pharmacokinetics profile of PhytoSERM. While this study was not powered for efficacy analysis, we conducted a pilot, retrospective analysis to identify potential responders to PhytoSERM treatment, and to determine the optimal populations to pursue in a phase II clinical trial of efficacy of the PhytoSERM formulation.. In this retrospective analysis involving 46 participants (n = 16, placebo; n = 18, 50 mg/d PhytoSERM; and n = 12, 100 mg/d PhytoSERM), the therapeutic effect of PhytoSERM was stratified by 2 genetic risk modulators for Alzheimer's disease: mitochondrial haplogroup and APOE genotype.. Our retrospective responder analysis indicated that participants on 50 mg of daily PhytoSERM (PS50) for 12 weeks significantly reduced hot flash frequency compared with their baseline (mean [95% CI])-1.61, [-2.79, -0.42], P = 0.007). Participants on 50 mg of PhytoSERM also had significantly greater reduction in hot flash frequency at 12 weeks compared with the placebo group (-1.38, -0.17 [median PS50, median placebo], P = 0.04). Fifty milligrams of daily PhytoSERM also preserved cognitive function in certain aspects of verbal learning and executive function. Our analysis further suggests that mitochondrial haplogroup and APOE genotype can modify PhytoSERM response.. Our data support a precision medicine approach for further development of PhytoSERM as a safe and effective alternative to hormone therapy for menopause-associated hot flash and cognitive decline. While definitive determination of PhytoSERM efficacy is limited by the small sample size, these data provide a reasonable rationale to extend analyses to a larger study set powered to address statistical significance.

Topics: Apolipoproteins E; Cognition; Cognitive Dysfunction; Double-Blind Method; Equol; Feasibility Studies; Female; Genistein; Haplotypes; Hot Flashes; Humans; Isoflavones; Menopause; Middle Aged; Mitochondria; Phytoestrogens; Pilot Projects; Retrospective Studies; Selective Estrogen Receptor Modulators; Treatment Outcome

Ketamine is a frequently used anesthetic in pediatric patients that can cause cognitive impairment. Genistein, a bioactive component of soy products, has been shown to suppress neuronal death through regulating the expression of apoptosis related genes. In this study, we hypothesized that genistein could alleviate ketamine-induced cognitive impairment by ameliorating hippocampal neuronal loss and tested this hypothesis in rats. Neonatal rats were treated with ketamine and genistein. Hippocampal tissue was harvested for histological and biochemical analysis to determine neuronal apoptosis and proteins involved in the apoptotic pathways. Behavioral assays including contextual fear conditioning test and Morris water maze test were performed to assess cognitive functions, including learning and memory. We found that in fear conditioning test, genistein restored freezing time in ketamine treated rats in a dose dependent manner. Similarly, genistein attenuated impaired learning and memory in Morris water maze test in rats treated with ketamine. Additionally, ketamine-induced neuronal apoptosis in rat hippocampus was attenuated by genistein treatment. Finally, we found that genistein partially restored proteins associated with apoptosis, including Bax, Bcl-2, cleaved caspase 3, and phosphorylated GSK-3ß and Akt. Genistein suppresses hippocampal neuronal loss and cognitive disruption induced by ketamine in rats.

Topics: Animals; Animals, Newborn; Apoptosis; Cognitive Dysfunction; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Fear; Genistein; Hippocampus; Ketamine; Male; Maze Learning; Neuroprotective Agents; Phytoestrogens; Rats; Rats, Sprague-Dawley

Genistein (GE), a plant-derived isoflavone, is a polyphenolic non-steroidal compound. Studies showed that GE possesses anti-cancer, anti-inflammatory, anti-microbial, anti-oxidant, and anti-apoptotic activities. However, the neuroprotective role of GE in amnesia has not been studied. This study aimed to evaluate the anti-amnesic potential of GE in a mice model of hypoxia-induced amnesia and to understand the underlying mechanism. Mice were exposed to hypoxia (10% O2) and administered vehicle or GE (10, 20, 30 mg/kg) orally for 28 days. Thereafter, Morris water maze (MWM), novel object recognition (NOR), and passive avoidance task (PAT) were performed to evaluate cognitive behavior. Next, we performed biochemical tests and gene expression analysis to uncover the mechanism underlying GE mode of action. Our results showed that GE-treatment ameliorated hypoxia-induced cognitive dysfunctions in mice. Further, GE-treatment suppressed the oxidative stress in the hippocampus of amnesic mice as evidenced by reduced lipid peroxidation, reduced nitrite and ROS levels, and increased levels of reduced glutathione (GSH) and increased total antioxidant capacity. GE treatment reduced the expression of pro-inflammatory cytokines TNFα, IL1β, IL6, and MCP-1 and increased the expression of anti-inflammatory cytokine IL10 in the hippocampus of amnesic mice. Finally, GE treatment enhanced the expression of neuroprotective genes including BDNF, CREB, CBP, and IGF1 in the hippocampus of amnesic mice. Altogether, our results showed that GE treatment prevents hypoxia-induced cognitive dysfunction in mice by reducing oxidative stress and suppressing neuroinflammation while increasing the expression of neuroprotective genes in the hippocampus.

Topics: Animals; Avoidance Learning; Cognitive Dysfunction; Dose-Response Relationship, Drug; Genistein; Hippocampus; Hypoxia; Inflammation; Male; Mice; Neuroprotective Agents; Oxidative Stress; Phytoestrogens

Topics: Animals; Cognitive Dysfunction; Cytokines; Disease Models, Animal; Estradiol; Female; Gene Expression Regulation; Hippocampus; Malondialdehyde; Maze Learning; Mice; Ovariectomy; Oxidative Stress; Phytoestrogens; Pueraria

Chronic neurocognitive impairments, commonly associated with pediatric human immunodeficiency virus type 1 (PHIV), are a detrimental consequence of early exposure to HIV-1 viral proteins. Strong evidence supports S-Equol (SE) as an efficacious adjunctive neuroprotective and/or neurorestorative therapeutic for neurocognitive impairments in adult ovariectomized female HIV-1 transgenic (Tg) rats. There remains, however, a critical need to assess the therapeutic efficacy of SE when treatment occurs at an earlier age (i.e., resembling a therapeutic for children with PHIV) and across the factor of biological sex. Utilization of a series of signal detection operant tasks revealed prominent, sex-dependent neurocognitive deficits in the HIV-1 Tg rat, characterized by alterations in stimulus-reinforcement learning, the response profile, and temporal processing. Early (i.e., postnatal day 28) initiation of SE treatment precluded the development of chronic neurocognitive impairments in all (i.e., 100%) HIV-1 Tg animals, albeit not for all neurocognitive domains. Most notably, the therapeutic effects of SE are generalized across the factor of biological sex, despite the presence of endogenous hormones. Results support, therefore, the efficacy of SE as a neuroprotective therapeutic for chronic neurocognitive impairments in the post-cART era; an adjunctive therapeutic that demonstrates high efficacy in both males and females. Optimizing treatment conditions by evaluating multiple factors (i.e., age, neurocognitive domains, and biological sex) associated with PHIV and HIV-1 associated neurocognitive disorders (HAND) affords a key opportunity to improve the therapeutic efficacy of SE.

Topics: Animals; Child; Cognitive Dysfunction; Conditioning, Operant; Disease Models, Animal; Female; HIV Infections; HIV-1; Humans; Male; Mental Status and Dementia Tests; Neuroprotective Agents; Phytoestrogens; Rats; Rats, Inbred F344; Rats, Transgenic; Reinforcement, Psychology; Sex Factors

Neonatal Hypoxia-Ischemia (HI) is a major cause of morbidity and mortality, and is frequently associated with short and long-term neurologic and cognitive impairments. The HI injury causes mitochondrial damage leading to increased production of reactive oxygen species (ROS). Phytoestrogens are non-steroidal plant substances structurally and functionally similar to estrogen. Coumestrol is a potent isoflavonoid with a protective effect against ischemic brain damage in adult rats. Our aim was to determine if coumestrol treatment following neonatal HI attenuates the long-term cognitive deficits induced by neonatal HI, as well as to investigate one possible mechanism underlying its potential effect.. On the 7th postnatal day, male Wistar rats were submitted to the Levine-Rice HI model. Intraperitoneal injections of 20 mg/kg of coumestrol, or vehicle, were administered immediately pre-hypoxia or 3 h post-hypoxia. At 12 h after HI the mitochondrial status and ROS levels were determined. At 60th postnatal day the cognitive deficits were revealed in the Morris water maze reference and working spatial memories. Following behavioral analysis, histological assessment was performed and reactive astrogliosis was measured by GFAP expression.. Results demonstrate that both pre- and post-HI administration of coumestrol were able to counteract the long-term cognitive and morphological impairments caused by HI, as well as to block the late reactive astrogliosis. The pre-HI administration of coumestrol was able to prevent the early mitochondrial dysfunction in the hippocampus of injured rat pups.. Present data suggest that coumestrol exerts protection against experimental neonatal brain hypoxia-ischemia through, at least in part, early modulation of mitochondrial function.

Topics: Animals; Brain; Cognition; Cognitive Dysfunction; Coumestrol; Hypoxia-Ischemia, Brain; Male; Maze Learning; Mitochondria; Neuroprotective Agents; Phytoestrogens; Rats; Rats, Wistar; Reactive Oxygen Species