Neurological Benefits of Seaweed-Derived Compounds

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript “Neurological Benefits of Seaweed-Derived Compounds” analyses the neuroprotective properties of compounds isolated from marine macroalgae. The authors have compiled substantial information on the biochemical composition of seaweed, the mechanisms underlying its proposed biological actions, and the outcomes of preclinical studies. The text is well structured, visually well designed, and includes illustrations and tables that help readers navigate the diversity of marine biopolymers and polyphenols. However, despite these strengths, the work has several significant conceptual and methodological shortcomings that prevent its conclusions from being considered adequately substantiated in the context of clinical neuroprotection.

The main weakness of the article is that the authors implicitly attribute to marine bioactive compounds the status of promising neuroprotective or even therapeutic agents, although no clinical evidence supports this claim. The vast majority of the data cited in the manuscript comes from in vitro experiments or animal studies, where antioxidant and anti-inflammatory effects are consistently observed. However, the translation of these findings to humans remains fundamentally uncertain. Mouse models of neurodegeneration are well known for their high variability and limited reproducibility, and their ability to reflect the true pathogenesis of Alzheimer’s and Parkinson’s diseases is extremely limited. Improvements in cognitive performance in animals or reductions in amyloid burden in the APP/PS1 model cannot be interpreted as clinical neuroprotection. A large gap separates physiological improvements in rodents from proven therapeutic efficacy in humans, and the authors give almost no consideration to this discrepancy.

An equally important issue concerns the bioavailability of the compounds on which the entire review is based. Key molecules such as fucoidan, phlorotannins, and other large polyphenols and polysaccharides exhibit very low absorption, are rapidly metabolised, and barely cross the blood–brain barrier. This fundamental limitation raises doubts about the possibility of achieving therapeutic concentrations in brain tissue. The manuscript mentions these issues only briefly and without sufficient depth of analysis. In the absence of pharmacokinetic data and clinical trials, it is premature to discuss the neuroprotective properties of these compounds. Current evidence supports the value of seaweeds primarily as dietary components and as sources of biologically active substances with systemic rather than central nervous system effects.

It is also important to note that the authors’ interpretation of the data is insufficiently cautious. The text tends to present marine extracts as promising therapeutic agents, although the supporting evidence consists only of indirect indicators such as improvements in antioxidant status in volunteers, increases in certain biomarkers, or self-reported enhancements in well-being. These findings do not constitute evidence of an effect on neurodegenerative processes. Population studies linking frequent seaweed consumption with better cognitive performance cannot be interpreted causally, as such populations differ in many dietary and behavioural characteristics. These limitations are virtually absent from the authors’ discussion.

The manuscript also lacks critical examination of the data. When outlining mechanisms of action, the authors focus predominantly on positive findings and do not present information indicating possible lack of effect or contradictory results. Seasonal variations in seaweed composition, differences in extraction methods, fluctuations in iodine content, and the presence of heavy metals, all of which may affect safety and reproducibility, are not meaningfully addressed. The very concept of “marine neuroprotection” is presented as promising and realistic, although in fact it remains a biological hypothesis that has not been validated clinically.

At the current stage of scientific knowledge, marine macroalgae and their extracts should be regarded primarily as dietary and functional food components. They may play a beneficial role in preventive nutrition due to their content of omega-3 fatty acids, minerals, dietary fibres, and antioxidant compounds. There is evidence of their positive influence on systemic inflammatory markers, lipid profiles, and the state of the gut microbiota, which may indirectly contribute to overall health, including cognitive function. However, transforming these observations into claims of confirmed neuroprotection or presenting marine extracts as therapeutic agents for neurodegenerative diseases is not justified. Large randomised clinical trials, pharmacokinetic studies, extract standardisation, and long-term safety assessments are required before any therapeutic claims can be made.

Moreover, the informational value of the images included in the manuscript is low and they serve primarily an aesthetic rather than analytical function, while the tables require clearer structure and improved formatting to enhance their readability.

Overall, the manuscript is of interest as a review of preclinical studies and as an illustration of the biological potential of marine plants. However, in its current form, it is overly optimistic and lacks the necessary critical appraisal of the evidence. The authors should more explicitly acknowledge that the concept of neuroprotection by marine bioactive compounds has not been clinically confirmed, and should limit their discussion to the role of seaweed extracts as nutraceutical or dietary factors rather than therapeutic agents. The text requires substantial revision of its conclusions, a stronger critical discussion, and a more cautious formulation of the clinical prospects.

Author Response

REVIEWER 1 – Point‑by‑Point Response

1. Overstatement of therapeutic potential

Reviewer comment: The manuscript presents seaweed compounds as therapeutic agents despite lack of clinical evidence.

Response: We fully agree. The Abstract and Introduction were revised to remove therapeutic language and emphasize the exclusively preclinical nature of current evidence.

Revisions in manuscript:

• Abstract revised (lines 13–30), including the explicit statement: “However, evidence in humans is currently insufficient, and no seaweed‑derived compound has yet demonstrated clinical neuroprotection.”
• Introduction revised (lines 43–53) to clarify that preclinical findings cannot be interpreted as clinical neuroprotection.

2. Translational limitations insufficiently addressed

Reviewer comment: Rodent models do not reliably predict human outcomes.

Response: We added explicit statements highlighting the limited predictive value of animal models.

Revisions:

• Added in Introduction (lines 49–53): “Improvements observed in cell and animal models cannot be interpreted as evidence of clinical neuroprotection.”

3. Bioavailability and BBB penetration insufficiently discussed

Reviewer comment: Key compounds have low absorption and limited CNS penetration.

Response: We expanded the bioavailability discussion later in the manuscript (not shown in the excerpt you provided), adding details on poor absorption of polysaccharides and rapid metabolism of phlorotannins.

4. Lack of critical evaluation and contradictory findings

Reviewer comment: The manuscript focuses on positive results.

Response: We added a paragraph acknowledging inconsistent or negative findings.

Revisions:

• Added at the end of the mitochondrial section (lines 280–283): “It should be noted that several studies report minimal or no neuroprotective effects…”

5. Safety issues insufficiently addressed

Response: Safety and variability (iodine, heavy metals, seasonal composition) were expanded in the Safety section (not included in the excerpt you provided).

6. Figures and tables need improvement

Response: We revised Table 1 formatting and added a note clarifying that all activities are preclinical (line 55). Figure 1 caption was expanded to clarify that it is conceptual (line 63).

7. Conclusions overly optimistic

Response: The Conclusions section was rewritten to reflect the preclinical nature of the evidence.

Sincerely, Leonel Pereira & Ana Valado

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript addresses the neurological benefits of seaweed-derived compounds, an area of growing interest given the abundance of marine bioactives with potential neuroprotective properties. While the topic is timely and relevant, the novelty of the review needs clearer articulation. Seaweed bioactives have been extensively discussed in earlier literature, especially in the context of antioxidative and anti-inflammatory mechanisms.

1. The manuscript is a wide-ranging review covering polysaccharides, polyphenols, carotenoids, peptides, sterols, and omega-3 fatty acids. While this breadth is commendable, the manuscript must ensure adequate depth within each category. Mechanistic pathways should be thoroughly discussed with supporting evidence from recent studies. It would strengthen the scientific value if the authors critically evaluated the strengths and limitations of current findings rather than merely summarizing them.

2. The manuscript highlights key neurological pathways, such as oxidative stress, synaptic plasticity, and mitochondrial dysfunction. But the exact biochemical and molecular mechanisms through which seaweed-derived compounds exert these effects require further elaboration. For example:

a) How do specific polysaccharides influence microglial activation?

b) What is the evidence for phlorotannins modulating amyloidogenesis/tau phosphorylation?

c) Which fatty acids or sterols have demonstrated mitochondrial stabilization/neurotrophic factor enhancement?

d) Clear mechanistic diagrams/tables would greatly improve clarity and scientific rigor.

3. The discussion on bioavailability, extract standardization, and regulatory barriers is appropriate, but the manuscript should provide more concrete examples. For instance:

a) How do sulfated polysaccharides behave in vivo with respect to absorption and metabolism?

b) What are the known pharmacokinetic limitations of phlorotannins?

c) Are there any ongoing clinical trials related to marine-derived neuroprotective agents?

d) Highlighting such details would strengthen the translational relevance.

4. While the manuscript states that both in vitro and in vivo studies support the neuroprotective potential of seaweed compounds, the strength of evidence varies greatly among compound types. Some areas, such as fucoidan and phlorotannins, are relatively well studied, whereas others lack robust experimental validation. A more critical differentiation between well-supported findings and preliminary data would improve scientific balance.

5. Provide a clear and comprehensive methodology describing how the articles for this review were identified, selected, and analyzed. This should include the databases searched, the specific keywords or search strings used, the time frame of the literature included, and the inclusion/exclusion criteria applied.

Author Response

REVIEWER 2 – Point‑by‑Point Response

1. Need for deeper mechanistic detail and critical evaluation

Reviewer comment: Each compound class requires more mechanistic depth.

Response: We expanded mechanistic explanations throughout Section 2 and Section 3.

Revisions:

• Added critical evaluation paragraph (lines 113–120).
• Added evidence‑strength paragraph (lines 132–136).

2. Need for more detailed biochemical mechanisms

Reviewer comment: More detail required on polysaccharides, phlorotannins, fatty acids, sterols.

Response: We added mechanistic details at the exact locations requested.

Revisions:

• Polysaccharides & microglia: lines 118–125.
• Additional microglia paragraph: lines 147–153.
• Fatty acids & sterols (DHA, EPA, fucosterol): lines 259–266.
• Phlorotannins & amyloid/tau: added before Section 4.1 (not shown in excerpt but included in full manuscript).

3. Need for concrete examples of bioavailability and clinical translation

Response: We expanded the Bioavailability section (not included in the excerpt) with specific examples of:

• Poor absorption of fucoidan
• Rapid metabolism of phlorotannins
• Lack of CNS penetration
• Absence of clinical trials demonstrating neuroprotection

4. Need to distinguish strong vs. preliminary evidence

Response: We added a dedicated paragraph differentiating evidence strength.

Revisions:

• Lines 132–136: “The strength of evidence varies considerably among compound classes…”

5. Need for a clear methodology section

Reviewer comment: A methodology section was missing.

Response: We added a complete Methodology section.

Revisions:

• New Section 2 (lines 66–80).

Final Statement

We thank both reviewers for their insightful and constructive comments. We believe the revised manuscript is now substantially improved in clarity, scientific rigor, and balance. We hope the revised version meets the expectations of the reviewers and the editorial board.

Sincerely, Leonel Pereira & Ana Valado

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The topic of this manuscript was important and it fitted to the scope of this journal. However, revisions were required.

1. More extensive literature survey for the bioactive constituents from algae should be done. As shown, only a limited number of well-known seaweed-derived compounds were reported in the manuscript. For instance, the reference ‘The Red Alga Gracilariopsis chorda and Its Active Constituent Arachidonic Acid Promote Spine Dynamics via Dendritic Filopodia and Potentiate Functional Synaptic Plasticity in Hippocampal Neurons’(J. Med. Food, 2018, 21(5): 481-488. doi: 10.1089/jmf.2017.4026.) was missing.
2. Similarly, only a limited number of seaweed extracts were reported in this manuscript. More extensive literature survey for the bioactive seaweed extracts should be done. For instance, the reference ‘The Edible Marine Alga Gracilariopsis chorda Alleviates Hypoxia/Reoxygenation-Induced Oxidative Stress in Cultured Hippocampal Neurons’(J. Med. Food, 2015, 18(9): 960-71. doi: 10.1089/jmf.2014.3369.) was missing.
3. According to pictures as shown in Figures 2–4, it is suggested to merge these three figures into one figure.

Author Response

Response: We agree. We expanded the section on bioactive constituents to include additional compounds and mechanisms not previously covered. The suggested reference on Gracilariopsis chorda and arachidonic acid has been added and discussed.

Manuscript changes:

• New text added at lines 113–120.
• Reference added to the bibliography.

2. Need for a more extensive survey of seaweed extracts

Reviewer comment: Only a limited number of extracts were included; additional studies such as the 2015 Gracilariopsis chorda extract paper should be incorporated.

Response: We agree. We expanded the section on seaweed extracts in neurodegenerative disorders and included the suggested study on Gracilariopsis chorda extract and its neuroprotective effects under hypoxia/reoxygenation.

Manuscript changes:

• New text added at lines 242–260.
• Reference added to the bibliography.

Comment on Merging Figures 2–4

Reviewer comment: “According to pictures as shown in Figures 2–4, it is suggested to merge these three figures into one figure.”

Response: We appreciate the reviewer’s suggestion. After careful consideration, we believe that merging Figures 2–4 would significantly reduce the clarity and pedagogical value of the manuscript. Each figure is intentionally placed within the subsection that describes its corresponding algal group (red, brown, and green algae). This structure allows readers to immediately associate:

• the taxonomic group being discussed,
• its morphological characteristics, and
• the specific bioactive compounds highlighted in that subsection.

If the three images were merged into a single composite figure, it would need to be relocated outside the individual subsections. This would:

1. Disrupt the logical flow of the manuscript,
2. Make it harder for readers—especially non‑specialists—to connect each algal group with its biochemical profile, and
3. Weaken the didactic function of the review, which relies on presenting each algal class alongside its representative species.

For these reasons, we respectfully maintain the figures as separate elements. To address the reviewer’s concern regarding consistency, we have ensured that all three figures now follow a uniform style and caption format.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Authors,

Thank you for the revised version. The authors have addressed some of my comments, but only partially. Several key concerns remain insufficiently resolved, and the manuscript still requires further refinement to avoid overinterpretation and to better align the narrative with the level of evidence currently available.

Despite the addition of some caveats regarding the preclinical nature of the data, the manuscript remains overly optimistic in several sections. Statements suggesting “therapeutic promise”, “clinical relevance”, or a “strong rationale” for clinical translation are difficult to reconcile with an evidence base that is still predominantly in vitro and animal based. Consequently, the overall message feels internally inconsistent. Disclaimers are present, yet the narrative continues to suggest clinical applicability.

Relatedly, the sections describing human data remain prone to overinterpretation. Most outcomes discussed in volunteers are indirect, such as antioxidant status, inflammatory or metabolic markers, fatigue, or well-being. These are not neurodegenerative or disease-modifying endpoints. The current text does not consistently remind the reader that such outcomes should be regarded as surrogate or indirect measures and cannot be used to support claims of neuroprotection or effects on neurodegenerative processes.

I appreciate that the discussion of bioavailability and pharmacokinetic barriers has been expanded, but some newly added statements are phrased too categorically, for example, broad claims that there is “no evidence” for CNS penetration. Without careful qualification, including compound-specific differences, potential roles of metabolites, delivery forms, and the limitations of available data, such absolute wording can be misleading. This section would be stronger if the boundaries between what is known and what remains uncertain were stated more consistently.

Because the manuscript covers many compound classes and a wide range of experimental models, it remains difficult for the reader to discern what is actually supported at each level of evidence. The review is rich in mechanistic detail but weaker in integrative synthesis. A concise summary table linking each compound or class to the type of evidence (in vitro, animal, or human), the main reported outcome, and the major limitations, including bioavailability or BBB issues, standardisation, and safety, would make the paper more transparent and balanced.

Although the revision now mentions that negative or inconclusive findings may be underrepresented, the manuscript still largely highlights positive results. Without at least a brief discussion of where effects were absent, inconsistent, or model dependent, and why, the review risks appearing selective. This is particularly relevant in neurodegeneration research, where reproducibility can be limited and conclusions often depend strongly on model design and experimental conditions.

Finally, the manuscript acknowledges variability related to species, seasonality, geography, and extraction methods, but the implications remain too general. It would be helpful to be more explicit about what should be standardised or controlled to enable meaningful comparison across studies, such as chemical profiling or marker compounds, iodine and heavy metals, extraction protocol, and stability. Otherwise, the discussion of “promising effects” remains difficult to interpret in terms of reproducibility and practical applicability.

A practical concern with the revision is that several newly added sentences, especially interpretive statements, mechanistic generalisations, and forward-looking claims, are not consistently supported by specific literature references. When additions go beyond descriptive summarising, they should be backed by clear citations. Otherwise, they should be explicitly presented as hypotheses or perspectives rather than evidence-based conclusions.

Author Response

Response to Reviewer 1

We sincerely thank the reviewer for the careful re‑evaluation of our revised manuscript and for the constructive and detailed feedback. We appreciate the reviewer’s continued engagement, and we agree that several sections required further refinement to ensure that the narrative remains fully aligned with the current level of evidence. In the revised version, we have implemented substantial changes to address all concerns raised. Below, we provide a point‑by‑point response.

1. Concern: Persistent overinterpretation and overly optimistic tone

Reviewer comment: The manuscript still contains statements implying “therapeutic promise”, “clinical relevance”, or a “strong rationale” for clinical translation, which are inconsistent with the predominantly preclinical evidence base.

Response: We fully agree. We have now systematically revised the manuscript to remove any language implying therapeutic efficacy, clinical applicability, or imminent translation. All sections have been rewritten to emphasize the exploratory and preclinical nature of the evidence. Phrases such as “therapeutic promise”, “clinical relevance”, “strong rationale”, “neuroprotective strategies”, and similar expressions have been removed or replaced with more cautious formulations (e.g., “preclinical interest”, “mechanistic relevance”, “investigated in experimental models”). We believe the revised text now maintains a consistent and appropriately conservative tone throughout.

2. Concern: Overinterpretation of human data

Reviewer comment: Human outcomes discussed are indirect (antioxidant status, inflammation, fatigue, well‑being) and should not be interpreted as neuroprotective or disease‑modifying.

Response: We agree entirely. We have revised the human‑data sections to explicitly state that these outcomes are surrogate, indirect, or non‑specific markers, and that they cannot be used to infer neuroprotection or effects on neurodegenerative processes. We now repeatedly clarify that no clinical evidence exists for neurodegeneration‑related endpoints, and we have removed any wording that could imply otherwise.

3. Concern: Overly categorical statements regarding CNS penetration

Reviewer comment: Statements such as “no evidence for CNS penetration” are too absolute and should be qualified.

Response: We appreciate this important clarification. We have revised the relevant sections to avoid categorical statements and now specify:

• that available data are limited,
• that compound‑specific differences may exist,
• that metabolites or delivery systems could alter distribution, and
• that current evidence is insufficient rather than absent.

The revised text now clearly distinguishes between what is known, what is uncertain, and what remains unexplored.

4. Concern: Need for integrative synthesis and a summary table

Reviewer comment: Given the diversity of compounds and models, a summary table linking each compound/class to the type of evidence, main outcomes, and limitations would improve transparency.

Response: We agree and have now added a comprehensive summary table that includes:

• compound or compound class,
• type of evidence (in vitro, animal, human),
• main reported outcomes,
• major limitations (bioavailability, BBB penetration, standardisation, safety).

This table provides a clearer synthesis and allows readers to quickly assess the strength and limitations of the evidence for each compound class.

5. Concern: Underrepresentation of negative, inconsistent, or model‑dependent findings

Reviewer comment: The manuscript still highlights positive results disproportionately.

Response: We appreciate this observation and have now incorporated a dedicated subsection discussing:

• studies reporting absent or inconsistent effects,
• model‑dependent variability,
• challenges in reproducibility,
• reasons for divergent outcomes (e.g., extraction method, dose, species differences).

This addition ensures a more balanced and realistic appraisal of the literature.

6. Concern: Variability in species, seasonality, geography, and extraction methods

Reviewer comment: The implications of variability remain too general; more explicit guidance on what should be standardized is needed.

Response: We agree and have expanded this section substantially. The revised text now specifies the need for standardization of:

• chemical profiling and marker compounds,
• iodine and heavy‑metal quantification,
• extraction and purification protocols,
• stability and storage conditions,
• batch‑to‑batch reproducibility.

We also clarify how these factors affect comparability, reproducibility, and interpretation of biological effects.

7. Concern: Newly added statements lack supporting citations

Reviewer comment: Interpretive or forward‑looking statements should be supported by references or clearly framed as hypotheses.

Response: We have carefully reviewed all newly added content. Where evidence exists, we have added appropriate citations. Where statements reflect hypotheses, perspectives, or conceptual frameworks rather than empirical findings, we now explicitly identify them as such. This ensures that the distinction between evidence‑based conclusions and forward‑looking considerations is consistently maintained.

Table 2, Summary of evidence for seaweed-derived bioactives across experimental levels, was added, and the other tables were renumbered.

Final remark

We are grateful for the reviewer’s insightful and constructive feedback, which has significantly strengthened the manuscript. The revised version now presents a more balanced, cautious, and evidence‑aligned narrative, with clearer boundaries between preclinical findings, indirect human outcomes, and unproven clinical implications.

Reviewer 2 Report

Comments and Suggestions for Authors

Significant improvement in the manuscript; the present form is now recommended for publication. 

Author Response

We thank the reviewer for the positive assessment and for acknowledging the improvements made in the revised manuscript.

Reviewer 3 Report

Comments and Suggestions for Authors

This manuscript was improved according to the reviewer’s comments.

There were two suggestions.

1. Please carry out more extensive literature survey again. In the last round, although two references were found missing, it did not mean only two references.
2. Please check the reference citations carefully. For instance, the citation [22] at the Line 275 was wrong.

Author Response

Response to Reviewer 3

We thank the reviewer for the positive assessment and for acknowledging the improvements made in the revised manuscript. We greatly appreciate the additional suggestions regarding the literature survey and the accuracy of reference citations. We address both points in detail below.

1. More extensive literature survey

Reviewer comment: “There were two suggestions.

1. Please carry out more extensive literature survey again. In the last round, although two references were found missing, it did not mean only two references.”

Response: We fully agree that the previous correction of two missing references did not guarantee completeness of the literature coverage. In response, we have now conducted a more extensive and systematic literature survey, with particular attention to:

• recent publications on seaweed‑derived bio‑actives and neurobiology,
• clinical and human studies, including those with indirect or surrogate endpoints,
• bioavailability, pharmacokinetics, safety, and toxicology,
• technological approaches (nano‑delivery, biotechnology, personalized nutrition).

Based on this re‑evaluation, we have:

• incorporated additional relevant references where gaps were identified,
• updated older citations where more recent and comprehensive reviews or primary studies were available,
• ensured that key statements—especially in the sections on mechanisms, human data, safety, and emerging technologies—are supported by appropriate and up‑to‑date literature.

We believe this expanded literature base improves the robustness, balance, and completeness of the review.

2. Careful checking of reference citations

Reviewer comment: “2. Please check the reference citations carefully. For instance, the citation [22] at the Line 275 was wrong.”

Response: We appreciate this important point. In the revised manuscript, we have:

• performed a comprehensive cross‑check of all in‑text citations against the reference list,
• corrected misaligned citations, including the specific case mentioned by the reviewer (former citation [22] at line 275),
• verified that each reference is cited in the appropriate context and corresponds to the correct study (compound, model, outcome),
• removed or adjusted citations where the original reference did not adequately support the statement.
• Table 2, Summary of evidence for seaweed-derived bioactives across experimental levels, was added, and the other tables were renumbered.

Additionally, after incorporating new references from the expanded literature survey, we carefully re‑numbered and re‑checked the entire citation sequence to avoid inconsistencies.

We are confident that the reference system is now consistent, accurate, and better aligned with the content of the manuscript.

Once again, we thank the reviewer for the helpful suggestions. They have contributed significantly to improving both the scientific completeness and the technical accuracy of the manuscript.

Round 3

Reviewer 1 Report

Comments and Suggestions for Authors

I thank the authors for their thorough and careful responses to my comments and for the substantial revisions to the manuscript. The authors have addressed all my questions and concerns satisfactorily, and the revised version presents the topic more clearly, with greater balance and alignment with the evidence. I have no further questions or comments at this stage.