Therapeutic Potential of Sea Cucumber-Derived Bioactives in the Prevention and Management of Brain-Related Disorders: A Comprehensive Review
Abstract
1. Introduction
2. Research Methodology
3. Bioactive Compounds in Sea Cucumbers
3.1. Saponin
3.2. Peptides and Proteins
3.3. Polysaccharides
3.4. Phenolic Compound
3.5. Fatty Acid and Phospholipid
3.6. Cerebrosides
3.7. Other
4. Potential Therapeutic Applications
4.1. Alzheimer’s Disease
4.2. Parkinson’s Disease
4.3. Stroke and Ischemic Injuries
4.4. Brain Cancer and Brain Tumors
5. Neuroprotective Mechanism Involved
5.1. Alzheimer’s Disease
5.1.1. In Lowering Oxidative Stress
5.1.2. In Improving Synaptic Plasticity and Ameliorating Nerve Fiber Tangles
5.2. Neuroprotective Mechanism Involved in Parkinson’s Disease
6. Preclinical and Clinical Evidence
6.1. Alzheimer’s Disease
6.2. Parkinson’s Disease
6.3. Stroke and Ischemic Injuries
6.4. Brain Cancer and Brain Tumors
7. Challenges and Future Outlook
8. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Category | Terms |
---|---|
Organism | Sea cucumber, Acaudina leucoprocta, Apostichopus japonicus, Cucumaria frondosa, Holothuria leucospilota, Holothuria edulis, Holothuria scabra, Holothuria tubulosa, Holothuria atra, Stichopus japonicus, Stichopus chloronotus, Stichopus variegatus |
Target Organ | Brain |
Diseases | Neurodegenerative disorders, age-related brain disorder, Alzheimer’s disease (AD), Parkinson’s disease (PD), stroke, depression, tumors, Brain tumor, brain metastases |
Pathologies | Toxic protein deposition in the brain, neurotoxicity, neuroinflammation, oxidative stress, Aβ40 aggregation, Lewy bodies, alpha-synuclein (α-Syn) aggregates, neurofibrillary tangles |
Therapeutic areas | Therapeutic potentials, anti-tumor, anti-inflammatory, antioxidant, anti-cancer, and neuroprotective effects of DHA/EPA-PLs |
Bioactive compounds | Sea cucumber (SC)-derived products, bioactive compounds, natural bioactive, peptides, phenols, triterpene glycosides, fucoidan, fucosylated chondroitin sulfate, cerebrosides, sphingoids, saponins, Frondoside A, Biopeptide, protein hydrolysates, sea cucumber peptides, sulfated fucan or fucoidan, non-sulfated polysaccharides, glucocerebrosides, 2-butoxytetrahydrofuran |
Enzymes | Acetylcholinesterase (AChE) activity in the brain, and Dopaminergic (DA) neuronal function |
Molecular targets | Amyloid precursor protein (APP), tau protein, dopamine |
Hypotheses | Hypothesis related to Alzheimer’s disease, Aβ deposition hypothesis, tau protein hypothesis, oxidative stress |
Barriers | Blood–brain barrier, blood-tumor-barrier (BTB) |
Applications | Nutraceuticals and functional foods of sea cucumber |
Brain Chemistry | Fatty acid and phospholipid, lipidomic profile of the brain |
Research Evidence | Clinical and pre-clinical evidence, In vivo and In vitro studies on sea cucumber bioactives |
Pathways | AlzPathway, PI3K/Akt/GSK3β pathway, daf-16/Forkhead box O (FOXO) pathway, BDNF/TrkB/CREB signaling pathway, DAF-16/FOXO insulin/IGF, and SKN-1/NRF2 signaling pathways |
Species | Body Part | Bioactive Compounds | Type of Activity | Model | Function | Reference |
---|---|---|---|---|---|---|
Stichopus japonicus | Whole body | Amino acids, peptides | Antioxidative | In vitro | - α-chy-III (200 μg/mL) enhanced cell viability by 80% and decreased ROS formation by 70% | [72] |
Glycosaminoglycan | Anticoagulant | - Heparin exhibited almost the same anticoagulant activity as intact HG at concentrations below 170 µg/mL | [123] | |||
Stichopus variegatus | Body wall, muscle | Fucosylated chondroitin sulfates (SvF1 and SvF2), Sulfated fucan (SvF3) | Cytotoxic activity | In vitro | - Effect of SvF3 on breast cancer cell line T-47D (23%) and MDA-MB-231 (26%) at 400 µg/mL dose. | [88] |
Non-Sulphated Triterpene Glycosides (Variegatusides) | Anti-fungal activity | In vitro | - Showed positive results against 6 fungal strains | [124] | ||
Phenolic compound, Carotenoid | Antioxidative | In vitro | - Antioxidant activity poorer than synthetic substances (DPPH and β-carotene bleaching assay: 6.31 mg/mL and 46.37%) | [125] | ||
Stichopus hermanii | Whole body | Saponin, tannin, flavonoid, terpenoid, steroid | Anti-cancer and anti-microbial | In vitro | - HE on ovarian cancer cells showed a positive result | [126] |
Stichopus horrens | Body wall | Phenolic compound | Antioxidative, cytotoxic activity | In vitro | - Aqueous extract (79.62%) showed strong antioxidant activity by effectively inhibiting β-carotene oxidation | [127] |
Holothuria leucospilota | Whole body | Peptide | Antioxidant activity | - | - Hydrolysate protein < −30 kDa scavenges DPPH and FRAP (maximum and lowest at 5 and 2 mg/mL) | [73] |
Holothuria parva | Tegument | Octadecanoic acid 2-hydroxy-1-(hydroxymethyl) ethyl ester, 2′, 6′ -Acetoxylidide 2-(diethylamino)-, 2-Palmitoylglycerol, 5-Cholesten3beta-ol formate, Diisooctyl phthalate, Hexadecanoic acid, and Arachidonic acid | Antiviral | In vitro | - Ethanolic extract at 46.5 μg/mL reduced HSV-1 viral titer in Vero cell culture | [128] |
Body wall | Glycerol, gluconic acid, ouabain, spectinomycin and capreomycin | Antibacterial | In vitro | - E. coli (150 mg/mL), P. aeruginosa (100 mg/mL), and E. faecalis (175 mg/mL) were inhibited | [129] | |
_ | Phenol and Flavonoid content, | Anti-cancer | In vitro | - After 24 h, 250 μg/mL extract reduced malignant B lymphocyte viability by 20% | [130] | |
Body wall | α-cyanostilbene | Anti-cancer | In vitro | - Cell viability in hepatocytes from HCC rats decreased considerably at concentrations of 5, 10, 20, 40, and 100 μg/mL | [131] | |
Holothuria forskali | Digestive tract, gonad, muscle, body wall and respiratory tract | Phenolic compound, fat-soluble vitamins, sterol | Antibacterial | In vitro | - Ethyl acetate extracts of the digestive tract showed the most potent effect at 2 mg/mL against E. coli | [132] |
Whole body | Amino acid, Peptide | Antioxidative, anti-hypertensive | In vitro | - Showed 170 μmol TE/L antioxidant activity via DPPH assay. - Produces 58% less ACE-I inhibition than teprotide (IC50 = 83.63 μM) | [133] | |
Holothuria mexicana | Body wall | Fucosylated polysaccharide sulfate | Antithrombotic activities | In vitro | - At 150 g/mL, showed higher APTT activity than heparin | [134] |
Holothuria lessoni | Body wall, Viscera | Saponin | Anti-fungal | In vitro | - anti-fungal activity against F. pseudograminearum and R. solani is strong at 40 μL | [53,57] |
Holothuria edulis | Body wall | Phenolic compound | Antioxidative, cytotoxic activity | In vitro | - Aqueous extract showed a strong radical scavenging capacity on DPPH (IC50 = 2.03 μg/mL), then organic extract - Aqueous extract active against cancer cell line TE1 cells (IC50 = 78.0 μg/mL), A549 (IC50 = 132.0 μg/mL) | [127] |
Sulfated polysaccharides (sulfated fucans, fucosylated chondroitin sulfates, neutral glucan) | Anticoagulant | In vitro | - APTT (2.86 μg/mL) and TT (16.03 μg/mL) testing showed that FCSs have anticoagulant properties lower than heparin but higher than sulfated fucans | [86] | ||
Holothuria nobilis | Body wall | Polysaccharide | Anticoagulant | In vitro | - APTT (4.33 μg/mL) and TT (22.66 μg/mL) testing showed that FCSs have anticoagulant properties lower than heparin but higher than sulfated fucans | [86] |
Holothuria polii | Body wall | Fucosylated chondroitin sulfate | Anticoagulant | - | - FCSs have an estimated anticoagulant activity of 220 units/mg | [135] |
Non-sulfated hexaoside | Anti-tumor | In vitro | - Extract showed an inhibitory effect on cancer cell line MCF7 (IC50:17.4 mg/mL) and HCT116 (IC50:18 mg/mL) | [136] | ||
Fucoidan Bivittoside | Hematopoietic activity | In vivo | - At dose (2/8 mg/kg), increased WBCs and neutrophils, indicating normalization of CTX-induced leukopenia and neutropenia in mice | [137] | ||
Holothuria thomasi | Body wall | Saponin | Anti-diabetic | In vivo | - Reduced level of serum glucose and increased serum insulin at 300 mg/kg B.wt in STZ-induced diabetic rats. - Reduce urea and creatinine levels | [138] |
Holothuria tubulosa | Body wall | Triterpene glycosides | Anti-fouling activities | _ | May inhibit photosystem Q(B) protein 1 in marine macro fouler (algae) | [38] |
Phenolic compound | Cytotoxic | In vitro | - Aqueous and methanolic extracts inhibited human cancer cells (A549, HeLa, PC-3, and MCF-7) at 200–1000 µg/mL | [139] | ||
Holothuria hilla | Body wall | Fucosylated chondroitin sulfates | Anticoagulant | In vitro | - The concentration of 2APTT was 2.8 ± 0.1 μg/mL - Effectiveness was higher than enoxaparin but lower than heparin | [140] |
Holothuria fuscocinerea | Body wall | Phenolic compound, Carotenoid | Antioxidative | In vitro | - Antioxidant activity poorer than synthetic substances (DPPH and β-carotene bleaching assay: 0.29 mg/mL and 45.75%) - Carotenoid concentration (33.64 ± 0.07 mol/g) was strongly correlated with antioxidant activity in sample extracts | [125] |
Holothuria atra | Whole Body | Flavonoids, phenolic components, terpenoids, saponins, alkaloids | Cytotoxic, antiviral | In vitro | - Methanolic extract showed anti-proliferative activity against cervical cancer cell line Hela (IC50: 468 μg/mL), MCF-7 (IC50: 352 μg/mL) - Demonstrated antiviral activity against HSV-1 and HSV-2 with a 75% inhibition rate at 2.4 × 103 pfu/mL | [141] |
Body wall | Phenolic compounds (chlorogenic acid, pyrogallol, rutin, coumaric acid, catechin, and ascorbic acid) | Antioxidative and hepatoprotective activity | In vitro, In vivo | - Extract showed great NO∙ scavenging activity (93.42% at 600 µg/mL) and low DPPH∙ activity (17.01% at 16.8 µg/mL) - Lipid peroxidation inhibition: 36.4% at 600 µg/mL | [100] | |
Holothuria arenicola | Body wall | Phenolic compound (chlorogenic acid, pyrogallol, rutin, coumaric acid | Anti-fibrotic | In vivo | - Oral extract (200 mg/k BW) decreased total conjugated and unconjugated bilirubin, serum aminotransferases, alkaline phosphatase, and in albino rats | [101] |
Holothuria (Metriaty Holothuria (Metriatyla) scabra | Body wall | Sulfated triterpene glycoside (Scabraside D), triterpene glycoside | Anti-cancer, | In vivo, In vitro | - Impaired HuCCA cell viability and migration (IC50:12.8 ± 0.05 μg/mL at 24 h) | [142,143] |
Whole body | Friedelin, 3-Hydroxybenzaldehyde and 4-Hydroxybenzaldehyde | Antioxidative | In vitro | - DPPH free radical scavenging activity was observed in 3 compounds (EC50: 33.77 ± 0.24, 14.63 ± 0.01, 14.62 ± 0.01, and 14.68 ± 0.11 mg/mL | [118] | |
Holothuria spinifera | Whole body | Cerebrosides (spiniferosides A, B, C, and holospiniferoside) and cholesterol sulfate | Anti-tumor | In vitro | - Spiniferosides A, B, C, and cholesterol sulfate showed significant cytotoxic effects with IC50 values of 13.83, 8.13, 8.27, and 35.56 µM, respectively - Holospiniferoside showed antiproliferative effect (IC50: 20.6 µM) | [144,145] |
Body wall | Fucosylated chondroitin sulfates | Anticoagulant | In vitro | - APTT assay showed a two-fold increase in clot formation at 2.6 ± 0.1 μg/mL | [146] | |
Holothuria impatiens | Whole body | Triterpene tetraglycosides (25-Hydroxyfuscocineroside B, Fuscocineroside B, Pervicoside C, Holothurin A) | _ | _ | _ | [147] |
Actinopyga lecanora | Whole body | Peptide | Antioxidative activity, antihypertension | In vitro | - Showed ACE inhibitory action (1.50–2.54 mg/mL) - Alcalase protein hydrolysate exhibited the strongest DPPH radical-scavenging activity (IC50: 0.181 mg/mL) | [76] |
Apostichopus japonicas | Body wall | Saponin (Holotoxin A1) | Anti-tumor | In vitro | - Showed antiproliferative effect strongest activity against HL-60 cells (IC50: 23.55 ± 3.40 µg/mL) | [148] |
Sulfated polysaccharide (Fucosylated chondroitin sulfate (FCS), sulfated fucan) | Anticoagulant | In vitro | - APTT (2.20 μg/mL) and TT (14.20 μg/mL) testing showed that FCSs have anticoagulant properties lower than heparin but higher than sulfated fucans | [86] | ||
Peptide | Anti-hyperuricemic and anti-inflammatory | In vivo | Reduces TLR4/MyD88/NF-κB signaling pathway activation, crucial for inflammatory response | [149] | ||
Acaudina leucoprocta | Body wall | Sulfated fucan (AL1-1) | Anticoagulant | In vitro | - At 0–20 μg/mL, intrinsic anticoagulant activity on APTT was less than heparin, but did not extend PT or TT | [150] |
Peptide | Anti-aging, anti-hyperuricemic and anti-inflammatory | In vivo | Extended the lifetime of nematodes Caenorhabditis elegans by 31.46% - Reduces TLR4/MyD88/NF-κB signaling pathway activation, crucial for inflammatory response | [149,151] | ||
Peptide | Anti-fatigue | In vivo | - SCP-1 and SCP-2 enhanced exercise performance and reduced tiredness in mice by reducing oxidative stress and increasing mitochondrial function via NRF2 and AMPK pathways | [75] | ||
Acaudina molpadioides | Body wall | Peptide | Antioxidative | In vitro | Microwave-assisted (300 W) hydrolysate had 100% more content and 109% more DPPH scavenging activity than non-irradiated sample | [34] |
Cerebroside | Hepatic adipopexis | In vivo | - Dietary SCC at the levels of 0.006% and 0.03% ameliorated the hepatic lipid accumulation in fatty liver rats | [152] | ||
Whole body | Fucosylated chondroitin sulfate | Anti-inflammatory | In vivo | Increased anti-inflammatory IL-10 mRNA levels (114.18%), and reduced body weight gain (26.38%) by altering gut microbiota | [153] | |
Fucoidan | - Inhibits pancreatic islet cell apoptosis by downregulating caspase 3 and 9 | [154] | ||||
Eupentacta fraudatrix | Whole body | Triterpene glycoside Cucumariosides I2, H, A5, A6, B2 and B6 | Cytotoxic, lysosomal | In vitro | - Cucumarioside H, A5, A6 showed moderate cytotoxicity against mouse Ehrlich cancer cells in ascites form (EC50 16.3, 17.3, 12.5 µg/mL) - Glycosides I2, A5, and B2 enhanced the lysosomal activity of macrophages by 15–17% at doses of 1–5 µg/mL | [155] |
Bohadschia cousteaui | Body wall | Saponin (coustesides A, B, C, D, E, F, G, H, I and J) | Anti-fungal activity | In vitro | -Inhibited Candida albicans growth in 10 μL (1 mg/mL) stock solution. | [156] |
Colochirus quadrangularis | _ | Sulfated triterpene glycoside (coloquadranoside A), triterpene glycosides (philinopside A, B, E and pentactaside B) | Anti-tumor, immunomodulatory activity | In vitro, In vivo | - In vitro: Coloquadranoside A may reduce tumor development and aggressiveness by decreasing neovascularization via tyrosine kinase autophosphorylation pathway. - In vivo: Coloquadranoside A (5–50 mg/kg) inhibited tumor growth in S-180 and H22 homograft mice (TGI > 35%), and at 50–500 mg/kg enhanced CTX-induced macrophage clearance and phagocytosis in immunosuppressed mice | [157] |
Triterpene glycosides (quadrangularisosides A, A1, B, B1, B2, C, C1, D, D1–D4, and E | Cytotoxic, | In vitro | - Compounds 1–13 showed dose-dependent inhibition of HT-29 cells at concentrations of 0–20 μM, measured by MTS assay | [158] | ||
Neothyonidium magnum | Whole body | Triterpene glycosides (magnumosides A1, A2, A3, A4, B1, B2, C1, C2, C4 and colochiroside B2) | Cytotoxic | In vitro | - Magnumoside A3, C1, C2, and C4 reduced Human Colorectal Adenocarcinoma DLD-1 Cell viability with IC50 values of 30.3, 34.3, 32.9, 37.1, and 33.9 μM - Magnumoside A3 and C1 reduced DLD-1 cancer cell colony size by 49% and 43% at 10 μM, respectively, and prevented spontaneous colony formation by 22% and 26% | [159] |
Isostichopus badionotus | Body wall, | Peptide | Anti-hypertension | In vitro | - The 10 kDa fraction showed the highest angiotensin enzyme inhibitory factor (80.7%), with an IC50 of 83 µg/mL | [160] |
Whole body | Fucosylated chondroitin sulfate | Anti-metastatic, anti-hyperlipidemic | In vivo, In vitro | - In MTT assay, the compound reduced 95D cell viability (IC50: 369.8 µg/mL) - Showed 24.4% tumor growth reduction at 5 mg/kg in Lewis lung carcinoma mouse models | [161] | |
Isostichopus fuscus | Tentacles | Peptides | Antioxidative | In vitro | - The 3 kDa fraction had the highest ORAC value (0.92 ± 0.04 μmol TE/mg protein) | [71] |
Parastichopus tremulus | Whole body | Amino acid, Peptide | Antioxidative | In vitro | - Antioxidant activity in ORAC assay is measured at 0.35 ± 0.05 TE/μg protein | [162] |
Athyonidium chilensis | Body without gut | Saponin | Antibacterial, anti-fungal, cytotoxic | In vitro | - Showed anti-microbial efficacy against Gram-positive bacteria but not Gram-negative bacteria at 10 mg/mL concentration - Exhibited efficacy against fungus at conc. 10 mg/mL - Showed cytotoxic activity on N2A tumor cells (IC50: 77.34 ± 1.6 μg ml−1) | [163] |
Stichopus vastus | Integument | Protein, Peptides | Antioxidative | In vitro | - Trypsin-hydrolyzed collagen hydrolysates reduced up to 71.3% of ABTS radicals | [164] |
Thelenota ananas | Body wal | Fucosylated chondroitin sulfate | Anticoagulant, antiviral | In vitro | - Compound’s APTT increasing activities dropped from 125.8 to 14.8 U/mg as fucosylation degrees reduced from 100% to 34% - Strong thrombin inhibition (EC50 < 286 ng/mL) was observed with heparin cofactor II in the depolymerized molecule - Strong antiviral activity against T-20-resistant bacteria (EC50: 0.76–1.13 μg/mL) | [165,166,167,168] |
Body wall and alimentary canal | Saponin (Desulfated holothurin A) | Anti-cholesterol, anti-atherosclerosis | In vitro, in vivo | - Treatment with 1 μg/mL increased mRNA expressions of SR-BI, ABCA1, and ABCG1 by 2-fold, 2.4-fold, and 2.3-fold, respectively | [169,170] | |
Paracaudina chilensis | Body wall | Fucosylated chondroitin sulfates | Anticoagulant | In vitro | - Effectiveness was higher than enoxaparin but lower than heparin | [140] |
Compound | Disease | Model | Effect | Dose | Reference |
---|---|---|---|---|---|
Hydrolysate | Alzheimer’s disease | Aβ-mCherry cells model |
| 0.5 mg/mL | [257] |
Crude Polysaccharide | Alzheimer’s disease | SH-SY5Y cells model |
| - | [258] |
Cerebrosides | Alzheimer’s disease | SAMP8 Mice and PC12 Cells |
| 200 mg/kg | [35] |
Glucocerebrosides | Alzheimer’s disease | SAMP8 mice model |
| 5 g/kg | [259] |
Saponin (Frondoside A) | Parkinson’s Disease | C. elegans |
| 0.1–10 µM | [260] |
Diterpene glycosides | Parkinson’s Disease | C. elegans |
| 1–10 μg/mL | [261] |
Frondoside A | Alzheimer’s disease | C. elegans |
| 1 μM | [66] |
Triterpene glycosides | Brain cancer | A172 and U87MG cell lines |
| 1–10 µg/mL | [143] |
Sulfated Polysaccharide | Parkinson’s Disease | SH-SY5Y cells |
| 300 μg/mL | [262] |
Sulfated Polysaccharide | Cerebral ischemia–reperfusion injury | PC12 cells |
| 100–500 µg/mL | [263] |
Cerebroside | Nervous system oxidative damage | PC12 cells |
| 400 μg/mL | [117] |
Glucocerebrosides | Dysregulated neurite outgrowth | PC12 cells |
| 200 μg/mL | [264] |
Phosphatidylcholine | Dementia | BALB/c mice |
| 5 g/kg | [108] |
EPA-Pl | Alzheimer Disease | Mice |
| 300 mg/kg·day | [107] |
2-butoxytetrahydrofuran (2-BTHF) | Alzheimer Disease | CL4176 and CL2006 C. elegans strain |
| 1 µg/mL | [119] |
Decanoic acid | Parkinson’s Disease | C. elegans |
| 5–25 μg/mL | [112] |
Palmitic acid | Parkinson’s Disease | Caenorhabditis elegans PD models. |
| 5 µg/mL | [265] |
EPA-PL | Parkinson’s Disease | Male C57BL/6J mice |
| 20.25 (g/1000 g) | [36] |
2-butoxytetrahydrofuran (2-BTHF) | Parkinson’s disease | Caenorhabditis elegans strain |
| 100 μM | [266] |
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Debi, P.R.; Barua, H.; Ahmmed, M.K.; Bhowmik, S. Therapeutic Potential of Sea Cucumber-Derived Bioactives in the Prevention and Management of Brain-Related Disorders: A Comprehensive Review. Mar. Drugs 2025, 23, 310. https://doi.org/10.3390/md23080310
Debi PR, Barua H, Ahmmed MK, Bhowmik S. Therapeutic Potential of Sea Cucumber-Derived Bioactives in the Prevention and Management of Brain-Related Disorders: A Comprehensive Review. Marine Drugs. 2025; 23(8):310. https://doi.org/10.3390/md23080310
Chicago/Turabian StyleDebi, Purnima Rani, Hrishika Barua, Mirja Kaizer Ahmmed, and Shuva Bhowmik. 2025. "Therapeutic Potential of Sea Cucumber-Derived Bioactives in the Prevention and Management of Brain-Related Disorders: A Comprehensive Review" Marine Drugs 23, no. 8: 310. https://doi.org/10.3390/md23080310
APA StyleDebi, P. R., Barua, H., Ahmmed, M. K., & Bhowmik, S. (2025). Therapeutic Potential of Sea Cucumber-Derived Bioactives in the Prevention and Management of Brain-Related Disorders: A Comprehensive Review. Marine Drugs, 23(8), 310. https://doi.org/10.3390/md23080310