NEUROPROTECTIVE COMPOSITION COMPRISING CAFFEIC ACID FOR TREATING ESTROGEN-DEFICIENT COGNITIVE DECLINE

Abstract

A neuroprotective composition is disclosed for treating cognitive impairment linked to estrogen deficiency. The composition comprises Caffeic Acid (CA) or its pharmaceutically acceptable salt or ester, combined with one or more neuroprotective agents chosen from antioxidants, cholinergic agents, and Nrf2 pathway activators. This composition is designed to improve cognitive function by promoting cholinergic neurotransmission, reducing oxidative stress, and activating the Nuclear Factor Erythroid-Derived 2-Like 2 (Nrf2) pathways in the brain.

Specification

Description:NEUROPROTECTIVE COMPOSITION COMPRISING CAFFEIC ACID FOR TREATING ESTROGEN-DEFICIENT COGNITIVE DECLINE

FIELD OF THE INVENTION
The present invention relates to neuroprotective compositions and methods for alleviating cognitive decline associated with estrogen deficiency. Specifically, it pertains to compositions containing Caffeic Acid (CA) and their use in preventing and treating cognitive impairments in postmenopausal conditions, with an emphasis on cholinergic function and oxidative stress regulation.

BACKGROUND OF THE INVENTION
Estrogen deficiency is known to exert profound effects on the central nervous system, particularly in areas related to memory, learning, and cognition. A number of researches have established a strong link between estrogen levels and cognitive health, with estrogen acting as a neuroprotective agent that promotes cholinergic neurotransmission, reduces oxidative stress, and regulates inflammation. However, in the absence of estrogen, these protective mechanisms become compromised, leading to cognitive deficits that often manifest in the form of Alzheimer's Disease (AD) or Mild Cognitive Impairment (MCI).
The primary mechanisms underlying estrogen-deficient cognitive decline are associated with two main issues: cholinergic dysfunction and increased oxidative stress. Cholinergic neurotransmission, which relies on acetylcholine (ACh) to transmit signals in the brain, plays a crucial role in memory formation, spatial cognition, and overall cognitive performance. The decline in estrogen disrupts this system, leading to a reduction in ACh levels and an increase in the activity of acetylcholinesterase (AChE), the enzyme responsible for breaking down ACh. This reduction in cholinergic function has been closely linked with the symptoms of Alzheimer's and other forms of dementia.
Simultaneously, estrogen deficiency also induces an increase in oxidative stress within the brain. Oxidative stress results from an imbalance between reactive oxygen species (ROS) production and the antioxidant defense systems. In estrogen-deficient states, the brain's ability to neutralize ROS diminishes, leading to cellular damage, lipid peroxidation (LOP), and neuronal dysfunction. Studies have shown that oxidative stress significantly contributes to cognitive decline, as it damages neural tissue and promotes the aggregation of proteins like Amyloid Beta (Aß), a hallmark of Alzheimer's pathology.
Hormone Replacement Therapy (HRT) has been a standard approach to counteract the cognitive impacts of estrogen deficiency, yet HRT carries several health risks, including cardiovascular disease (CVD) and certain cancers, limiting its use in many patients. Therefore, there is a pressing need for alternative treatments that address estrogen-deficient cognitive decline without the associated risks of HRT.
In light of this need, the present invention introduces Caffeic Acid (CA) as a promising non-hormonal neuroprotective agent for treating cognitive impairment in estrogen-deficient subjects. CA is a naturally occurring phenolic compound found in various plants, known for its potent antioxidant and anti-inflammatory properties. Research suggests that CA can positively influence cognitive health by modulating oxidative stress pathways and improving cholinergic function. CA has demonstrated the ability to activate the Nrf2 signaling pathway, a critical regulator of antioxidant responses, thereby helping to counteract the oxidative damage associated with estrogen deficiency.

The present invention provides a CA-based composition for improving cognitive function in subjects experiencing estrogen-deficient conditions. The invention leverages the synergistic effects of CA's antioxidant, anti-inflammatory, and neuroprotective properties to enhance cognitive performance, modulate cholinergic function, and reduce oxidative stress through the Nrf2 pathway in order to overcome the limitations of existing solutions in the domain.

OBJECTIVE OF THE INVENTION
The objective of the present invention is to provide a neuroprotective composition comprising Caffeic Acid (CA) for treating cognitive impairments associated with estrogen deficiency, particularly in postmenopausal women.
The composition of the present invention aims to address key neurodegenerative risks linked to estrogen deficiency by enhancing cholinergic function and reducing oxidative stress in the brain.
The present invention targets the Nuclear Factor Erythroid-Derived 2-Like 2 (Nrf2) pathways to activate intrinsic antioxidant defenses and improve acetylcholine levels in key brain regions affected by cognitive decline, such as the hippocampus, prefrontal cortex, and amygdala.
Further, the present invention seeks to offer an effective, non-hormonal alternative to conventional hormone replacement therapies (HRTs), reducing risks of systemic side effects while providing a targeted approach for neuroprotection.
The present invention also aims to lay a foundation for future clinical application in managing cognitive deficits related to estrogen loss, ultimately supporting improved quality of life for individuals facing neurocognitive risks due to hormonal changes.

BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying figures illustrate several embodiments of the disclosure and, together with the description, serve to explain the principles of the disclosure. One of ordinary skill in the art readily recognizes that the embodiments illustrated in the figures are merely exemplary, and are not intended to limit the scope of the present disclosure.
FIG. 1 illustrates an exemplary diagrammatic representation of an exemplary experimental hypothesis of the present disclosure.
FIG. 2 illustrates an exemplary diagrammatic representation of an exemplary experimental protocol of the present disclosure.
FIG. 3 discloses effect of Caffeic acid on bilateral ovariectomy induced changes on the body weight (A) Estradiol level (B) on Day-1 and Day-60 and Uterus weight (C) on Day-60.
FIG. 4 discloses effect of Caffeic acid on bilateral ovariectomy induced changes in learning and memory formation in terms of escape latency from Day-56 to Day-59 (A), time spent in target quadrant (B), Percentage of total distance travelled in target quadrant (C) and Swimming speed (D) on Day-60 of MWM test protocol.
FIG. 5 discloses effect of Caffeic acid on bilateral ovariectomy induced changes in spontaneous alteration behavior (A) and Total arm entries (B) on Day-60 during the Y maze task.
FIG. 6 discloses effect of Caffeic acid on bilateral ovariectomy induced alteration in cholinergic functions in terms of level of ACh (A) in different memory sensitive brain regions.
FIG. 7 discloses effect of Caffeic acid on bilateral ovariectomy induced changes in the level of LPO (A) and activities of SOD (B) and CAT (C) in selected brain regions.
Further areas of applicability of the present disclosure will become apparent from the complete description provided hereinafter.
It should be understood that the complete description of exemplary embodiments is intended for illustration purposes only and is, therefore, not intended to necessarily limit the scope of the present disclosure.

DETAILED DESCRIPTION OF THE INVENTION
The present invention is more particularly described in the following present specification that is intended as illustrative only since numerous modifications and variations therein will be apparent to those skilled in the art. Various embodiments of the present disclosure are now described in detail. Referring to the drawings, like numbers, if any, indicate like components throughout the views. As used in the description herein and throughout the claims that follow, the meaning of "a", "an", and "the" includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein and throughout the claims that follow, the meaning of "in" includes "in" and "on" unless the context clearly dictates otherwise. Moreover, titles or subtitles may be used in the specification for the convenience of a reader, which shall have no influence on the scope of the present disclosure. Additionally, some terms used in this specification are more specifically defined below.
The terms used in this specification generally have their ordinary meanings in the art, within the context of the present disclosure, and in the specific context where each term is used. Certain terms that are used to describe the present disclosure are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner regarding the description of the disclosure.
For convenience, certain terms may be highlighted, for example using italics and/or quotation marks. The use of highlighting has no influence on the scope and meaning of a term; the scope and meaning of a term are the same, in the same context, whether or not it is highlighted. It will be appreciated that the same thing can be said in more than one way. Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein, nor is any special significance to be placed upon whether or not a term is elaborated or discussed herein. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms.
The use of examples anywhere in this specification including examples of any terms discussed herein is illustrative only, and in no way limits the scope and meaning of the disclosure or of any exemplified term. Likewise, the disclosure is not limited to various embodiments given in this specification.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In the case of conflict, the present document, including definitions will control.
As used herein, "around", "about" or "approximately" shall generally mean within 20 percent, preferably within 10 percent, and more preferably within 5 percent of a given value or range. Numerical quantities given herein are approximate, meaning that the term "around", "about" or "approximately" can be inferred if not expressly stated.
As used herein, "plurality" means two or more.
As used herein, the terms "comprising," "including," "carrying," "having," "containing," "involving," and the like are to be understood to be open-ended, i.e., to mean including but not limited to.
As used herein, the phrase at least one of A, B, and C should be construed to mean a logical (A or B or C), using a non-exclusive logical OR. It should be understood that one or more steps within a method may be executed in a different order (or concurrently) without altering the principles of the present disclosure.
The detailed description of the present invention provides an in-depth understanding of the therapeutic potential of Caffeic Acid (CA) in addressing estrogen-deficient cognitive impairment. The present invention centers on a composition containing CA, which is administered to subjects to ameliorate cognitive deficits caused by estrogen deficiency. The neuroprotective effects of the composition may be achieved by targeting cholinergic dysfunction and oxidative stress, two central factors in cognitive decline. The present invention may be relevant, primarily but not limited to, postmenopausal women who are at increased risk of neurodegenerative diseases, including but not limited to Alzheimer's Disease (AD), due to reduced estrogen levels.
The present disclosure of the invention further provides a composition comprising CA, a phenolic compound with established antioxidant and anti-inflammatory properties, and its administration as a therapeutic approach for estrogen-deficient neurodegenerative conditions, focusing on cognitive impairments linked to Alzheimer's Disease (AD) and other related disorders. The invention leverages CA's ability to improve cholinergic function, reduce oxidative stress, and modulate critical neuroprotective pathways, positioning it as an alternative to hormone replacement therapy (HRT) for postmenopausal women at risk for cognitive decline.

Mechanism of Action and Nrf2 Pathway Modulation
The present invention further provides neuroprotection in estrogen-deficient conditions by modulating the Nuclear Factor Erythroid-Derived 2-Like 2 (Nrf2) signaling pathway. Nrf2 is a transcription factor that plays a critical role in cellular defense against oxidative stress. Under normal conditions, Nrf2 remains inactive, bound to its inhibitor protein Kelch-like ECH-associated protein 1 (Keap1). However, in response to oxidative stress, Nrf2 is released, translocate to the nucleus, and initiates the transcription of antioxidant response elements (AREs). These AREs encode various antioxidant enzymes, such as Superoxide Dismutase (SOD) and Catalase (CAT), which protect cells from oxidative damage. By activating the Nrf2 pathway, CA enhances the body's intrinsic antioxidant defenses, thereby reducing oxidative stress in estrogen-deficient subjects.

Experimental Design and Validation of Neuroprotective Effects
The neuroprotective effects of the present invention may be evaluated through a rigorously designed experimental study using an ovariectomy-induced estrogen-deficient rat model, a widely recognized method for simulating the postmenopausal condition in female humans.
For the purpose of this invention, the Caffeic acid, 17-ß-estradiol, and Trigonelline are acquired from Sigma-Aldrich Pvt. Ltd. Bangalore, India. All the chemicals and reagents used in the evaluation are of high quality and according to industrial standards.
For the purpose of this evaluation, preferably but not limited to, thirty-six female Wistar rats may be used, divided into six distinct groups to comprehensively assess the neurochemical and cognitive impacts of CA in estrogen-deficient conditions.
The experimental groups included:
• Control Group: Normal, non-ovariectomized rats with no treatment.
• Sham Group: Rats that underwent a surgical procedure similar to the Ovx group but without ovary removal.
• Ovx Group: Ovariectomized rats that are not administered any treatment, serving as the estrogen-deficient baseline.
• Ovx + CA Group: Ovariectomized rats administered CA at a dose in a range of 1 mg/kg to 500mg/kg, preferably 40 mg/kg.
• Ovx + Trigonelline + CA Group: Ovariectomized rats administered both Trigonelline (an Nrf2 inhibitor) and CA, allowing evaluation of Nrf2 pathway involvement.
• Ovx+Estradiol Group: Ovariectomized rats administered 17-ß-estradiol at a dose of 2.5 mg/kg to compare CA's effects against a standard hormone therapy.
These groups may receive their respective treatments daily over a period of 60 days following ovariectomy, except for the Control and Sham groups, which received normal saline.
Figure 3 discloses effect of bilateral ovariectomy on subject Body (A) and Estradiol levels (B) on Day-1 and Day-60 and Uterus weight (C) on Day-60. Statistical analysis reveals that there is significant difference in body weight and estradiol level among the groups ([F (5, 60) = 4.6; p < 0.05] and [F (5, 60) = 24.9; p < 0.05] respectively) and ([F (1, 60) = 29.7; p < 0.05] and [F (1, 60) = 66.5; p < 0.05] respectively). Further, there is significant interaction in between the body weight and Estradiol level ([F (5, 60) = 3.3; p < 0.05] and [F (5, 60) = 17.2; p < 0.05] respectively). Post-hoc test showed that Caffeic acid significantly attenuated the increased body weight and estradiol level on Day-1 and Day-60 in ovariectomized female rats. However, the Trigonelline reduces the therapeutic effect of Caffeic acid in ovariectomized rat.
Caffeic acid attenuated the decreased uterus weight ([F (5, 30) = 59.9; p < 0.05]) on Day-60, similar to the Estradiol treatments in ovariectomized rat. However, Trigonelline blocks the therapeutic effect of Caffeic acid.
All values are mean ± SEM (n = 6). ap<0.05 compared to Sham, bp<0.05 compared to Ovx, cp<0.05 compared to Ovx+CA, dp<0.05 compared to Ovx+Trig+CA, ep<0.05 compared to Ovx+Estradiol.
Further, behavioral and biochemical assessments may be conducted after the treatment period to evaluate the cognitive and neurochemical effects of CA. The behavioral assessments may be focused on evaluating learning, memory, and spatial cognition through the Morris Water Maze (MWM) and Y-maze tests.

Behavioral Assessments: Morris Water Maze and Y-Maze Tests
The cognitive effects of CA administration may be assessed through two key behavioral tests: the Morris Water Maze (MWM) and Y-maze tests. These assessments are designed to evaluate spatial learning, memory, and working memory in the test subjects, providing a robust measure of cognitive function.
1. Morris Water Maze Test (MWM): The MWM test is a widely used tool for assessing spatial learning and memory by measuring the time taken by a subject to locate a hidden platform in a water maze. In a behavioral assessment of the present invention, an MWM test is administered over five days, from Day 56 to Day 60 of the experimental regimen, with the escape latency (time taken to find the platform) and time spent in the target quadrant recorded as indicators of cognitive performance. Results indicated that the Ovx+CA group demonstrated significantly reduced escape latency and increased time spent in the target quadrant compared to the Ovx group, suggesting that CA administration effectively mitigates cognitive impairment induced by estrogen deficiency.
Figure 4 represents effect of Caffeic acid on learning and memory formation in ovariectomized female rats in terms of escape latency on Day-56 to Day-59 (A), time spent in target quadrant (B), percentage of total distance travelled in target quadrant (C) and swimming speed (D) on Day-60 of Morris water maze test paradigm. Repeated measure of two-way ANOVA revealed that there is significant difference in the escape latency among groups ([F (5, 120) = 31.8; p < 0.05] and [F (3, 120) = 84.2; p < 0.05]). Further, there is significant interaction between groups and day [F (15, 120) = 3.1; p < 0.05]. Post-hoc test showed that Caffeic acid attenuated increase in the escape latency on day-56 of MWM task treatments ([F (5, 90) = 74.7; p <0.05])
and this effect was persisted to day-59. However, trigonelline administration reverse the therapeutic effect of Caffeic acid in ovariectomized rats.
Caffeic acid attenuated the decreased in time spent in target quadrant ([F (5, 30) = 33.6; p < 0.05]) and percentage of total distance travelled in target quadrant ([F (5, 30) = 29.4; p < 0.05]) on the day-60 of Morris water maze paradigm similar to effect of estradiol in ovariectomized rat. However, trigonelline significantly abolished therapeutic effect of Caffeic acid on time spent on target quadrant and percentage distance travelled in target quadrant during the MWM test protocol. Further, there is no significant in swimming speed ([F (5, 30) = 0. 4; p > 0.05]) of the rats among the group.
All values are mean ± SEM (n = 6). ap<0.05 compared to Sham, bp<0.05 compared to Ovx, cp<0.05 compared to Ovx+CA, dp<0.05 compared to Ovx+Trig+CA, ep<0.05 compared to Ovx+Estradiol.
2. Y-Maze Test: Further, in addition to the MWM test, the Y-maze test may be conducted on Day 60 to evaluate working memory through spontaneous alternation behavior, which is indicative of spatial memory. In the further behavioral assessment of the present invention, Enhanced alternation behavior was observed in the Ovx+CA group compared to the Ovx group, supporting CA's role in improving working memory functions. Notably, these cognitive benefits were reversed when CA was co-administered with Trigonelline, confirming the involvement of the Nrf2 pathway in CA's neuroprotective mechanism.
Figure 5 discloses effect of Caffeic acid on alteration of spatial memory formation in terms of spontaneous alteration behavior (A) and Total arm entries (B) in ovariectomized rat during Y maze test paradigm. One-way analysis revealed that there is significant difference in spontaneous alteration behavior ([F (5, 30) = 7.1; p < 0.05]) among groups. Post hoc test reveals that the repeated treatment of Caffeic acid significantly improves the spontaneous alteration behavior during the Y-maze test on day-60. However, trigonelline reverse the therapeutic effect of caffeic acid. Further, there is no significant difference in total arm entry ([F (5, 30) = 0.1; p > 0.05]) among the groups.
All values are mean ± SEM (n = 6). ap<0.05 compared to Sham, bp<0.05 compared to Ovx, cp<0.05 compared to Ovx+CA, dp<0.05 compared to Ovx+Trig+CA, ep<0.05 compared to Ovx+Estradiol.

Biochemical Analysis
To gain a deeper understanding of the neurochemical impacts of CA, a series of biochemical analyses may be conducted, focusing on cholinergic function and oxidative stress markers in brain regions implicated in cognitive functions. The analyses may include:
1. Cholinergic Function Analysis: Estrogen deficiency has been linked to cholinergic dysfunction, which is characterized by decreased acetylcholine (ACh) levels in critical brain regions such as the hippocampus (HIP), prefrontal cortex (PFC), and amygdala (AMY). The present invention demonstrates that CA administration significantly increased ACh levels in these brain regions, effectively counteracting the cholinergic deficits induced by estrogen deficiency. This improvement is crucial, as ACh is essential for cognitive processes such as learning and memory, and its enhancement by CA highlights the therapeutic potential of the invention for neurodegenerative diseases.
2. Oxidative Stress Markers: Estrogen deficiency is known to exacerbate oxidative stress, as evidenced by increased lipid peroxidation (LPO) and reduced activities of antioxidant enzymes. The administration of CA resulted in a marked decrease in LPO levels, along with increased activities of key antioxidant enzymes such as SOD and CAT. These biochemical improvements underscore CA's ability to fortify the brain's antioxidant defense system, effectively mitigating oxidative damage associated with estrogen deficiency.
3. Role of Nrf2 Pathway Inhibition with Trigonelline: To further elucidate the mechanism of action, one experimental group received Trigonelline, an Nrf2 pathway inhibitor, in conjunction with CA. The results showed that Trigonelline administration reversed the cognitive and biochemical benefits of CA, including the reduction in ACh levels, increased LPO, and decreased SOD and CAT activities. These findings confirm that the neuroprotective effects of CA are mediated at least in part through the Nrf2 pathway, as its inhibition resulted in the loss of the therapeutic benefits.
Figure 6 discloses effect of Caffeic acid on cholinergic dysfunctions in terms of activity of level of ACh (A) activity in ovariectomized rat HIP, PFC and AMY brain regions. Repeated analysis revealed that there is significant difference in the level of ACh among the groups ([F (5, 90) = 50.0; p < 0.05] and [F (2, 90) = 18.0; p < 0.05] respectively). Further there is insignificant interaction between treatments and brain regions in the level of Ach [F (10, 90) = 0.2; p > 0.05]. However, trigonelline blocks the therapeutic effect of Caffeic acid in ovariectomized rat memory sensitive brain regions.
All values are mean ± SEM (n = 6). ap<0.05 compared to Sham, bp<0.05 compared to Ovx, cp<0.05 compared to Ovx+CA, dp<0.05 compared to Ovx+Trig+CA, ep<0.05 compared to Ovx+Estradiol.
Figure 7 discloses effect of Caffeic acid on altered level of (A) LPO and the activities of (B) SOD and (C) CAT in ovariectomized rat among HIP, PFC and AMY brain regions. Statistical analysis revealed that there was significant difference in the level of LPO and activities of SOD and CAT among the treatments [(F (5, 90) = 71.0; p < 0.05), (F (5, 90) = 70.6; p < 0.05) and (F (5, 90) = 55.4; p < 0.05) respectively]. Further there is significant difference in the level of LPO and activities of SOD and CAT among brain regions [(F (2, 90) = 160.3; p < 0.05), (F (2, 90) = 14.2; p < 0.05) and (F (2, 90) = 3.3; p < 0.05) respectively]. Further, there is insignificant interaction between the treatment and brain regions in ameliorating oxidative stress [(F (10, 90) = 3.1; p >0.05) and (F (10, 90) = 0.2; p > 0.05) and (F (10, 90) = 0.5; p > 0.05) respectively]. However, trigonelline blocks the therapeutic effect of the Caffeic acid in ovariectomized rat among HIP, PFC and AMY brain regions.
All values are mean ± SEM (n = 6). ap<0.05 compared to Sham, bp<0.05 compared to Ovx, cp<0.05 compared to Ovx+CA, dp<0.05 compared to Ovx+Trig+CA, ep<0.05 compared to Ovx+Estradiol.
Therefore, the present invention represents a substantial advancement in treating estrogen-deficient cognitive impairment by providing a non-hormonal neuroprotective composition containing Caffeic Acid (CA). Through Nrf2 pathway activation, CA enhances antioxidant defenses, reduces oxidative stress, and improves cholinergic function, effectively reversing cognitive deficits associated with estrogen deficiency. The disclosed invention offers a safe, non-hormonal alternative to HRT for managing postmenopausal cognitive decline, with potential applications for a range of neurodegenerative conditions associated with estrogen loss.
The present invention, therefore, provides a robust foundation for future clinical research aimed at validating these findings in human populations and developing therapeutic interventions that support cognitive health in postmenopausal women.
The embodiments described hereinabove are exemplary of the present invention. The disclosure may enable those skilled in the art to make and use embodiments having alternative elements that likewise correspond to the elements of the invention. The intended scope of the invention may thus include other embodiments that do not differ or that insubstantially differ from the literal language of the invention. However, the scope of the present invention is accordingly defined as set forth in the present complete specification.
, Claims:We Claim;

1. A neuroprotective composition for treating cognitive impairment associated with estrogen deficiency, the composition comprising:
Caffeic Acid (CA), or a pharmaceutically acceptable salt or ester thereof, and
one or more additional neuroprotective agents selected from the group consisting of antioxidants, cholinergic agents, and Nrf2 pathway activators,
wherein said composition is administered to improve cognitive function by enhancing cholinergic neurotransmission, reducing oxidative stress, and modulating the Nuclear Factor Erythroid-Derived 2-Like 2 (Nrf2) signaling pathway in a subject's brain.

2. The composition as claimed in claim 1, wherein the neuroprotective agent is selected from antioxidants group of Superoxide Dismutase (SOD) enhancers, Catalase (CAT) enhancers, or agents that promote endogenous production of these enzymes.

3. The composition as claimed in claim 1, wherein the cholinergic agent is selected from compounds that increase acetylcholine (ACh) levels or prevent ACh degradation in the hippocampus, prefrontal cortex, and amygdala.

4. The composition as claimed in claim 1, wherein the additional Nrf2 pathway activator is selected from compounds capable of releasing Nrf2 from Keap1, facilitating its translocation to the nucleus to activate antioxidant response elements (AREs) in the brain.
5. The composition as claimed in claim 1, wherein the composition is formulated as a pharmaceutically acceptable oral dosage form of tablets, capsules, or liquid solutions.

6. The composition as claimed in claim 1, wherein the composition is administered to mitigate cognitive impairment related to neurodegenerative diseases associated with estrogen deficiency, including Alzheimer's Disease (AD).

7. The composition as claimed in claim 1, wherein the Caffeic Acid (CA) content in the composition ranges between 1 mg to 500 mg per dosage unit, with the neuroprotective agents in an amount effective to enhance the Nrf2 pathway's antioxidant response.
8. The composition as claimed in claim 1, wherein the Caffeic Acid (CA) content in the composition ranges between 40 mg to 80 mg per dosage unit, with the neuroprotective agents in an amount effective to enhance the Nrf2 pathway's antioxidant response.

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