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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 8  |  Issue : 2  |  Page : 83-92

Neuroprotective effects of phytoestrogens: A potential alternative to estrogen therapy in Alzheimer's disease patients


1 Department of Zoology, Deshbandhu College, University of Delhi, New Delhi, India
2 Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India
3 Department of Biochemistry, Deshbandhu College, University of Delhi, New Delhi, India
4 Department of Chemistry, Deshbandhu College, University of Delhi, New Delhi, India
5 Department of Dravyaguna Vigyan, College of Ayurved, Bharati Vidyapeeth Deemed University, Pune, Maharashtra, India

Date of Submission29-Jul-2021
Date of Decision30-Sep-2021
Date of Acceptance09-Oct-2021
Date of Web Publication31-Jan-2022

Correspondence Address:
Dr. Varsha Baweja
Department of Zoology, Deshbandhu College, University of Delhi, Kalkaji, New Delhi-110 019
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jgmh.jgmh_33_21

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  Abstract 


Alzheimer's disease (AD) is classified as an age-related neuro-degenerative disorder leading to loss of memory and decline in cognitive abilities, often characterized as dementia. According to the WHO report 2020, out of 50 million people battling with dementia worldwide, 60%–70% cases account for AD. Some researchers have reported two to three times higher incidence of AD among women than men and further confirmed that postmenopausal women are more prone to AD than healthy men of the same age. This hints at the potential neuroprotective role of estrogen hormone, whose level drops to <30 pg/mL postmenopause. Several epidemiological studies also suggest early postmenopausal use of estrogens may contribute to the prevention, attenuation, or even delay in the onset of AD. Collectively, this evidence supports the further development of estrogen-like compounds for the treatment and prevention of AD, with a rising interest in phytoestrogens as potential interventions with lower side effects. This review highlights multiple pathways of estrogen-mediated neuroprotection against neurodegenerative diseases like AD and discusses the role of selective estrogen receptor molecules mainly phytoestrogens, in AD progression so that latter can be considered and used as an alternate therapy for treating Alzheimer patients.

Keywords: Alzheimer's disease, cognition, estrogen, estrogen receptor, neuroprotection, phytoestrogen


How to cite this article:
Baweja V, Himanshu, Tandon A, Goyal M, Mishra R, Deshpande M. Neuroprotective effects of phytoestrogens: A potential alternative to estrogen therapy in Alzheimer's disease patients. J Geriatr Ment Health 2021;8:83-92

How to cite this URL:
Baweja V, Himanshu, Tandon A, Goyal M, Mishra R, Deshpande M. Neuroprotective effects of phytoestrogens: A potential alternative to estrogen therapy in Alzheimer's disease patients. J Geriatr Ment Health [serial online] 2021 [cited 2022 May 23];8:83-92. Available from: https://www.jgmh.org/text.asp?2021/8/2/83/336907




  Introduction Top


Alzheimer's disease (AD), the leading global epidemic of the 21st century has been progressively inclining its statistics since the past 2–3 decades which is evident by twice the number of deaths from AD between 2000 and 2016 making it 5th leading cause of death in 2016 compared to 14th in 2000 (WHO). With the current research including various evidence from in-vitro and in-vivo study models, the role of estrogen in the prevention of AD has become evident in recent years. A recently published meta-analysis by Song et al. summarized that ERT in post-menopausal women significantly reduces the risk of onset and/or development of AD.[1] However, one of the major implications in continuous therapy with estrogens is increased risk of uterine cancer as well as venous thrombosis. Thus, estrogen therapy for AD can be a success with the discovery of estrogenic drugs that are devoid of these side effects yet retain their potent neuroprotective and antioxidant activities.

Owing to the structural similarity to the female sex hormone, 17-β-estradiol (estrogen), phytoestrogens can exert anti-estrogenic or pro-estrogenic effects by binding to estrogen receptors (ERs). Their antioxidant properties are likely known to contribute to their pro-health effects like decrease in the intensity of menopausal symptoms and reducing the risk of osteoporosis, cardiovascular disease, obesity, metabolic syndrome, and the risk of breast, prostate, and intestine cancer. The two studied attributes of phytoestrogens, i.e., antioxidant properties and mechanistic binding with the ERs can appear to be related with neuroprotective functions in the brain. Yet, it has not been unequivocally established whether phytoestrogens provide positive effects on cognition and markers of AD or improve memory function in postmenopausal women.[2] Through this review, we aim to motivate researchers worldwide to look at the prospects of phytoestrogens as a drug compound providing neuroprotection in AD patients.

Pathogenesis of Alzheimer's disease

In AD, commonly studied molecular markers-Aβ plaques and neurofibrillary tangles (NFTs) are cleaved from Amyloid precursor proteins (APP-encoded by chromosome 21) and Tau Hyperphosphorylation, respectively. The same plaque formation physiology and decline in cognitive functions was observed in Down's syndrome (trisomy 21), thus confirming the chromosomal location of APP. Moreover in 1991, a family with autosomal dominant early-onset AD exhibiting a mutation in gene encoding APP was discovered. Based on these findings, APP was accounted for the pathogenesis of AD and APP cascade hypothesis was formulated.[3] APP is a transmembrane protein with extracellular domains involved in AD pathogenesis. It is physiologically cleaved by α-secretases, (metalloprotease like ADAM10 and ADAM17) to produce soluble nontoxic protein fragments. Particularly in AD, β-secretases (BACE1) and γ-secretases (intramembrane aspartyl protease, a complex of 4 proteins-presenilin, nicastrin, anterior pharynx defective 1 (Aph 1) and Psen2) cleave APP to form insoluble Aβ fragments. The Aβ aggregations constitute 2 kinds of Aβ polymers: Aβ40 and Aβ42. Aβ40 is more abundant and less neurotoxic than Aβ42 being less abundant and more toxic. The insoluble Aβ fibrils form oligomers that diffuse into the synapses of local neurons, hindering, and disturbing synaptic signaling. Further aggregation of these fibrils leads to formations of Aβ amyloid plaques, causing the pathogenic blockage of ion channels, mitochondrial oxidative stress, disruptions in energy metabolism, disbalance in calcium homeostasis, and reduced neuronal health thus, leading to apoptosis. Aβ plaques activate toll-like receptors of microglia leading to immune activation and microglial recruitment in the brain, causing neurotoxicity. Tau, a microtubule stabilizing protein, gets phosphorylated by kinases, activated by Aβ plaques, causing disruptions in microtubule assembly and resulting in aggregation of tau proteins to form insoluble helical protein filaments, called NFTs. These NFTs cause loss in neuron intracellular signaling.[4]

The oxidative stress, disruptions in signaling, activated immune responses caused by the mentioned factors ultimately lead to apoptosis and neurodegeneration.

Brain and estrogen

Estrogen the female sex hormone affects both reproductive and nonreproductive systems of the body. In addition to ovaries, estrogen is synthesized in bone, muscle, heart, and brain. Synthesis of estrogen in the brain occurs via the two fore mentioned pathways, de novo pathway utilizing cholesterol and by modifications of C-19 steroid precursors such as 16α-OH DHEA, androstenedione, and testosterone using a series of enzymes. Aromatase enzyme plays a key role in estrogen synthesis by hydroxylating steroid precursors to estrogen. Women suffering from AD have reported to have low activity of aromatase than healthy women of the same age.[5]

Estrogen has been proved to protect central nervous system (CNS) from oxidative stress, reduce inflammatory actions and inhibit microglial activation.[6] In vitro studies confirmed the neuroprotective action of estrogen, especially 17-β estradiol.

In CNS, estrogen's prime function is cell proliferation and synaptogenesis that could be achieved by targeting nuclear or membrane receptors, by inhibiting neuroinflammatory signaling pathways associated with interleukin (IL)-1β, affecting various neurotransmitter systems (like dopaminergic or glutamatergic neurotransmission), reducing the production levels of nitric oxide (NO) and reactive oxygen species (ROS), altering the expression of genes related to transcriptional regulation, and involvement of tyrosine kinases as well as the activation of phosphorylation cascades causing an increase in the intracellular extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK), phosphatidylinositol-3-OH kinase-protein kinase B (PI3K-Akt) signaling pathway.[7]

Estrogen receptors and cell survival signaling pathways

To study the neuroprotective efficacy of various phytoestrogens in AD pathogenesis, it is essential to understand the mechanism of how estrogen molecules bind to and regulate their effects on the neuron. The neuroprotective functions of estrogen are regulated by two different signal transduction pathways:

  1. The nuclear receptor-initiated steroid signaling-estradiol binds to nuclear receptors, ER alpha (ERα), and ER beta (ERβ) localized in the nucleus and cytoplasm, which, on sterol activation, binds to the DNA at hormone-response element and activates cAMP response element-binding protein (CREB)-regulated gene transcription. Thus, enhancing the expression of desired genes which promote neuronal survival.[7]

    Human polymorphic studies on the ERα gene demonstrate the role of ERα receptors in the maintenance of memory.[8] This makes ERα, one of the main downstream effectors controlling AD pathogenesis
  2. The membrane receptor-initiated steroid signaling-plasma membrane ER (mER) and the G protein-bound ER-1 (GPER-1) activate various intracellular cascades (e.g., PI3K-Akt and MAPK signaling pathways) resulting in CREB-mediated transcription for cell survival.[7]


In contrast to ERα and ERβ which mediate genomic effects with a time lag of hours to days, GPER mediates rapid nongenomic actions that appear in seconds or minutes,[7] whereas in contrast to ERα, ERβ seems less effective in inducing transcription of neuronal survival genes.[8] It has been reported that based on differences in concentrations of receptors, differences in activation and function might appear, as observed in CNS, ERα acts as an agonist, but ERβ might act as an antagonist inhibiting estrogen-mediated effects based on its concentration difference (on underexpression of ERβ, the activation tends to have antagonistic effects). The receptor concentrations might as well be temporally controlled, it has been shown that long period ovariectomy causes substantial reduction of ERα than ERβ of the hippocampus in rats.[8] Thus, at different levels of estrogen activation, unique spatial and temporal differences in activation of these pathways together act as a combinatorial code, fine-tuning the gene expression of the cell with regard to estradiol activation.

Estrogen through its downstream effector genes mediates AD protection. Any interference with such effectors may cause the dearth of estradiol neuroprotection, even in the presence of sufficient ligands.[9] A selective AD indicator-1 (seladin-1) gene is considered as a fundamental mediator of estrogen-mediated neuroprotective actions and downregulation of seladin-1 has been observed in AD susceptible brain regions. Seladin-1 inhibits the activation of caspase-3, a key modulator of apoptosis. Luciani et al.[9] 2005 demonstrated the same by silencing estrogen downstream effector gene seladin-1/3beta-hydroxysterol Delta24-reductase (involved in catalyzing the synthesis of cholesterol from desmosterol). Silencing seladin-1 eliminated the protective effects of E2 against Aβ, oxidative stress toxicity, and caspase-3 activation, suggesting the significant involvement of seladin-1 as a fundamental mediator of estrogen-mediated neuroprotection [Figure 1].[8],[10]
Figure 1: Neuroprotection provided by estrogen and phytoestrogen through gene Seladin 1

Click here to view


ER sub-receptors are used in significant neuroprotection through the activation of various cell survival signaling pathways like:

Mitogen-activated protein kinase signaling pathway

MAPKs are serine/threonine protein kinases and are made up of ½ ERK, P38 kinases, and c-Jun N-terminal kinases (JNK). P38 is highly expressed in AD patients. Tau phosphorylation occurs due to Aβ-induced P38 activity. Activation of ERK is required for synaptic plasticity and memory.[11] These studies indicate that MAPKs could accelerate AD development.

E2 binding ERα or ERβ receptors activates the ERK/MAPK signaling pathway and promotes neuronal survival in the ischemic brain.[5] The activated GTP bound Ras transmits the survival signal by activating the protein kinases Raf, which further activate MEK1/2 through serine phosphorylation at the MAPKK-typical motif in their activation loop.[11] Finally, the phosphorylation of the threonine and tyrosine by MEK1/2 activates ERK1/2 signaling pathway.[7] ERK cascade is primarily involved in dopaminergic signaling and, in turn, activates CREB for cell survival. ERK1/2 also inhibits pro-apoptotic caspase-8 and activated glycogen synthase kinase-3β (GSK3β) to prevent the cell from apoptosis and promote neural cell survival. The presence of ROS activates the ERK thus, reducing ROS-induced cell death.[12]

From the transgenic AD over-expressing Aβ, hippocampal slides show chronic activation of ERK. In addition, increased phospho-ERK has also been found in brain extracts from AD patients.[12]

Sun et al. 1993;[13] Liu et al. 1995;[14] Groom et al. 1996[15] observed neuroprotective role of MKP-1 (MAPK Phosphatase 1) that inhibits MAPK activity by dephosphorylating it at tyrosine and threonine residues.

Phosphatidylinositol-3-OH kinase – Akt (also known as protein kinase B) signaling pathway

It has been reported that short-term E2 therapy in the ovariectomized (OVX) mice may lead to attenuation of neuronal injury and apoptosis by activating the PI3K/Akt signaling pathway. This pathway seems to be very significant component for mediating neuronal survival under a wide range of circumstances.[7]

The trophic factors such as NGF, insulin-like growth factor 1 (IGF-I), or BDNF activate a variety of signaling cascades, including the PI3K–Akt signaling pathway, the Ras–MAPK, and the cAMP/protein kinase A (PKA) pathways. In astrocytes, BDNF activates Src which further mediates ERK activation. Therefore, ERK and Akt activation by BDNF may depend on Src in astrocytes, which is likely to contribute to cell survival. The survival factors, by binding to their cognate tyrosine kinase receptors, bring out the recruitment of PI3K to the vicinity of the plasma membrane.[12]

The important substrate like transcription factors may further regulate the expression of components of the cell death machinery, Bcl-2 family members, endothelial NO synthase, the telomerase reverse transcriptase subunit, the tumor suppressor BRCA1, and protein kinases such as Raf, IκB kinase, or GSK-3.[12]

Regulation of intracellular Ca2+ signaling

Impairment of neuronal Ca+2 homeostasis has been linked to AD. In nuclear-initiated steroid signaling, E2 bound ERs mediates CREB-regulated gene transcription thus, promoting neuronal survival.[8] E2 also prevents oxidative stress and conserves ATP levels by enhancing oxidative phosphorylation and reducing ATPase activity. Several studies demonstrate that E2 increases antiapoptotic proteins, Bcl-2 and Bcl-xL, which prevents activation of the permeability transition pore, protecting against E2-induced increase in mitochondrial Ca+2 sequestrations. These effects are assumed to be enhanced further by the antioxidant properties of estrogen, thus preventing the initiation of the deleterious “mitochondrial spiral.”[16]

The presence of amyloid-beta (Aβ) has shown to disrupt gliotransmission, neurotransmitter uptake, and alter Ca+2 signaling in astrocytes of AD individuals as well as in AD in vitro and in vivo animal models.[17]

An in vitro study indicated that MAPK pathway-mediated Bcl2 expression accounted for one of the key mechanisms implicated in the dopaminergic neuroprotective effects of E2.[17]

Studies revealed that both ERα-and ERβ-selective agonist – propylpyrazoletriol (PPT) and diarylpropionitrile (DPN) efficiently initiate a dynamic intracellular Ca+2 influx in neurons that activates downstream MAPK signaling and ERK phosphorylation which is necessary for neuroprotection.[8]

Inhibition of daxx translocation

In the cytoplasm, Daxx (Death domain-associated protein) initiates the apoptosis signal-regulating kinase 1 (ASK1)-c-JNK signaling cascades which ultimately leads to apoptosis by accelerating the sodium hydrogen exchanger isoform-1 function. However, in the case of neurons, the restricted expression of Daxx to the nucleus defends cells against the deathstimuli, hence, significant for neuroprotective functions. Since the initiation of the Ask1 is a crucial strategy in the Aβ-induced neurotoxicity thus, it is proposed that E2 could defend cells against Aβ1–42 toxicity by inhibiting the Ask1 cascade (by inducing PKB expression) or modulating Trx1 (thioredoxin-1), which is a multifunctional redox protein having antiapoptotic effects. Both Ask1 activity and Aβ toxicity are inhibited by thioredoxin-1 (Trx1).[8]

Mateos et al.[18] 2012 found that neurons can be protected from Aβ1–42 damage by blocking of cytosolic translocation of Daxx by Trx1. Further, they reported that the neuroprotective function of E2 is exerted by an ERα stimulation mechanism, Akt activation, and Ask1 inhibition, but not dependent on ERβ activation. These findings suggest the great possibility of ERα and Ask1 as targets for the development of novel neuroprotective medicines.

mERα plays a role in neuroprotection by regulating intracellular calcium dynamics. Interaction of caveolin 1 and mERα stimulates mGluR1/5 (metabotropic glutamate receptors 1/5) to initiate intracellular signaling cascades that lead to downstream MAPK signaling and accumulation of pERK (phosphorylated ERK), both of which are essential for neuroprotection. mERα also promotes the maturation of autophagosomes into functional autolysosomes through pERK and Ca+2 influx.[8]

Inhibition of glutamatergic excitotoxicity

In excitotoxicity, glutamate N-methyl-D-aspartate receptors (eNMDARs) trigger the increase of intracellular Ca+2 levels. This is followed by upregulation of nNOS (neuronal nitric oxide synthase) which produces NO leading to lipid peroxidation, dysfunction of mitochondria leading to ROS formation, and activation of calpains which lead to activation of proapoptotic caspase 3. Experimental evidence suggests that soluble oligomers of Aβ1–42 trigger dementia by imitating the stimulation of extracellular glutamate of eNMDARs leading to synaptic dysfunction, successive synaptic loss, and hence, cognitive failure in AD.[8]

The protective role of ER on glutamate-mediated nerve cell injury was observed in rats through the application of a selective ERα modulator and showed that ERα agonists can prevent glutamate-mediated cell death. However, when they coupled glutamate excitotoxicity and oxidative stress, the effectiveness of ERα agonist was curbed.[19]

A study showed that mERα via caveolin 1 activates mGluR2/3 (metabotropic glutamate receptors 2/3)-based signaling that inhibits glutamate excitotoxic injury through the estrogen signaling pathway.[8]

Resistance to glutamate excitotoxicity in suprachiasmatic nucleus cell lines (SCN2.2) found to be dependent on ERK/MAPK signaling.[20]

Lee et al.[21] reported that G1, a selective G protein-coupled receptor 30 (GPR30) agonist-mediated expression of glutamate transporter-1 (GLT1) and enhance CREB binding to GLT1 promoter in astrocytes, which would inhibit glutamate-mediated death of neuron due to excitotoxicity. Thus, suggesting that GPR30 can be used as a potential target for developing therapeutics of excitotoxic neuronal injury.

Various studies in rat hippocampal neurons have shown that PPT and DPN, selective ER agonists for ERα and ERβ, respectively, can inhibit glutamate toxicity by enhancement of the anti-apoptotic Bcl-2 reserve and modulate the stress-activated protein kinase signaling pathways.[7]

Interaction with insulin-like growth factor-1R

The relationship between insulin resistance states associated with aging in females, and the cross-talk between estradiol and proteins includes in the insulin receptor substrate–1 (IRS-1)/PI3-k/Akt and IGF-1-IR signaling pathways, can be used to understand estradiol-mediated neuroprotection.

IRS-1 induces the activation of downstream pathways of PI3k, which has a pivotal role in the metabolic actions of insulin, including insulin-stimulated glucose transport through the specific translocation of Glut-4 from the intracellular pool to the plasma membrane, and the MAPK cascades. Therefore, it seems possible that ER can interact with PI3-k and IRS-1 signaling pathways, to promote neuroprotective effects in the brain.[22],[23]

Various experimental studies reported that estradiol may enhance the proliferation and neuronal survival rate by binding to GPR30 and hence, causing expression of IGF-1.[8]

Pro-inflammatory responses

In experiment done by[24] Zheng et al., they observed notable reduction of gliosis in the hippocampus in Aβ1-42 mice treated with E2 during the early stage of AD pathology. E2 mediated proinflammatory responses such that there was an upregulation of activation in anti-inflammatory signaling pathways (CD206, FIZZ1, Ym1, and TGFβ) and downregulation of activation in proinflammatory signaling pathways IL-1β, tumor necrosis factor-alpha [TNFα], and IL-6. Thus, suggesting that E2-induced neurogenesis, at least in part, through the BDNF/TrkB pathway.[24] ERs, which transduce the actions of estrogen, co-localize to cells that express BDNF and its receptor trkB, and estrogen further regulate the expression of this neurotrophin system.[25] PI3K/Akt and Ras-MEK-MAPK pathways are reported to be the key mechanisms of neurotrophin-induced survival.[26]

The aggregation of Aβ42 activates different astrocyte and microglial cell receptors, inducing the production of ROS and numerous proinflammatory cytokines (TNF-α and IL-1β), all of which consequently stimulate MAPK signaling pathways. Oxidative stress activates JNK and p38 and induces β secretase gene expression, whereas β-secretase gene expression is negatively regulated by ERK1/2.[12]

Voltage-dependent anion channel modulation

The voltage-dependent anion channel, (VDAC) (present at the neuronal membrane) in association with ERα has been shown to be disrupted in neuronal lipid rafts of AD brains.[27] Estrogens, through its binding to ERα, have been shown to contribute to VDAC phosphorylation, thus inducing neuroprotective effects against Aβ toxicity.[8],[27],[28] Marin et al. demonstrated that both VDAC and mERα interact at the plasma membrane of neurons as well as in microsomal fractions of the HT22 hippocampal tissues thus, suggesting that VDAC-mERα association at the plasma membrane level may participate in the modulation of Aβ-induced cell death.

Neuroprotective role of dietary phytoestrogens and Alzheimer's disease

Phytoestrogens are polyphenolic, nonsteroid compounds that naturally occur in more than 300 plants. These plant compounds (xenoestrogens) are functionally similar to the 17 β-estradiol and bind specifically to the β-ER as an agonist to stimulate the secondary responses in the brain.[29] Four groups of phenolic compounds are classified as phytoestrogens: Isoflavones, lignans, coumestans, and stilbenes. Foods containing various phytoestrogens are listed in [Table 1].
Table 1: List of some important food items which contain significant amount of phytoestrogens

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Phytoestrogen acts as estrogen agonist and helps in the metabolism of amyloid precursor proteins (APP) via the protein kinase C pathway. These proteins decline as age increases due to low estrogen levels. These proteins do proteolysis of amyloid-beta peptides and prevent AD. Phytoestrogen also downregulates the transcription of nuclear factor kappa beta, by increasing the expression of macrophages, monocyte chemoattractant I, and monocyte chemoattractant II. Due to the downregulation of this entire mentioned system, AD initiation can be prevented as overexpressing these effectors prevents aging in turn decreases neurodegeneration. It also helps in iron export, neuron plasticity, and synapse formation.[35]

Role of different molecules of phytoestrogen and various pathways through which they work

Phytoestrogens such as daidzein and baicalein bind to the ER-α receptor and activate the MCF7 breast cells. When this combination is given in dose-dependent manner then they partially prevent the neuronal cytotoxicity by stimulating luciferase activity and ER phosphorylation which ultimately prevents the formation of amyloid-beta peptides.[29]

Isoflavones are found mainly in soy products (e.g., tofu) and red clover. It also includes genistein and daidzein, which can be further converted by gut bacteria to a more active form, S-equol.[36] S-equol binds selectively with the ER-β receptor which is highly expressed in the hippocampal region.[37] Isoflavone are also present in two forms: Glucosides and aglycones. Glucosides are the inactive form which is converted into its active form aglycones by the gut bacteria microflora. Flaxseed is a rich source of lignans, whereas clover and alfalfa are major sources of coumestans. Stilbenes, such as resveratrol, are abundant in the skin of grapes, berries, peanuts, and Japanese knotweed.[36]

Genistein increase acetylcholinesterase (AChE) activity even when protein kinases are blocked. GPR30 is activated using genistein by inducing mRNA and promoter activity of AChE. It can rapidly activate the production of cAMP via activation of transcription factor CREB, then it will bind to the CRE binding site on the ACHE gene that leads to the transcription of AChE. AChE hydrolyze acetylcholine into acetate and choline, it leads to the termination of cholinergic signaling in the brain. Estrogen generally acts on the cholinergic system. They bound to GPR30 and activate adenylcyclase/cAMP-dependent PKA signaling pathway. Coumestrol binds to β ER and have stronger estrogenic activity. It prevents bone loss, increase in uterine weight, lowered cholesterol level, leads to change in lipid and carbohydrate metabolism. Its treatment over OVX rats leads to the significant increase in brain mitochondrial respiratory ratio and decrease in lag phase and prevent adipogenesis by regulating Akt and Wnt/β-catenin signaling and induce mitochondrial biogenesis by activate sirt1 activity.[38]

8-prenylnaringenin is a potent phytoestrogen, belonging to prenylated flavonoids. Due to the presence of the prenyl group, its hydrophobicity increases and therefore shows interaction with biological membranes and lipophilic proteins. It generally binds to the ER-α receptors. It does not cross blood-brain barrier. Due to which it does not perform any role in AD control. Rather than that, it helps in the prevention of osteoporosis, by inhibiting osteoclast activity and stimulates osteoblast activity.

Phytoestrogens show effects over calbindin (calcium-binding protein in the brain) and COX-2. Calbindin regulates intracellular calcium present in the brain and protects against neurotoxicity and neurodegenerative disease. In males who fed phytoestrogen-rich diet shows the decrease in the calbindin concentration in the frontal lobe (i.e., increase neurotoxicity) and increasing concentrations of COX-2.[39]

Phytoestrogens like resveratrol enhance the expression and activity of endothelial NO synthase and thus, stimulates the NO production and availability using the MAPK pathway.[36] NO/cGMP signal transduction system in neurons modulates the synaptic transmission, decreasing latency period and provide plasticity in the hippocampus, cortex, and cerebellum region of the brain. NO helps in vasodilation and is considered the intracellular messenger, thereby helps in memory improvement, especially in postmenopausal women.[40]

In different cell lines expressing wild-type Aβ, resveratrol markedly lowers the levels of secreted or intracellular Aβ peptides by promoting the intracellular degradation of Aβ by a mechanism that implicates the proteasome.[41]

Animal studies

Animal models show positive effects when treated with resveratrol, i.e., decrease hippocampal neurodegeneration and increased spatial memory performance. Better cognitive improvement in terms of memory and neuroimaging assessment was observed in a study performed on 22 overweight people, aged 25–75 years and treated with 200 mg/d dose of resveratrol for 26 weeks.[37]

In rat models having β-amyloid deposition, oxidative stress markers like reduced levels of super dioxide dismutase and elevated levels of malondialdehyde were observed. When these models were treated with genistein, levels of decreased while there was no impact over nitrite content and superoxide dismutase activity. It suggests that the effect of genistein does not occur mainly via its antioxidant capacity or can say genistein might show somehow its antioxidant property by decreasing oxidant production in mitochondria.[42]

Influence of sex

Cognitive improvement was found to be different in different sexes like phytoestrogen-fed females showed positive cognitive improvement than phytoestrogen-free diet females; whereas phytoestrogen-fed males showed cognitive decline than phytoestrogen-free diet males. This sex difference is most likely due to the presence of testosterone in the male brain and the tendency of phytoestrogens to bind to the ERs and alter many of the biological responses that are evoked by physiological estrogens. It was further observed that phytoestrogen intake could increase dementia in males while the rate of dementia found to be lower in females. One major surprisingly observation which was observed during experimentation is when both sexes were placed together in radial arm maze test and supplementing with phytoestrogen-rich diet then males showed better cognitive improvement than females. While when they were placed alone then phyto-rich diet cause decline in cognitive functions in males. The reason behind this is still not known, but it was thought this might be due to sexual dimorphism.[39]

Effect on different-age groups and localities

Phytoestrogens show different effect in different populations of different age group and localities, like In Chinese, people having age 68 years, show effects of dementia when he took higher tofu. In Japanese– Americans, people having age in between 71 and 93 phytoestrogens rich diet show poor cognitive test performance, enlargement of brain ventricles, and lower brain weight (negative effects of tofu consumption). In Indonesian, people having age in between 52 and 98, shows the negative effect of tofu on verbal memory. In rat model of AD disease, when ate tempe (unfermented soyabean), shows positive effects on memory impairment, brain cholinergic activities, and reduce neuroinflammation. Tempe shows positive benefits because of the presence of genistein and daidzein and negative effects due to the presence of cobalamine and folate. Studies also suggest two UK postmenopausal women, having the age of 50–60 years, when consume phytoestrogen-rich diet found positive effects of isoflavone consumption on measures of memory and tests of frontal lobe function like flexibility and planning, after treatment durations of 6–12 weeks.[43] It was found that breast cancer and AD rates in American and European population is seven to eight times higher than the Asian population which takes high soy isoflavones rich diet. It was also observed that approximately 85% of North American postmenopausal women and 70% of European postmenopausal women suffers from hot flashes, while only 35% of Japanese and 18% of Chinese postmenopausal women showed hot flashes. This is due to the high intake diet of soy isoflavones by the Asian population (i.e., Japanese and Chinese population).

Positive impact of phytoestrogen

Phytoestrogens suppress the effects of oxidative damage by mitochondrial dysfunction and thus protect the nigrostriatal dopaminergic neurons for undergoing apoptosis and ultimately AD. Phytoestrogens improve cognitive functions as well as sleep via estrogenic and serotonergic activities.[44]

Phytoestrogen supplementations are observed to help in improving type 2 diabetes by reducing insulin resistance and improves glycemic control in postmenopausal women and also reduce cardiovascular risk by lowering LDL cholesterol, effects as well mediated by estradiol.[45]

A selective combination of phytoestrogens (like genistein + daidzein + equol) in a specific concentration can increase estrogenic activities in cognitive functions and provide evidence for the ERα/β-binding profile. This combination also has the potential to address the compositional complexity and potential antagonistic interactions that occur in soy extracts.[46]

Different molecules show different positive effects such as daidzein and baicalein help in preventing the formation of amyloid-beta peptides.[29] Genistein shows antioxidant, anticancer properties provides relief in postmenopausal conditions, prevents cardiovascular disease, in the brain it improves cognitive functioning, synapse development, and regulates transcription factor of the neurotropic gene in the hippocampal region of adult animals.[47]

Negative impact of phytoestrogen

Phytoestrogens suppress thyroid functions like genistein inhibits the activity of thyroid peroxidase (essential enzyme in the synthesis of thyroid hormone) and sulfotransferase enzymes (needed for iodide re-utilization).[43] They interact with the pathways of thyroid hormone synthesis, metabolism, and hormone transport proteins. Soy consumption aggravates the dysfunction of the thyroid gland in subclinical thyroid cases than in euthyroid.[48]

Phytoestrogens in the form of unfermented soy (tofu) were found to cause negative effects in terms of poor cognitive skills in Chinese, Japanese-Americans, and Indonesian populations of over 68 years of age. Whereas, consumption of Tempe (fermented soy) was found to exert better memory in the elderly Indonesian population. Moreover, reversal of memory impairment, enhancing brain cholinergic activities and in reducing neuro-inflammation was also observed in the rat model of AD disease. It was considered that these positive effects might be due to the presence of more genistein and daidzein in fermented form of soy than unfermented form and also due to the presence of cobalamin and folate.[43]

The negative effects of isoflavones diet on cognitive skills were reported in a US study on Asian and non-Asian women at the beginning of menopausal age and living in the USA, whereas positive effects were depicted in UK studies on postmenopausal women. These cross-cultural variations were reported to be due to the ability to convert isoflavones to their bioactive metabolites and also because of dissimilarities in soy products consumed.[49]

Some concerns regarding feminizing effects of phytoestrogens in the male are reported. However, an updated meta-analysis of the clinical study concluded that neither soy nor isoflavones intake in men influences their reproductive hormones.[50]

Why phytoestrogenic drugs wins over hormone replacement therapy for neuroprotection in Alzheimer's disease and its clinical implications

According to the Women's Health Initiative Memory Study, the overall risks associated with estrogen-containing hormone therapy (HT) outweighs its potential benefits. Long-term administration of HT has been linked with an increased risk of breast cancer, stroke in women receiving either estrogen-alone or combined therapy.

In recent years, substantial research has focused on the development of alternative approaches to HT that do not elicit any adverse effects but have equally potent estrogenic benefits. The search for these alternatives led researchers to focus on plant-based natural molecules which cannot elicit any serious side effects.

A prominent study named SOPHIA was conducted on postmenopausal women. After 12 weeks of daily Isoflavone supplementation (110 mg/day) to women, their cognitive functions were assessed to find out that the treatment significantly improved performance in the recall of pictures and sustained attention and planning tasks.[51] In another case–control study, men were supplemented with dietary isoflavone in form of soya-containing foods, like soya milk drinks or puddings, soya flour, or soybeans for 10 weeks (100 mg/day), indicated improved cognitive function. Spatial memory in men was observed to be significantly enhanced after having daily supplementation of oral isoflavone (116 mg) in form of capsules (68 mg daidzein, 12 mg genistein, 36 mg glycitein) for 6 weeks.[52]

Recently, in 2020, animal studies revealed that genistein alleviates AD-related pathologies including Aβ deposition and the levels of hyper-phosphorylated tau protein apart from improving brain insulin signaling in diabetes mellitus-induced brain damage.[53] Similar results were reported by Park et al. wherein they showed that genistein exerts a protective effect against neurodegeneration in mice.[54] These animal studies proved that cell growth and survival, synaptic plasticity, and cognitive functions are significantly improved by phytoestrogen supplementation in animal models.

Thus, the influence of phytoestrogens on cognitive functions of animal and human models hint at the potential phytoestrogens hold in being a preventive strategy for cognitive decline and neurodegeneration associated with diseases like Alzheimer's (AD) in both men and women.

Simultaneously, few experiments have revealed that neuroprotective effects induced by various phytoestrogens and their derivatives are of much lower magnitude as opposed to those induced by the female gonadal 17 β-estradiol.

In an experiment, the combination of genistein, daidzein, and equol resulted in the greatest binding selectivity (30% increased) for Erβ. Apart from overall improved safety profile when compared with single or other combined formulations, this formulation showed (1) an enhanced survival of primary neurons against toxic insults; (2) an enhanced promotion of neural proactive defense mechanisms against neurodegeneration, including mitochondrial function and β-amyloid degradation. These observations suggested that specific phytoestrogens in combination could be deployed for long-term safe use with an implication of preventing cognitive decline and providing neuroprotection to AD patients.[46] Hence, the development of an effective phytoestrogen formulation would benefit both women and men to improve neurological health and reduce the risk of AD.

Thus, the direct clinical implication of using such phytoestrogenic molecules as drugs would be the improvement in cognitive abilities, less dependence of the patient on other people for day-to-day activities, improved memory in Alzheimer patients, with minimum or no side effects. Hence, phytoestrogen can be safer and equally potent alternatives to conventional estrogen therapy.

Clinical trials, drug development and their potential safety (Up till 2020)

A randomized, double-blinded, placebo-controlled clinical trials of resveratrol for AD provided evidence that the use of phytoestrogen is safe and well tolerated. The study also depicted the ability of resveratrol in the reduction of cerebrospinal fluid as well as plasma Aβ 40 levels.[55] In another similar type of the study, Schneider et al. developed Phyto selective estrogen receptor beta (ERβ) modulator, a combination of three Phytoestrogenic ER β-specific modulators S-equol, genistein, and daidzein in equal parts and tested on noncognitively impaired perimenopausal women of the age of 45–60 years. They reported that this formulation induced a synergistic rather than antagonistic effect and can thus, serve as an effective and safe alternative to hormone replacement therapy.[56]

Many randomized controlled trials have been performed by various groups of researchers on groups of people differing on the basis of age, geographic region using different combinations of phytoestrogenic molecules, dosage, and duration of treatment. After the treatment, cognitive tests were performed on these groups considering various domains of cognitive functions such as verbal memory, visual memory, attention, language, and processing speed. When different combination ratios of Genistein, Daidzein, Glycitein were tested in Brazil (Santos-Galduro'z et al. {2010})[57] and US patients (Henderson et al. {2012})[58], they showed improved verbal recall and facial recall, respectively.[59]

S-equol (AUS-131), a Phytoestrogenic drug candidate sponsored by Ausio pharmaceuticals underwent Phase 2 clinical trials (May 2017–Jun 2020) for its therapeutic potential of improving synaptic functioning and neuronal survival by acting as an agonist of nonhormonal ER-β located on mitochondria.[60]

Another agent bioactive dietary polyphenol preparation (BDPP) proposed as disease-modifying therapy was under Phase 2 clinical trials from Jun 2015 to 2020. Being a combination of grape seed polyphenolic extract and resveratrol, BDPP was developed by Johns Hopkins University, Mount Sinai School of Medicine for its therapeutic potential of preventing amyloid and tau aggregation.[60]


  Conclusion Top


Phytoestrogen compounds are already recommended by doctors worldwide as health-promoting food components or supplements due to their anti-oxidant properties. Various studies suggest that consuming foods rich in phytoestrogens reduces the risk of symptoms in menopause, cardiovascular disease, and many types of cancer, including prostate cancer and uterine cancer.

Since dietary intake of isoflavones has been linked to reduced risk of cerebral infarction and myocardial infarction in Japanese women. This suggests that phytoestrogen usage can be taken as an alternative method other than estrogen replacement therapy to prevent AD-related symptoms. Apart from the positive influence, some negative effects of phytoestrogens over certain age group and localities people has been reported. However, this may be due to imbalance or differences in their hormonal level and diet.

In our view, the pros of consuming phytoestrogen-rich compounds out-number the cons thus, the scientific groups must not neglect the therapeutic potential of phytoestrogens, particularly isoflavones in preventing AD-related symptoms.

In view of the above findings, the authors conclude that phytoestrogens can be used as a potent exogenous estrogen therapy alternative to premenopausal, postmenopausal, and menopausal women as well as to those women having low levels of endogenous estrogen due to the low estrogen phase of their monthly female reproductive cycles or due to intake of some medicines, like Tamoxifen, etc. [61,62]

At present, some Phytoestrogenic drugs like Biochanin A, Formononetin are under clinical trials for treating postmenopausal osteopenia. Profound studies have also confirmed the health benefits of phytoestrogens like genistein in relieving hot flashes, rebalancing hormone levels, and in fighting hormonal cancers like breast cancer, prostate cancer.[63]

However dedicated studies are required to study the neuroprotective functions of phytoestrogen in AD models, and the possible side effects, if any, of using the same as an alternative to estrogen therapy. Furthermore, the exact combination, potency, and concentration of phytoestrogenic drugs suitable to the human body need to be determined.

Since, at present, US FDA does not regulate the phytoestrogenic molecules hence, potential medical research using these molecules remains slow-paced.

Yet, further studies are still required to understand why the action of phytoestrogens differs with different geographical locations in different sexes and different age groups. This would be helpful in establishing phytoestrogens either as alternative or as supplement to current estrogen therapy for the cure of memory impairment and cognitive decline during AD. Clinical trials have generally indicated no serious side effects in animal models. However, in many cases, the results are controversial, and the neuroprotective and other beneficial effects of phytoestrogens require intense research.

Acknowledgments

Authors Dr. Varsha Baweja, Himanshu, Akreti Tandon, Muskan Goyal and Ruby Mishra are sincerely indebted to Prof. Rajiv Aggarwal, the Principal, Deshbandhu College, University of Delhi for encouragement and all the support rendered during this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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