Anti-Inflammatory and Neuroprotective Effects of Undaria pinnatifida Fucoidan

1. Introduction

Fucoidans are a class of highly sulphated polysaccharides which are abundantly present in the cell walls of brown algae, including Undaria pinnatifida [1]. These polysaccharides have attracted considerable scientific attention due to their diverse and potent biological activities in the treatment of inflammatory-related diseases [2], metabolic disorders [3], cardiovascular conditions [4], and several cancers [5,6,7]. The structure of common fucoidans typically consists of a backbone of L-fucose residues linked by α-(1→3) or alternating α-(1→3) and α-(1→4) glycosidic bonds, with varying degrees and patterns of sulfation (mainly at C2, C3, or C4), and may include minor sugars such as galactose, mannose, xylose, and uronic acids, resulting in highly branched and heterogeneous molecules [8]. Their structural diversity, shaped by factors such as seaweed species, degree and position of sulphation, molecular weight, and extraction methods, plays a crucial role in determining their bioactivity [9,10,11,12].

Among the various sources of fucoidan, recent research has increasingly focused on Undaria pinnatifida fucoidan (UPF), which has shown notable anti-inflammatory [13], antioxidant [14], immunomodulatory [15], antiviral [16], and neuroprotective effects [17] suggesting a significant potential in biomedical applications.

This review focuses specifically on the anti-inflammatory and neuroprotective activities of UPF, highlighting the molecular mechanisms responsible for these biological effects. It also evaluates the therapeutic potential of UPF in the management of chronic inflammatory conditions and neurodegenerative diseases, offering insights that may guide future research and clinical applications.

2. Anti-inflammatory Activity of UPF

2.1. In Vitro Studies

Several in vitro studies have indicated that UPF effectively reduces the expression of key pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), Interleukin - 1 beta (IL-1β), and IL-6, to mitigate diverse inflammation-related responses. A recent investigation has shown that a 4-hour pre-treatment with UPF (10, 50, and 100 µg/ml) significantly suppressed lipopolysaccharide (LPS)-induced upregulation of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, in human macrophages and peripheral blood mononuclear cells (PBMCs) [18]. A low molecular weight UPF (100 µg/ml) also exhibited significant anti-inflammation effects by downregulating the gene expression of these pro-inflammatory cytokines in LPS-induced RAW264.7 cells [19]. Similarly, in a viral challenge model, UPF (200 µg/ml) reduced pro-inflammatory cytokines, including IL-6, IFN-α, interferon gamma (IFN-γ), and TNF-α, in SARS-CoV-2 infected Caco-2-N^int cells [16]. These effects are primarily mediated through inhibition of key inflammatory signalling pathways, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK), which are known to regulate cytokine gene transcription [20]. For example, treatment with UPF suppresses the nuclear translocation of NF-κB p65 and reduces the phosphorylation of p38 and extracellular signal-regulated kinases (ERK)1/2 MAPKs, leading to a marked decrease in pro-inflammatory cytokine expression [1,19,20]. Vaamonde-García et al. (2021) reported that UPF (5 µg/ml) treatment attenuated IL-1β-induced inflammation in osteoarthritic chondrocytes by blocking nuclear translocation of NF-κB and inhibiting its activation [21]. In addition, UPF inhibited NF-κB signalling and downregulated IL-6 and TNF-α in human colon carcinoma cell line (Caco-2) cells [22].

The suppression of oxidative stress represents a fundamental mechanism by which UPF alleviates inflammation. Oxidative stress, driven by excess reactive oxygen species (ROS), is a key initiator of inflammatory signalling cascades in various cell types [23]. In intestinal epithelial cell line (IEC-6) cells, UPF (100 µg/ml) significantly reduced oxidative damage induced by hydrogen peroxide (H₂O₂), as evidenced by decreased levels of malondialdehyde (MDA) and increased activity of antioxidant enzymes, including catalase (CAT), total superoxide dismutase (T-SOD), and glutathione (GSH) [24]. These changes were associated with protection against apoptosis and inhibition of pro-inflammatory responses, indicating that UPF enhances cellular antioxidant defences to maintain redox balance. Moreover, in RAW264.7 macrophages, low molecular weight UPF (100 µg/ml) inhibited LPS-induced ROS production and suppressed the phosphorylation of key MAPK signalling proteins (p38, ERK1/2, and JNK), leading to a significant reduction in the expression of inflammatory markers such as TNF-α, IL-6, and IL-1β [19]. Phull et al. (2017) found that UPF (15.52–500 µg/ml) exerted significant antioxidant activity in a dose-dependent manner in various in vitro antioxidant assays, including iron chelating, hydroxyl, nitric oxide, and DPPH activity, along with a reduction in inflammation responses in rabbit articular chondrocytes [25]. Another in vitro study also indicated that Undaria pinnatifida water extract (UPE) obtained by ultrasonication (200 and 400 µg/ml) significantly suppressed ROS production and restored H₂O₂-induced viability reduction in monkey kidney (Vero) cells in a dose-dependent manner. [26]. The cell-protective activity of the extract in this study was attributed to its capability to decrease pro-apoptotic protein (Bax) and increase anti-apoptotic protein (Bcl-2) [26].

Interestingly, there are an increasing number of studies correlating the antioxidant properties of UPF with its sulphate content and molecular weight [26,27,28,29,30,31]. For instance, UPF fractions with higher sulphation levels have been shown to exhibit significantly greater antioxidant activity compared to their lower-sulphated counterparts [29]. Moreover, fractionation studies revealed that low molecular weight UPF components possess enhanced antioxidant effects relative to high molecular weight forms, particularly in assays such as DPPH radical scavenging and ferric-reducing antioxidant power (FRAP) tests [30].

UPF inhibits major inflammatory mediators, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), nitric oxide (NO), and prostaglandin E2 (PGE2) whose overproduction exacerbates inflammatory responses and tissue damage [32,33]. For instance, low molecular weight UPF (100 µg/ml) alleviated LPS-induced inflammation in RAW264.7 cells by suppressing iNOS and COX2 activities [19]. Similarly, Song et al. in 2015 demonstrated that UPF (50 µg/ml) significantly inhibited iNOS and COX-2 expression, as well as attenuated the production of NO and PGE2 in LPS-stimulated RAW264.7 macrophages [34]. Lim et al. (2022) also reported that high molecular weight UPF (500 µg/ml) mitigated MG-11-induced inflammation in Caco-2 cells by suppressing protein expression of COX-2 and iNOS and inhibiting NF-κB activation [22]. Additionally, UPF exerted potent anti-inflammatory effects in rabbit articular chondrocytes, where UPF significantly reduced COX-2 expression in a dose (0–100 µg/ml, 24h) and time (30 µg/ml, 0–48 h) dependent manner [25]. Moreover, Vaamonde-García et al. found that UPF (5 µg/ml) significantly inhibited IL-1β-induced production of NO, PGE2, and IL-6 in osteoarthritic chondrocytes, suggesting an immunomodulatory role of UPF in inflammatory conditions [21].

Recent in vitro investigations have suggested that UPF is capable of suppressing chemokine secretion in various inflammatory cells. Chemokines, also known as chemotactic cytokines, are a family of small signalling proteins that significantly contribute to regulating the migration and activation of immune cells during inflammatory responses [1,35]. According to the structure of N-terminal cysteine residues, chemokines are classified into four major subfamilies, including CXXXC (fractalkine), C-X-C (IL-8), C-C (monocyte chemoattractant protein [MCP-1], or monocyte inflammatory protein [MIP-1α], and MIP-1β), and C chemokines (lymphotactin) [35]. Chen et al. (2025) demonstrated that sulphated Undaria pinnatifida polysaccharides (50 and 200 µg/ml) significantly reduced MCP-1 production in vitro during oxalate crystal-induced inflammation in renal cells [36]. This reduction was linked to decreased cellular inflammation and oxidative stress, indicating the potential role of UPF in modulating chemokine-driven immune cell recruitment [36]. Kim et al. also reported that UPF treatment (100 µg/ml) significantly suppressed MCP-1 expression in 3T3-L1 adipocytes, indicating that UPF inhibits inflammation-associated chemokine signalling during adipocyte differentiation [37]. In addition, Vaamonde-García et al. (2022) indicated that UPF (5 µg/ml) significantly downregulated IL-6 and IL-8 (CXCL8) in IL-1β-induced human chondrocyte cells [38]. Similarly, Wimmer et al. (2025) demonstrated that UPF significantly reduced the secretion of pro-inflammatory chemokines (IL-8 and MCP-1) and increased production of anti-inflammatory cytokines (IL-6 and IL-10) in the Caco-2/THP-1 co-culture system after microbial stimulation [39], indicating that UPF can suppress immune cell recruitment and inflammatory signalling at the gut mucosal level. Moreover, a study on atopic dermatitis found that UPF significantly inhibited the mRNA expression of several key chemokines, including thymus- and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC), and RANTES (also known as CCL5), in TNF-α or IFN-γ-induced human epidermal keratinocytes [40].

The major outcomes derived from in vitro investigations into the anti-inflammatory effects of UPF are listed in Table 1.

2.2. In Vivo Studies

A substantial body of in vivo studies further supports the notion that UPF exerts its anti-inflammatory effects by suppressing pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 [13,41,42,43]. Herath et al. (2020) reported that a 7-day oral administration of UPF (400 mg/kg/day) significantly attenuated particulate matter (PM) and ovalbumin (OVA)-induced IL-4, IL-17a, and IL-33 increase in lungs of a murine model of allergic airway inflammation [42]. In a later study, 27 days of UPF supplementation (400 mg/kg/day) significantly reduced TNF-α, IL-6, and IL-1β, and mitigated inflammation responses in the colon of dietary fibre deficiency (FD)-induced mice [24]. Similar effects of UPF were reported by Shi et al. (2024) in a Syrian hamster model of virus infection, where 6 days oral administration of UPF (200 mg/kg/day) alleviated SARS-CoV-2-induced lung and gastrointestinal tract injury by suppressing gene expression of TNF-α and IL-6 [16]. Lim et al. (2022) also indicated that 4 weeks oral administration of high molecular weight UPF (25 mg/kg/day) significantly inhibited MG-H1-caused TNF-α increase in mouse colon tissues [22]. Similarly, a 10-week oral administration of UPF (400 mg/kg/day) suppressed systemic inflammation in a high-fat diet (HFD)-induced obese mouse model [13]. The results of the study showed that UPF significantly reduced the expression of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in skeletal muscle, small intestine, and hypothalamus [13].

The antioxidant properties of UPF have been well demonstrated in animal models of inflammatory-related disorders. In HFD-fed mice, a 10-week oral administration of sulphated polysaccharides from Undaria pinnatifida significantly (100, 300, and 500 mg/kg/day) reduced markers of oxidative stress, including MDA and SOD in liver tissues, alongside an inhibition of triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), and TNF-α production, suggesting that the suppression of oxidative stress contributed to hepatic lipid metabolism improvements, and mitigated HFD-induced inflammatory conditions [44]. Similarly, 7 days of UPF oral gavage (100 and 400 mg/kg/day) attenuated MDA in the serum and lungs of PM-induced allergic airway inflammatory mice [42]. Phull et al. (2017) also reported that 25 days UPF administration (150 mg/kg/day) significantly decreased arthritis-induced endogenous antioxidant enzymes such as CAT, peroxidase (POD), and SOD [25]. This reduction was mainly due to UPF capability to scavenge the free radicals, abrogate ROS-induced oxidative stress, and maintain the oxidative flux [25]. In contrast, Kang et al. found that 14 days UPF intraperitoneal administration (100 mg/kg/day) markedly prevented oxidative stress in carbon tetrachloride (CCL₄)-induced rats by increasing antioxidant enzymes (CAT, SOD, and glutathione peroxidase [GPx]), and decreasing markers of oxidative damage (MDA) in liver [45]. These results are in line with the findings of Zheng et al. (2023), where 27 days of UPF treatment (400 mg/kg/day) significantly elevated the levels of CAT and T-SOD, and attenuated myeloperoxidase (MOP) and MDA production in the colon tissues of FD-induced mice [24], suggesting that UPF exerts a protective effect against inflammation-associated oxidative damage by enhancing endogenous antioxidant defences and reducing lipid peroxidation, thereby contributing to the amelioration of oxidative stress in various inflammatory disease models.

Recent studies have also demonstrated that UPF exhibits strong antioxidant activities in an in vivo zebrafish model, a vertebrate species with notable biochemical and physiological similarities to mammals [31,46]. The findings suggest that UPF effectively mitigates oxidative stress induced by 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) and H₂O₂, as evidenced by increased survival rates, reduced cellular apoptosis, decreased heart rate, and lower levels of ROS and lipid peroxidation [31,46].

UPF has been shown to ameliorate inflammatory responses by modulating gut microbiota composition. A bidirectional relationship exists between gut dysbiosis and host inflammation, whereby microbial imbalance promotes inflammatory processes, which in turn further disrupt the gut microbial ecosystem [47,48,49,50]. Recent studies have indicated that UPF treatment significantly attenuated intestinal inflammation by restoring microbial balance, notably decreasing Firmicutes and increasing Bacteroidetes in the gut of HFD-induced obese mice [44,51,52,53,54]. Comparable outcomes were observed in FD-induced inflammatory mouse models, where 27 days of oral UPF administration (300 and 400 mg/kg/day) led to a marked increase in Bacteroidetes and a reduction in Firmicutes within colon tissues [24,55]. As the dominant phyla in the gut, Firmicutes and Bacteroidetes play key roles in maintaining intestinal homeostasis [56], and imbalances in their ratio have been associated with various inflammatory disorders [57,58,59,60]. The anti-inflammatory effects of UPF may also derive from its prebiotic properties, as evidenced by reductions in pathogenic taxa (Faecalibaculum, Desulfovibrionales, Proteobacteria, and Clostridia) and enrichment of beneficial bacteria (Akkermania muciniphila, Bacteroides, Bifidobacterium spp., and Lactobacillus) [52,53,54,61]. Additionally, Park et al. (2024) reported that 4 weeks of UPF supplementation (50, 100, and 200 mg/kg/day) significantly increased the abundance of Papillibacter cinnamivorans, a butyrate-producing bacterium, in immunosuppressed rats [62]. Butyrate, one of the short-chain fatty acids (SCFAs), mitigates inflammation by interacting with immune cells, promoting anti-inflammatory cytokines, and suppressing pro-inflammatory mediators through G-protein coupled receptors (GPR41/43) and inhibition of histone deacetylases (HDACs) [63,64]. Similarly, Zheng et al. (2023) have suggested that 27 days of UPF supplementation (400 mg/kg/day) significantly restored HFD-induced reduction in colonic SCFAs, including acetate, propionate, and butyrate [24], suggesting that UPF may exert its anti-inflammatory effects, at least in part, by restoring SCFA levels and modulating immune responses through established SCFA-mediated pathways.

UPF has been reported to attenuate immune cell infiltration, including macrophages and T cells, and to ameliorate inflammatory responses in allergic conditions. Herath et al. (2020) indicated that 7 days of UPF oral gavage (400 mg/kg/day) significantly reduced PM-exacerbated infiltration of inflammatory cells, such as F4/80⁺ macrophages, CD4⁺ T lymphocytes, Gr-1⁺ granulocytes, and eosinophils, in the trachea and lungs of OVA-sensitised mice [42]. The results also showed that UPF decreased serum level of immunoglobulin E (Ige) and suppressed inflammatory provocation-induced increase in goblet cell hyperplasia and mucus secretion [42], suggesting potent therapeutic effects of UPF in allergic airway inflammation. Similarly, Yu et al. (2024) demonstrated that 16 days administration of ethanol-extracted UPE (50, 100, and 200 mg/kg/day) mitigated combined allergic rhinitis and asthma syndrome by inhibiting the accumulation of inflammatory cells, including epithelial cells, eosinophils, neutrophils, lymphocytes, and macrophages, in both nasal and bronchoalveolar lavage fluid, as well as a reduction in Th2 cytokines expression (IL-4, IL-5, and IL-13) [65].

The capability of UPF to re-establish immune homeostasis also plays a significant role in mitigating inflammatory conditions. Several in vivo studies have demonstrated that UPF exerts immunomodulatory effects by upregulating the expression of the anti-inflammatory cytokine IL-10 while concurrently downregulating the production of pro-inflammatory cytokines in various animal models of inflammatory intestinal diseases [44,53,55,66].

The main results of in vivo evaluations of UPF effects are listed in Table 2.

2.3. Clinical Trials

A growing body of clinical evidence supports the therapeutic potential of UPF in modulating metabolic, immune, and inflammatory responses in humans. Various human studies have demonstrated that incorporating Undaria pinnatifida (4–6 g/day) into diets help improve metabolic parameters, including suppressed postprandial glycaemia, modulated appetite sensations, reduced waist circumference and blood pressure, as well as a decrease in total cholesterol, LDL-cholesterol, and resistin levels [67,68,69,70]. Undaria pinnatifida also exerts potent immunostimulatory properties to manage Herpes infections by promoting healing and preventing reactivation [71]. Moreover, a clinical trial showed that a single dose of UPF (1 g) modulated microRNA expression related to immune response and inflammation, highlighting its systemic regulatory potential [72]. Additionally, a combination of UPF and Fucus vesiculosus fucoidan significantly increased faecal lysozyme levels, a protein known for its antimicrobial and anti-inflammatory functions, suggesting that UPF may promote mucosal barrier integrity and reduce mucosal inflammation [73]. Cox et al. (2023) reported that 3 weeks of UPF supplementation (1 g/day) significantly increased salivary immunoglobulin (Ig) A contents after an intensified training, indicating UPF properties to enhance mucosal immunity and provide protective anti-inflammatory benefits [74,75]. In a double-blind randomised placebo-controlled clinical trial, 2 weeks of UPF administration (1 g/day) significantly suppressed the upregulation of inflammatory cytokines induced by high-intensity exercise [76]. Similarly, UPF combined with green-lipped mussel mitigated joint pain and prediabetes in a randomised, double-blinded clinical setting, demonstrating that UPF elicits antioxidant and anti-inflammatory effects [77].

3. Neuroprotective Effect of UPF

Scientific literature has reported an increasing number of studies highlighting the neuroprotective effects of UPF in promoting brain health and mitigating the progression of neurodegenerative diseases such as Alzheimer’s (AD). These effects arise from a multifactorial interplay involving anti-inflammatory [13], anti-apoptotic [78], antiviral [17], and antioxidant activities [79] of UPF. Findings from both in vitro and in vivo investigations demonstrate that UPF can attenuate neuronal apoptosis, inhibit amyloid-β (Aβ) aggregation, and suppress the activation of microglia and astrocytes by reducing oxidative stress and neuroinflammation across various experimental models of neurodegenerative conditions [13,17].

3.1. In Vitro Studies

Several in vitro studies demonstrated that UPF is capable of suppressing inflammation in neurodegenerative conditions, primarily through inhibition of the NF-κB signalling pathway and modulation of the Akt/mTOR and AMPK/mTOR pathways. Notably, Giuliani et al. (2025) reported that UPF (100 µg/ml) significantly attenuated herpes simplex virus type I (HSV-1)-induced AD-like pathology. This included a reduction in amyloid precursor protein (APP) production and Aβ synthesis, alongside inhibiting NF-κB pathway activation and reducing IL-6 expression [17]. Ethanol-extracted UPE (5 µg/ml) also has been suggested to reduce endoplasmic reticulum (ER) stress and increase cell viability in hypothalamic neurons via Akt/mTOR signalling, highlighting its anti-inflammatory and neuroprotective potential [80]. ER stress is closely linked to the activation of inflammatory responses and is increasingly recognised as a contributing factor in the pathogenesis of various neurodegenerative diseases [81]. Additionally, Chen et al. (2025) suggested that low molecular weight UPF (0.125 mg/ml) significantly ameliorated LPS-induced macrophage inflammatory state by promoting its polarisation from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype through the AMPK/mTOR pathway [82]. Literature has indicated that modulating the AMPK/mTOR pathway regulates microglia polarisation and reduces neuroinflammation [83].

UPF has also been shown to exert neuroprotective effects in various in vitro cell models of neurodegeneration by enhancing cell viability and attenuating cytotoxicity, particularly in response to neurotoxic insults such as Aβ and oxidative stress [17,78,79,84,85,86]. For instance, Wei et al. (2017) demonstrated that pre-treatment with UPF (100, 200, 400 µg/ml) for 24 hours protected PC12 cells from apoptosis induced by Aβ_25–35 and d-galactose (D-Gal), alongside elevated levels of SOD and GSH [79]. Similar effects were observed in a rat cholinergic basal forebrain neuron model of AD conditions, where treatment of a commercial UPF (1 µM) inhibited cellular and neurotoxic effects of Aβ₁₋₄₂ and suppressed ROS production [84]. In addition, UPF demonstrated strong free radical-scavenging activity, effectively inhibiting DPPH and hydroxyl radicals, and reducing ROS production as well as Aβ synthesis in HSV-1-infected retinal pigment epithelium (RPE) cells [17]. HSV-1 infection and Aβ synthesis have been associated with the development of AD [87]. Mohibbullah et al. (2018) also reported that ethanol-extracted UPE (15 µg/ml) enhanced cell viability and reduced cytotoxicity in hippocampal neurons by decreasing ROS generation, membrane phosphatidylserine exposure, genomic DNA degradation, and restoring hypoxia-induced mitochondrial depolarization [86]. Notably, although both fucoidans reduced Aβ_1–42-induced oxidative stress and apoptosis levels, UPF exhibited stronger neuroprotective effects than Fucus vesiculosus fucoidan, likely due to its distinct structural features such as higher sulphate content and specific molecular weight distribution [78].

The key in vitro outcomes regarding the neuroprotective activity of UPF are comprehensively outlined in Table 3.

3.2. In Vivo Studies

UPF has emerged as a promising neuroprotective agent due to its ability to attenuate neuroinflammation. For example, 10 weeks of UPF oral administration (400 mg/kg/day) significantly attenuated HFD-induced neuroinflammation in obese mice by downregulating the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IFN-γ) in hypothalamic tissues and suppressing the production of inflammation-related proteins (leucine-rich repeat serine/threonine-protein kinase 2 [Lrrk2], wolframin [Wfs1], and neuroglobin [Ngb]) in the nucleus accumbens [13]. Hu et al. (2014) also reported that a 10-day intrathecal injection of commercial UPF (15, 50, and 100 mg/kg/day) mitigated rat neuropathic pain induced by L5 spinal nerve ligation (SNL). The findings suggested that UPF inhibited microglia and astrocyte activation in the lumbar spinal cord and reduced TNF-α, IL-1β, and IL-6 expression in the spinal dorsal horn [88]. Similarly, Che et al. (2017) demonstrated that intraperitoneal injection of commercial UPF (80 and 160 mg/kg/day) for 7 days significantly ameliorated cerebral ischemia-reperfusion injury (IRI)-caused neurological impairment in rats and significantly decreased the levels of pro-inflammatory cytokines, including IL-1β, IL-6, MPO, and TNF-α [89].

Several in vivo studies have highlighted the effects of UPF in neuroprotection and rehabilitation, demonstrating its beneficial properties in inhibiting oxidative stress and attenuation neurotoxic protein aggregation. Specifically, 21 days of oral administration of UPF (50, 100, and 200 mg/kg/day) improved learning and memory impairments in AD-model mice induced by D-Gal, where UPF exhibited potent antioxidant effects, enhancing SOD and GSH activity [79]. The ability of UPF to promote learning and memory in this study is largely attributed to its enhancement of acetylcholine (ACh) content and choline acetyl transferase (ChAT) enzyme activity, along with the inhibition of acetylcholine esterase (AChE) enzyme activity, which are key factors involved in the cognitive dysfunction characteristic of AD [79]. UPF also has been reported to reduce oxidative stress-related proteins (SOD and MDA), suppress pro-apoptotic proteins (p-p53 and Bax), and elevate anti-apoptotic protein (Bcl-2) in IRI-induced rats by inhibiting MAPK pathway [89]. Similarly, Wang et al. (2016) illustrated that intraperitoneal pre-treatment of low molecular weight commercial UPF (50 mg/kg) significantly suppressed neuronal damage and neurological deficits in aged mice after traumatic brain injury (TBI), where UPF exerted these protective effects by inhibiting oxidative stress (reduced MDA, 4-hydroxynonenal [4-HNE], ROS and increased CAT, SOD, GPx) and mitochondrial dysfunction (suppressed cytochrome c release) [90]. In addition, the neuroprotective effects of UPF have been found in an invertebrate model of AD, where UPF (500 ng/ml) alleviated Aβ-induced paralysis by decreasing Aβ deposition and ROS production in transgenic Caenorhabditis elegans [91]. Taken together, these findings suggest that UPF confers neuroprotection across diverse experimental models by modulating oxidative stress, mitochondrial integrity, and apoptosis-related pathways, supporting its potential as a therapeutic agent in the prevention and treatment of neurodegenerative disorders (Table 4).

4. Conclusions

In summary, Undaria pinnatifida fucoidan (UPF) exhibits robust anti-inflammatory and neuroprotective properties, as demonstrated by both in vitro and in vivo studies. UPF exerts its anti-inflammatory effects through the suppression of pro-inflammatory cytokines, inhibition of key signalling pathways (NF-κB, MAPKs), reduction of oxidative stress, and modulation of immune responses, including chemokine expression and gut microbiota composition. Its neuroprotective potential is similarly multifaceted, involving attenuation of neuroinflammation, oxidative damage, and amyloidogenic processes, alongside enhancement of antioxidant defences and neuronal function. Despite these promising findings, the molecular mechanisms underlying UPF’s actions remain incompletely understood, and its therapeutic effects in humans have yet to be fully confirmed. Future studies should prioritise detailed mechanistic investigations, standardisation of UPF extraction and characterisation, and the development of targeted delivery systems to enhance its bioavailability. Most critically, well-designed clinical trials are essential to validate UPF’s efficacy and safety, and to support its integration into evidence-based therapeutic strategies.