Neuroprotective Bioactive Compounds from Marine Algae and Their By-Products Against Cerebral Ischemia–Reperfusion Injury: A Comprehensive Review

Abstract

Cerebral ischemia–reperfusion (I/R) injury is a leading cause of death and long-term disability worldwide, characterized by a complex interplay of pathophysiological mechanisms and currently limited therapeutic options. This critical unmet need underscores the importance of exploring novel multi-targeted neuroprotective agents. Marine algae represent a rich and underexplored source of structurally diverse bioactive compounds with promising therapeutic potential against cerebral I/R injury. This comprehensive review systematically summarizes the preclinical evidence on the neuroprotective effects and underlying mechanisms of key bioactive compounds found in marine algae, including polysaccharides (e.g., fucoidan, laminarin, porphyran), carotenoids (e.g., astaxanthin, fucoxanthin, lutein, zeaxanthin), polyphenols (e.g., dieckol, phlorotannins), and sterols (e.g., β-sitosterol). These compounds consistently demonstrate significant efficacy across various in vitro and in vivo models, primarily through multifaceted actions encompassing anti-excitotoxic, antioxidant, anti-inflammatory, and anti-apoptotic effects, as well as the modulation of crucial signaling pathways and preservation of blood–brain barrier integrity. While the existing preclinical evidence is highly promising, successful clinical translation necessitates further rigorous research to overcome challenges related to precise molecular understanding, translational relevance, pharmacokinetics, and safety. Beyond their pharmacological significance, the sustainable utilization of marine by-products as renewable sources of bioactive agents further highlights their dual value, offering not only novel therapeutic avenues for cerebral I/R injury but also contributing to marine resource valorization.

1. Introduction

Cerebral ischemia, predominantly caused by thrombotic or embolic stroke (ischemic stroke), constitutes a leading cause of death and long-term adult disability worldwide [1]. This pathological condition is characterized by a significant reduction in cerebral blood flow, resulting in insufficient delivery of oxygen and nutrients to the brain tissues [2]. Due to the brain’s substantial metabolic demand and limited energy reserves, it exhibits an inherent vulnerability to ischemic damage [3]. The brain’s heightened susceptibility to ischemic injury provides the context for understanding how energy failure rapidly initiates a sequence of secondary pathological processes. The primary ischemic event in the brain triggers a complex and detrimental cascade of pathophysiological events, including excitotoxicity, oxidative stress, blood–brain barrier (BBB) breakdown, neuroinflammation, and ultimately neuronal death [4,5,6]. These intricate events not only precipitate immediate neuronal damage but also paradoxically exacerbate secondary injury following reperfusion, compounding the overall neurological deficit [7,8].

Despite remarkable advances in the acute management of cerebral ischemia, notably through interventions such as recombinant tissue plasminogen activator and endovascular thrombectomy, the overall therapeutic landscape remains constrained. This limitation primarily stems from narrow therapeutic windows and a critical absence of clinically approved neuroprotective drugs [9,10]. Recognizing the inherently complex and multifaceted nature of cerebral ischemia–reperfusion (I/R) injury, it has become evident that single-target approaches have yielded limited clinical success. This underscores an urgent and unmet need for novel, multi-targeted neuroprotective agents capable of simultaneously modulating diverse injury pathways implicated in cerebral I/R pathology [11,12]. Consequently, there is a burgeoning scientific interest in identifying naturally derived bioactive compounds, particularly those with multi-target capabilities, to effectively mitigate the various pathological processes associated with cerebral I/R injury [13,14].

Marine algae, categorized into brown (Phaeophyceae), red (Rhodophyceae), and green (Chlorophyceae) species, are abundant sources of structurally diverse and biologically active compounds, including polysaccharides, carotenoids, polyphenols, and sterols [15,16]. These marine algae thrive in challenging marine environments, leading to the biosynthesis of unique secondary metabolites not commonly found in terrestrial plants, making them a rich reservoir for novel therapeutic agents [17]. Indeed, over the last two decades, an increasing number of studies have demonstrated the neuroprotective potential of various compounds found in marine algae in experimental models of cerebral I/R [18,19,20].

In this comprehensive review, we aim to systematically outline the major pathophysiological mechanisms involved in cerebral I/R injury. Furthermore, we summarize the accumulating preclinical evidence supporting the neuroprotective effects and elucidating their underlying mechanisms of action, with a particular focus on selected bioactive compounds found in marine algae. Finally, we discuss current limitations in this research area and delineate future perspectives for the translational development of these promising compounds as potential therapeutic agents against cerebral I/R injury. In addition, by framing marine algae and their by-products as sustainable and renewable resources, this review underscores their dual significance: not only as potential neuroprotective agents but also as valuable contributors to marine resource utilization and valorization.

2. Pathophysiology of Cerebral I/R Injury

Cerebral I/R injury is a multifactorial process characterized by a complex interplay of overlapping cellular and molecular mechanisms, ultimately leading to neuronal death and neurological dysfunction [8]. A comprehensive understanding of these pathophysiological cascades is therefore essential for identifying effective therapeutic targets to mitigate cerebral I/R injury [12]. As illustrated in Figure 1, the main pathophysiological mechanisms contributing to cerebral I/R injury are summarized and detailed below.

2.1. Excitotoxicity

One of the earliest events in cerebral I/R injury is glutamate-mediated excitotoxicity [21]. The interruption of blood supply leads to acute energy failure, severely impairing Na⁺/K⁺ adenosine triphosphatase activity and consequently causing rapid depolarization of neuronal membranes [22]. This profound depolarization triggers the excessive release of excitatory neurotransmitters, most notably glutamate, into the synaptic cleft. Subsequent overactivation of ionotropic glutamate receptors, such as N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, results in an uncontrolled influx of Ca²⁺ and Na⁺ into neurons [23,24]. This massive influx of intracellular Ca²⁺ serves a critical trigger, activating a deleterious series of calcium-dependent enzymes, including proteases, phospholipases, and endonucleases. These enzymes aggressively degrade cytoskeletal proteins, initiate lipid peroxidation, and induce DNA fragmentation [25]. Thus, prolonged excitotoxic signaling not only leads to immediate irreversible neuronal injury but also initiates and amplifies subsequent downstream pathophysiological processes [26].

2.2. Oxidative Stress

Cerebral I/R markedly exacerbates neuronal damage through the excessive production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) [27,28]. This phenomenon, known as oxidative stress, plays a critical role in the pathogenesis of cerebral I/R injury [29]. Major endogenous sources of ROS during cerebral I/R include mitochondrial dysfunction, activation of xanthine oxidase, nicotinamide adenine dinucleotide phosphate oxidase, and uncoupled nitric oxide synthase. These sources collectively lead to the generation of highly reactive molecules such as superoxide anion (O₂⁻), hydrogen peroxide (H₂O₂), and hydroxyl radical (•OH) [30]. Concurrently, RNS, particularly peroxynitrite (ONOO⁻), are formed through the reaction between nitric oxide (NO) and superoxide. These highly reactive species inflict severe damage on crucial cellular macromolecules, including lipids (via lipid peroxidation), proteins (via carbonylation), and DNA (via strand breaks). This widespread damage ultimately compromises cell membrane integrity, disrupts vital enzyme function, and perturbs intracellular signaling pathways [27,29]. Furthermore, oxidative stress activates redox-sensitive transcription factors, such as nuclear factor-kappa B (NF-κB) and activator protein-1, thereby promoting the expression of pro-inflammatory cytokines and pro-apoptotic genes [28,31]. Although endogenous antioxidant systems (e.g., glutathione [GSH)], superoxide dismutase [SOD], catalase [CAT], and peroxiredoxins) typically serve to counteract ROS/RNS, their capacity is severely overwhelmed and compromised following cerebral I/R, further exacerbating the pervasive oxidative damage [32].

2.3. Inflammatory Response

Neuroinflammation is a pivotal component of cerebral I/R injury and significantly contributes to both acute and chronic neuronal damage [33,34]. The initial ischemic insult activates resident glial cells, primarily microglia and astrocytes, within the brain parenchyma. Concurrently, it promotes the infiltration of various peripheral immune cells, including neutrophils, monocytes, and lymphocytes, across the compromised BBB into the injured brain tissue [35,36]. These activated and infiltrated immune cells collectively release a wide range of pro-inflammatory mediators. These include pivotal cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6; potent chemokines like monocyte chemoattractant protein-1 and C-X-C motif chemokine ligand 10; and various matrix metalloproteinases (MMPs), including MMP-2 and MMP-9, thereby profoundly exacerbating neuronal injury and promoting secondary brain damage [36]. The complex inflammatory cascade is largely driven by key intracellular signaling pathways, such as the toll-like receptor-mediated activation of NF-κB and mitogen-activated protein kinases (MAPKs), which critically regulate the transcription of numerous inflammatory genes [33,37]. Although acute inflammation responses can paradoxically support initial tissue repair and debris clearance, persistent, dysregulated or excessive inflammation leads to detrimental outcomes, including sustained neurotoxicity, glial scarring, impaired synaptic remodeling, and progressive neurodegeneration [38]. Consequently, modulating or targeting neuroinflammation represents a promising and critical therapeutic strategy for mitigating cerebral I/R injury and functional recovery [39,40].

2.4. Apoptosis and Necrosis

Neuronal death is a critical pathological outcome following cerebral I/R injury, involving both apoptosis and necrosis, which manifest with distinct spatial and temporal characteristics [41]. Necrosis primarily occurs in the ischemic core, characterized by rapid and uncontrolled cell death due to severe energy failure, irreversible loss of ion homeostasis, and widespread membrane rupture [42]. In contrast, apoptosis, or programmed cell death, is more prevalent in the ischemic penumbra, unfolding in a regulated manner via two main pathways: the intrinsic (mitochondrial) and extrinsic (death receptor-mediated) pathways [43,44]. The intrinsic pathway is activated by cellular stressors, leading to mitochondrial outer membrane permeabilization (MOMP) and subsequent cytochrome c (Cyt c) release. This process is regulated by the B-cell lymphoma-2 (Bcl-2) family proteins. Pro-apoptotic members, including Bcl-2 associated X protein (Bax) and Bcl-2 homologous antagonist/killer (Bak), promote MOMP, whereas anti-apoptotic members, such as Bcl-2 and Bcl-extra large, actively inhibit it [45,46]. Cyt c release consequently activates the caspase cascade (caspase-9, caspase-3), ultimately leading to cellular dismantling [47,48]. Conversely, the extrinsic pathway is triggered by the binding of ligands, including Fas ligand (FasL) and TNF-α, to their specific death receptors, resulting in the activation of caspase-8 and downstream caspases [49]. Additionally, caspase-independent apoptosis, exemplified by apoptosis-inducing factor translocation from mitochondria to the nucleus, also contributes to neuronal death following cerebral I/R injury [50]. This intricate interplay of diverse neuronal cell death pathways highlights the complexity of cerebral I/R injury.

2.5. Autophagy

Autophagy, a highly conserved lysosome-dependent cellular process, plays a crucial role in maintain cellular homeostasis by degrading and recycling damaged cellular components [51]. However, its role in cerebral I/R injury is complex and context-dependent, exhibiting both protective and deleterious effects [52]. Specifically, moderate autophagy, particularly in the form of mitophagy (selective removal of damaged mitochondria), can be neuroprotective by eliminating dysfunctional mitochondria, thereby reducing the production of ROS and promoting neuronal survival [53,54]. In contrast, excessive or dysregulated autophagy can induce neuronal death [53,55]. The induction of autophagy following cerebral I/R injury is largely influenced by cellular energy status. Energy depletion during ischemia activates AMP-activated protein kinase, which in turn inhibits the mammalian target of rapamycin (mTOR). This inhibition relieves mTOR’s repressive effect on Unc-51 like autophagy activating kinase 1 (ULK1), thereby initiating the autophagic process [56]. ULK1 then forms a complex with autophagy related 13 and FAK-family interacting protein of 200 kDa, leading to phosphorylation of Beclin 1 and facilitating autophagosome nucleation [55,57]. The subsequent transformation of microtubule-associated protein light chain 3 (LC3)-I to LC3-II serves as a key marker of autophagosome membrane elongation and maturation [56]. Experimental studies using focal cerebral I/R models have consistently demonstrated the protective role of autophagy. For instance, pharmacological induction of autophagy by rapamycin, an mTOR inhibitor, significantly increases the expression of autophagy markers such as Beclin 1 and LC3-II, leading to reduced infarct volumes and improved neurological outcomes. Conversely, inhibition of autophagy with 3-methyladenine diminishes these neuroprotective effects, further suggesting that optimally regulated autophagy plays a critical protective role during cerebral I/R injury [58,59]. These findings underscore the importance of precise, context-dependent autophagy regulation for effective neuroprotection against cerebral I/R injury.

2.6. BBB Breakdown

The BBB, a complex structure comprising endothelial cells, astrocytic endfeet, pericytes, and a basement membrane, plays a crucial role in maintaining brain homeostasis by strictly regulating the exchange of substances between the blood and brain parenchyma, thereby protecting the brain from harmful substances and maintaining a stable microenvironment [60]. However, cerebral I/R injury severely disrupts the structural and functional integrity of the BBB, a critical event that exacerbates neuronal injury. This breakdown is characterized by increased endothelial permeability, which facilitates the extravasation of plasma proteins, infiltration of peripheral immune cells, and the consequent development of vasogenic edema [61]. Multiple intricate mechanisms drive BBB breakdown following cerebral I/R injury. For instance, the excessive generation of ROS directly damages endothelial cells and leads to the degradation of tight junction proteins such as claudins, occludin, and zonula occludens-1, thereby compromising barrier integrity [62]. Furthermore, increased expression and activity of MMPs, particularly MMP-2 and MMP-9, progressively degrade the extracellular matrix and basement membrane, critically weakening the BBB structure [63]. Concurrently, pro-inflammatory cytokines released following cerebral I/R injury induce endothelial cell activation, leading to dysfunction and increased permeability of the BBB [64]. Beyond exacerbating neuronal injury by promoting neuroinflammation and edema, BBB impairment also poses a significant challenge for the effective delivery of therapeutic agents to the ischemic brain region [60,65]. Therefore, preserving BBB integrity or promoting its restoration represents an important and active target for therapeutic intervention in cerebral I/R injury [37].

2.7. Other Pathophysiological Mechanisms

Beyond the primary mechanisms already described above, several other pathophysiological processes contribute to cerebral I/R injury. Specifically, cholinergic dysfunction is observed following cerebral I/R injury, which leads to impaired cognitive function through reduced acetylcholine levels and disrupted cholinergic signaling [66,67]. Similarly, white matter injury, characterized by oligodendrocyte loss and axonal degeneration, is also a significant contributor, especially in aged or subcortical stroke models, ultimately leading to persistent neurological deficits [68]. Moreover, epigenetic modifications, such as changes in DNA methylation, histone acetylation, and non-coding RNA expression, significantly impact the expression of genes related to inflammation, apoptosis, and repair mechanisms [69]. Furthermore, the dysfunction of the neurovascular unit and the glymphatic system further intensifies cerebral I/R injury by impairing blood flow regulation and the clearance of toxic metabolites [70,71]. These additional mechanisms highlight the intricate complexity of cerebral I/R injury and underscore the urgent need for multi-targeted therapeutic strategies.

3. Neuroprotective Effects and Underlying Mechanisms of Bioactive Compounds Found in Marine Algae

Marine algae contain structurally diverse bioactive compounds that exert pleiotropic neuroprotective effects in cerebral I/R injury. These agents commonly act by reducing oxidative stress and inflammation, inhibiting apoptosis, and preserving BBB integrity. The following subsections summarize the major classes of these compounds (Figure 2), including polysaccharides, carotenoids, polyphenols, and sterols, and outline the preclinical evidence supporting their neuroprotective mechanisms.

3.1. Polysaccharides

Marine algae-derived polysaccharides, especially sulfated polysaccharides, have garnered considerable attention due to their diverse and potent pharmacological properties, including antioxidant, anti-inflammatory, and anti-apoptotic effects [72]. A growing body of preclinical evidence demonstrates that various marine algal polysaccharides, such as fucoidan, laminarin, and porphyran, exert significant neuroprotective actions. These effects are mediated through the modulation of multiple pathophysiological mechanisms implicated in cerebral I/R injury. Below, we summarize the key preclinical findings supporting their neuroprotective efficacy against cerebral I/R injury (Table 1).

3.1.1. Fucoidan

Fucoidan (Figure 2A), a sulfated polysaccharide primarily isolated from brown algae such as Fucus vesiculosus and Undaria pinnatifida, has demonstrated robust neuroprotective potential in various animal models of cerebral I/R. Kim et al. (2019) reported that intraperitoneal (i.p.) administration of fucoidan (50 mg/kg/day for 3 days before I/R) significantly attenuated hippocampal neuronal death in gerbils subjected to transient global cerebral I/R [19]. This protective effect was associated with reduced activation of astrocytes and microglia (evidenced by decreased immunoreactivity of glial fibrillary acidic protein [GFAP, a marker for astrocyte] and ionized calcium binding adapter molecule 1 [Iba-1, a marker for microglia]), lowered oxidative stress markers (4-hydroxy-2-noneal [4-HNE, a marker for lipid peroxidation] and dihydroethidium [DHE, a probe detecting O₂⁻]), and elevated levels of endogenous antioxidant enzymes (SOD1 and SOD2) [19]. Building on this, in another study using high-fat diet-induced obese gerbils, the same fucoidan dosing regimen provided effective neuroprotection by mitigating oxidative stress, thereby demonstrating the compound’s protective efficacy even under conditions of metabolic stress [73]. Che et al. (2017) also investigated the neuroprotective role of fucoidan in a rat model of transient focal cerebral I/R [74]. Fucoidan administration (80 and 160 mg/kg/day, i.p.) for 7 days prior to I/R significantly reduced neurological deficits and infarct volume. Mechanistically, this protection was associated with decreased levels of inflammatory mediators (IL-1β, IL-6, TNF-α, and myeloperoxidase [MPO, a marker of neutrophil infiltration]), reduced oxidative stress (evidenced by malondialdehyde [MDA, a marker for lipid peroxidation]), modulation of apoptosis-related proteins (reduced phospho-p53 and Bax, alongside increased Bcl-2), and suppression of mitogen-activated protein kinase (MAPK) pathway activation, specifically evidenced by reduced phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 [74]. Nambi et al. (2023) further evaluated the effects of fucoidan (50 mg/kg, i.p.) administered immediately following transient focal cerebral I/R in rats, in combination with cerebrolysin, a multimodal neuropeptide preparation [75]. This combination therapy significantly reduced neurological deficits and infarct size, while also effectively preserving BBB integrity, as evidenced by a reduction in Evans blue dye extravasation (indicative of albumin leakage). Additionally, it lowered the levels of several inflammatory markers (TNF-α, NF-κB, IL-1α, IL1-β, IL-6, cluster of differentiation 68 [CD68], and cyclooxygenase [COX]-2) and downregulated the expression of inflammatory genes (IL-1α, IL-1β, IL-6, Iba-1, and COX-2) compared to monotherapy [75].

In a rat model of systemic inflammation-exacerbated cerebral I/R injury, Kang et al. (2012) administered fucoidan (50 mg/kg, i.p.) 1 h prior to transient focal cerebral I/R [76]. This treatment significantly reduced neutrophil infiltration into the ischemic cortex (indicated by decreased MPO activity) and suppressed the expression of inflammatory cytokines (TNF-α and IL-8), ultimately resulting in reduced infarct volume and improved neurological outcomes [76].

Furthermore, cognitive outcomes demonstrated improvement following chronic administration of fucoidan. Kharkongor et al. (2025) administered fucoidan (50 mg/kg/day, i.p.) to rats for 7 and 30 days following transient global cerebral I/R, either alone or in combined with environmental enrichment [77]. Chronic fucoidan administration significantly improved cognitive deficits, preserved hippocampal neurons, reduced inflammatory markers (GFAP, IL 1β, IL 6, NF-κB, and TNF α) and oxidative stress (lipid peroxidation [LPO]), enhanced antioxidant enzyme activities (SOD, CAT, GSH, glutathione-s-transferase [GST], and glutathione peroxidase [GPX]), and elevated synaptic protein markers (brain derived neurotrophic factor [BDNF], synaptophysin [SYP], and postsynaptic density protein 95 [PSD-95]). These beneficial effects were particularly pronounced when fucoidan was combined with environmental enrichment, suggesting a synergistic therapeutic potential [77].

Collectively, these findings suggest that fucoidan exerts potent neuroprotection through both acute and chronic dosing strategies, with effective doses ranging from 50 to 160 mg/kg, administered via intraperitoneal injection. Beneficial outcomes are achievable with both pre- or post-I/R administration, highlighting fucoidan’s versatile therapeutic potential in cerebral I/R injury. Notably, fucoidan is often derived from marine by-products of brown algae processing, underscoring its potential value as a sustainable biomedical resource.

3.1.2. Laminarin

Laminarin (Figure 2B), a water-soluble β-1,3-glucan primarily isolated from brown algae such as Laminaria species, has been investigated for its neuroprotective potential in experimental models of cerebral I/R. In an in vitro study using PC12 cells subjected to oxygen glucose deprivation/reoxygenation (OGD/R), administration of laminarin (0.5, 2.5, and 5 µg/mL) for 2 h significantly increased cell viability [78]. This treatment also notably reduced the levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), oxidative stress markers (ROS, lactate dehydrogenase [LDH], and MPO), and pro-apoptotic proteins (Bax and caspase-3), while simultaneously increasing the level of anti-apoptotic protein Bcl-2. These protective effects were specifically associated with the activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway and suppression of phosphatase and tensin homolog (PTEN) expression [78].

In vivo studies have further corroborated laminarin’s neuroprotective efficacy. Lee et al. (2020) demonstrated in a gerbil model of transient global cerebral I/R that pre-administration of laminarin (50 and 100 mg/kg/day, i.p.) for 7 days prior to I/R significantly reduced neuronal death and attenuated astrocytic and microglial activation in the hippocampal CA1 region [79]. Consistent with these findings, Park et al. (2020) similarly reported that pre-administration of laminarin (50 mg/kg/day, i.p.) in aged gerbils effectively protected hippocampal CA1 neurons and reduced oxidative stress markers (DHE and 4-HNE) and pro-inflammatory cytokines (TNF-α and IL-1β) [80]. Additionally, this administration significantly increased levels of endogenous antioxidant enzymes (SOD1 and SOD2) and beneficial anti-inflammatory cytokines (IL-4 and IL-13) [80].

Beyond pre-treatment strategies, Luo et al. (2022) investigated the effects of post-I/R administration in a rat model of transient focal cerebral I/R [81]. They administered laminarin (10 mg/kg/day, i.p.) for 7 days post-I/R, which significantly reduced infarct volume and improved neurological deficits. Importantly, transcriptomic analysis revealed that laminarin modulated gene expression associated with key processes such as angiogenesis, vascular development, immune and inflammatory responses, and cell death. This modulation involved a significant downregulation of inflammatory and apoptosis-related genes. These observed transcriptomic changes corresponded to improved histological and behavioral outcomes [81].

Collectively, these findings suggest that laminarin exerts potent neuroprotective effects at intraperitoneal doses ranging from 10 to 100 mg/kg/day. Its significant neuroprotective benefits are demonstrated in both pre- and post-I/R therapeutic strategies, primarily mediated through potent antioxidant, anti-inflammatory, and anti-apoptotic mechanisms involving key signaling pathway modulation. Given that laminarin can be obtained from by-products of Laminaria processing, its utilization highlights the broader potential of marine resource valorization in biomedical applications.

3.1.3. Porphyran

Porphyran (Figure 2C), a sulfated galactan derived from red algae including Porphyra yezoensis, has been studied less extensively than fucoidan and laminarin. Nevertheless, it has demonstrated considerable promise as a neuroprotective agent in animal models of cerebral I/R. In a study by Sun et al. (2018), rats were administered porphyran (100 mg/kg/day, i.p.) for 7 days prior to transient focal cerebral I/R [82]. This pretreatment significantly reduced infarct volume and neurological deficits. Mechanistically, these neuroprotective effects were accompanied by increased activities of endogenous antioxidant enzymes, including SOD, CAT, and GSH, as well as decreased levels of pro-inflammatory markers such as IL 1β, IL 6, TNF α, and nuclear NF-κB activation [82].

More recently, Kim et al. (2024) investigated porphyran’s effects following oral administration (50 mg/kg/day for 7 days prior to I/R) in a gerbil model of transient global cerebral I/R [83]. This pretreatment effectively suppressed microglial activation and proliferation. Crucially, it attenuated nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing protein-3 (NLRP3) inflammasome-mediated neuroinflammation by reducing the expression levels of key components, including NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), cleaved caspase-1, IL-1β, and IL-18. These actions collectively lead to preserved neuronal survival in the hippocampal CA1 region [83].

Additionally, Ahn et al. (2025) demonstrated that the therapeutic potential of post-I/R administration [84]. Oral administration of porphyran (50 mg/kg/day) for 5 days following transient global cerebral I/R significantly improved cognitive performance and restored acetylcholine (ACh) levels. The treatment also markedly reduced microglial activation and levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α). Furthermore, porphyran improved BBB integrity, as indicated by mitigated immunoglobulin G (IgG) leakage, in the gerbil hippocampus [84].

Collectively, these findings indicate that porphyran exerts neuroprotective effects through diverse mechanisms, including antioxidant and anti-inflammatory mechanisms. It demonstrates efficacy when administered via either intraperitoneal or oral routes, at doses ranging from 50 to 100 mg/kg/day. Importantly, both pre- and post-I/R therapeutic treatment approaches have shown significant neuroprotective benefits. As porphyran is frequently extracted from by-products generated during Porphyra cultivation and processing, its neuroprotective application exemplifies the conversion of marine by-products into high-value therapeutic agents.

Table 1. Neuroprotective activity of polysaccharides found in marine algae against cerebral I/R injury.

Compound	Algal Origin (If Any)	Effective Dose	Experimental Model	Significant Findings	Signaling Pathway	Pharmacological Markers	Reference
Fucoidan	Brown algae	50 mg/kg	Rat model of transient focal cerebral I/R with LPS	↓Infarct volume; ↓neutrophil infiltration; ↓inflammation	N/A	↓MPO; ↓TNF-α and IL-8	[76]
Fucoidan	Brown algae	80 and 160 mg/kg	Rat model of transient focal cerebral I/R	↓Neurological deficits; ↓infarct volume; ↓inflammation; ↓oxidative; ↓apoptosis	MAPK pathway	↓IL-1β, IL-6, TNF-α, and MPO; ↓MDA; ↑SOD; ↓phospho-p53 and Bax; ↑Bcl-2; ↑phospho-p38, phospho-ERK, and phospho-JNK	[74]
Fucoidan	Fucus vesiculosus (brown algae)	50 mg/kg	Gerbil model of transient global cerebral I/R	↓Hyperactivity; ↓neuronal death; ↓glial cell activation; ↓oxidative stress	N/A	↑GFAP and Iba-1; ↓DHE and 4-HNE; ↑SOD1 and SOD2	[19]
Fucoidan	Fucus vesiculosus (brown algae)	50 mg/kg	Obese gerbil model of transient global cerebral I/R	↓Neuronal death; ↓oxidative stress	N/A	↓DHE, 8-OHG, and 4-HNE; ↑SOD1 and SOD2	[73]
Fucoidan + cerebrolysin	Fucus vesiculosus (brown algae)	50 mg/kg	Rat model of transient focal cerebral I/R	↓Neurological deficits; ↓infarct volume; ↓BBB integrity; ↓inflammation	N/A	↓Evans blue dye extravasation; ↓TNF-α, NF-κB, IL-1α, IL-1β, IL-6, Iba-1, CD68, and COX-2; ↑IL-10 and CD31	[75]
Fucoidan + enriched environment	Brown algae	50 mg/kg	Rat model of transient global cerebral I/R	↑Cognitive deficits; ↓neuronal death; ↓inflammation; ↓oxidative stress; ↑synaptic markers	N/A	↓GFAP, IL-1β, IL-6, NF-κB, and TNF-α; ↓LPO; ↑SOD, CAT, GSH, GST, and GPX; ↑BDNF, SYP, and PSD-95	[77]
Laminarin	Laminaria digitate (brown algae)	50 and 100 mg/kg	Gerbil model of transient global cerebral I/R	↓Neuronal death; ↓glial cell activation	N/A	↓GFAP and Iba-1	[79]
Laminarin	Laminaria digitate (brown algae)	50 mg/kg	Aged gerbil model of transient global cerebral I/R	↓Neuronal death; ↓oxidative stress; ↓inflammation	N/A	↓DHE and 4-HNE; ↑SOD1 and SOD2; ↓TNF-α and IL-1β; ↑IL-4 and IL-13	[80]
Laminarin	Brown algae	0.5, 2.5, and 5 µg/mL	OGD/R model in PC12 cells	↑Cell viability; ↓oxidative stress; ↓inflammation ↓apoptosis	PI3K/Akt pathway	↑PCNA and Ki67; ↓ROS, LDH, and MPO; ↓TNF-α, IL-1β, and IL-6; ↓Bax and caspase-3; ↑Bcl-2; ↑PI3K, phospho-AKT, and PTEN	[78]
Laminarin	-	10 mg/kg	Rat model of transient focal cerebral I/R	↓Neurological deficits; ↓infarct volume; transcriptomic changes	N/A	N/A	[81]
Porphyran	Porphyra yezoensis (red algae)	100 mg/kg	Rat model of transient focal cerebral I/R	↓Neurological deficits; ↓infarct volume; ↓oxidative stress; ↓inflammation	N/A	↑SOD, CAT, and GSH; ↓IL-1β, IL-6, TNF-α, and nuclear NF-κB	[82]
Porphyran	-	50 mg/kg	Gerbil model of transient global cerebral I/R	↓Hyperactivity; ↓neuronal death; ↓microglial activation and proliferation; ↓inflammation	N/A	↓Iba-1; ↑NLRP3, ASC, cleaved caspase-1, IL-1β, and IL-18	[83]
Porphyran	-	50 mg/kg	Gerbil model of transient global cerebral I/R	↑Cognitive function; ↓cholinergic dysfunction; ↓microglial activation; ↓inflammation; ↓BBB leakage	N/A	↓Ach; ↓Iba-1, IL-1β, IL-6, and TNF-α; ↓IgG	[84]

N/A: not applicable; -: information not available.

Table 1. Neuroprotective activity of polysaccharides found in marine algae against cerebral I/R injury.

Compound	Algal Origin (If Any)	Effective Dose	Experimental Model	Significant Findings	Signaling Pathway	Pharmacological Markers	Reference
Fucoidan	Brown algae	50 mg/kg	Rat model of transient focal cerebral I/R with LPS	↓Infarct volume; ↓neutrophil infiltration; ↓inflammation	N/A	↓MPO; ↓TNF-α and IL-8	[76]
Fucoidan	Brown algae	80 and 160 mg/kg	Rat model of transient focal cerebral I/R	↓Neurological deficits; ↓infarct volume; ↓inflammation; ↓oxidative; ↓apoptosis	MAPK pathway	↓IL-1β, IL-6, TNF-α, and MPO; ↓MDA; ↑SOD; ↓phospho-p53 and Bax; ↑Bcl-2; ↑phospho-p38, phospho-ERK, and phospho-JNK	[74]
Fucoidan	Fucus vesiculosus (brown algae)	50 mg/kg	Gerbil model of transient global cerebral I/R	↓Hyperactivity; ↓neuronal death; ↓glial cell activation; ↓oxidative stress	N/A	↑GFAP and Iba-1; ↓DHE and 4-HNE; ↑SOD1 and SOD2	[19]
Fucoidan	Fucus vesiculosus (brown algae)	50 mg/kg	Obese gerbil model of transient global cerebral I/R	↓Neuronal death; ↓oxidative stress	N/A	↓DHE, 8-OHG, and 4-HNE; ↑SOD1 and SOD2	[73]
Fucoidan + cerebrolysin	Fucus vesiculosus (brown algae)	50 mg/kg	Rat model of transient focal cerebral I/R	↓Neurological deficits; ↓infarct volume; ↓BBB integrity; ↓inflammation	N/A	↓Evans blue dye extravasation; ↓TNF-α, NF-κB, IL-1α, IL-1β, IL-6, Iba-1, CD68, and COX-2; ↑IL-10 and CD31	[75]
Fucoidan + enriched environment	Brown algae	50 mg/kg	Rat model of transient global cerebral I/R	↑Cognitive deficits; ↓neuronal death; ↓inflammation; ↓oxidative stress; ↑synaptic markers	N/A	↓GFAP, IL-1β, IL-6, NF-κB, and TNF-α; ↓LPO; ↑SOD, CAT, GSH, GST, and GPX; ↑BDNF, SYP, and PSD-95	[77]
Laminarin	Laminaria digitate (brown algae)	50 and 100 mg/kg	Gerbil model of transient global cerebral I/R	↓Neuronal death; ↓glial cell activation	N/A	↓GFAP and Iba-1	[79]
Laminarin	Laminaria digitate (brown algae)	50 mg/kg	Aged gerbil model of transient global cerebral I/R	↓Neuronal death; ↓oxidative stress; ↓inflammation	N/A	↓DHE and 4-HNE; ↑SOD1 and SOD2; ↓TNF-α and IL-1β; ↑IL-4 and IL-13	[80]
Laminarin	Brown algae	0.5, 2.5, and 5 µg/mL	OGD/R model in PC12 cells	↑Cell viability; ↓oxidative stress; ↓inflammation ↓apoptosis	PI3K/Akt pathway	↑PCNA and Ki67; ↓ROS, LDH, and MPO; ↓TNF-α, IL-1β, and IL-6; ↓Bax and caspase-3; ↑Bcl-2; ↑PI3K, phospho-AKT, and PTEN	[78]
Laminarin	-	10 mg/kg	Rat model of transient focal cerebral I/R	↓Neurological deficits; ↓infarct volume; transcriptomic changes	N/A	N/A	[81]
Porphyran	Porphyra yezoensis (red algae)	100 mg/kg	Rat model of transient focal cerebral I/R	↓Neurological deficits; ↓infarct volume; ↓oxidative stress; ↓inflammation	N/A	↑SOD, CAT, and GSH; ↓IL-1β, IL-6, TNF-α, and nuclear NF-κB	[82]
Porphyran	-	50 mg/kg	Gerbil model of transient global cerebral I/R	↓Hyperactivity; ↓neuronal death; ↓microglial activation and proliferation; ↓inflammation	N/A	↓Iba-1; ↑NLRP3, ASC, cleaved caspase-1, IL-1β, and IL-18	[83]
Porphyran	-	50 mg/kg	Gerbil model of transient global cerebral I/R	↑Cognitive function; ↓cholinergic dysfunction; ↓microglial activation; ↓inflammation; ↓BBB leakage	N/A	↓Ach; ↓Iba-1, IL-1β, IL-6, and TNF-α; ↓IgG	[84]

N/A: not applicable; -: information not available.

3.2. Carotenoids

Carotenoids are lipid-soluble pigments renowned for their diverse biomedical properties, including potent antioxidant and anti-inflammatory activities. These compounds are abundantly found in various marine algae species such as Haematococcus pluvialis and Undaria pinnatifida [85,86]. Several specific carotenoids, including astaxanthin, fucoxanthin, zeaxanthin, and lutein have demonstrated promising neuroprotective effects in experimental models of cerebral I/R. These beneficial effects are mediated through the modulation of multiple pathophysiological mechanisms involved in cerebral I/R injury. In the following sections, we summarize the compelling preclinical evidence supporting the efficacy of these carotenoids present in marine algae in mitigating cerebral I/R injury (Table 2).

3.2.1. Astaxanthin

Astaxanthin (Figure 2D), a xanthophyll carotenoid primarily found in marine microalgae such as Haematococcus pluvialis, has demonstrated robust neuroprotective effects in various in vitro and in vivo models of cerebral I/R. In a rat model of transient focal cerebral I/R, Shen et al. (2009) reported that intracerebroventricular (i.c.v.) administration of astaxanthin (0.1 mM in 20 μL) approximately 10–15 min prior I/R significantly improved neurological function and reduced infarct volume [87]. These beneficial effects were associated with attenuated oxidative stress, excitotoxicity, and apoptosis. This was reflected by restored aconitase activity, reduced MDA and glutamate levels, fewer terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, and inhibited mitochondrial Cyt c release [87]. Similarly, Lu et al. (2010) found that oral pretreatment of astaxanthin (50 and 80 mg/kg, twice at 5 and 1 h prior to I/R) effectively reduced neurological deficits and infarct volume in a dose-dependent manner in rats subjected to transient focal cerebral I/R [88].

In vitro studies have further elucidated astaxanthin’s mechanisms of action. Lee et al. (2010) observed that pretreatment of astaxanthin (10, 25, 50 and 100 µM) for 24 h prior to OGD/R significantly enhanced cell viability and reduced oxidative stress in SH-SY5Y human neuroblastoma cells [89]. These protective effects involved inhibition of nitric oxide (NO) production, downregulation of inducible nitric oxide synthase (iNOS), and upregulation of antioxidant proteins such as heme oxygenase-1 (HO-1) and heat shock protein 70 (Hsp70) [89]. Furthermore, in a subsequent in vivo study, astaxanthin administration (30 mg/kg, i.p.) immediately and 30 min after transient global cerebral I/R in rats significantly reduced neuronal death in the hippocampal CA1 region, accompanied by the inhibition of poly(ADP-ribose) polymerase 1 (PARP-1) activation, which is linked to DNA repair and cell death pathways [89]. Expanding on in vitro findings, Zhang et al. (2020) demonstrated that pretreatment of astaxanthin (5, 10, 20, and 40 μM for 24 h) significantly improved cell viability, decreased apoptosis, and attenuated oxidative stress in SH-SY5Y cells exposed to OGD/R [90]. This protection was primarily achieved via activation of the PI3K/Akt/glycogen synthase kinase 3β (GSK3β)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway and subsequent upregulation of HO-1 [90].

Extending these findings to long-term outcomes and different routes, Xue et al. (2017) reported that oral administration of astaxanthin (10 mg/kg/day for 28 days) following repeated cerebral I/R significantly improved learning and memory deficits and rescued hippocampal neuronal loss in mice [91]. These effects correlated with attenuated oxidative stress (reduced MDA level; restored GSH and SOD activities) and inhibited apoptosis (reduced Cyt c, cleaved caspase-3, and Bax levels; increased Bcl-2 level) in the hippocampus [91]. Pan et al. (2017) further showed that oral administration of astaxanthin (5 and 10 mg/kg/day for 7 days) before transient focal cerebral I/R markedly improved neurological outcomes and reduced infarct volume in rats [92]. This was accompanied by decreased oxidative stress (lowered MDA level; elevated SOD activity; upregulated mRNA expressions of Nrf2, HO-1, and NAD(P)H quinone dehydrogenase 1 (NQO1), suppressed apoptosis (reduced Bax level; increased Bcl-2 level), and enhanced neural regeneration markers (GFAP, microtubule-associated protein 2 [MAP-2], brain-derived neurotrophic factor [BDNF] and growth-associated protein 43 [GAP43]) [92].

Nai et al. (2018) also evaluated neuroprotective effects of orally administered astaxanthin (20, 40, and 80 mg/kg, exact administration timing unspecified) in rats subjected to transient focal cerebral I/R [93]. Astaxanthin treatment significantly reduced neurological deficits and cerebral edema dose-dependently. These effects were associated with enhanced antioxidant enzyme activities (SOD, CAT, and GPX), reduced MDA level, and increased mRNA expressions of BDNF and nerve growth factor (NGF) [93]. Further expanding on functional recovery, Wang et al. (2019) demonstrated that oral administration of astaxanthin (30 mg/kg, twice daily for 28 days) in mice subjected to permanent focal cerebral ischemia significantly improved motor function and promoted axonal regeneration and reconnection [94]. These improvements were attributed to the activation of the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP-response element-binding protein (CREB) signaling pathway and increased GAP43 expression [94].

Supporting these observations, Cakir et al. (2020) reported that oral administration of astaxanthin (25 mg/kg, three times daily for 5 days) prior to transient focal cerebral I/R significantly improved neurological function and reduced neuronal loss in rat cortex and hippocampus [95]. Astaxanthin effectively enhanced antioxidant defense mechanisms (evidenced by elevated total antioxidant status [TAS], Nrf2 and Hsp70 levels), while simultaneously reducing oxidative stress and inflammation. This reduction was indicated by lowered total oxidant status (TOS), oxidative stress index (OSI), LPO, 8-hydroxy-2′-deoxyguanosine (8-OHdG, a marker of oxidative DNA damage), advanced oxidation protein products (AOPP), MPO, TNF-α, and IL-6 levels. Concurrently, it suppressed apoptosis, manifested by decreased caspase-3, -8, and -9 levels [95]. Yang et al. (2021) similarly demonstrated that oral astaxanthin pretreatment (100 mg/kg/day for 3 days prior to transient focal cerebral I/R) significantly improved neurological function, reduced brain edema, and decreased infarct volume in rats [96]. These beneficial effects were associated with decreased apoptosis (reduced Bax expression; increased Bcl-2 expression), alleviated oxidative stress (enhanced activities of CAT, SOD, and GPX; decreased MDA levels), and anti-inflammatory actions (reduced TNF-α, IL-1β, and IL-6 levels), most likely through activation of the Nrf2/HO-1 signaling pathway [96]. Taheri et al. (2022) further confirmed the dose-dependent neuroprotection by astaxanthin [97]. Administered intraperitoneally at doses of 25, 45, and 65 mg/kg, 15 min after transient focal cerebral I/R in rats, higher doses significantly reduced neurological deficits and infarct volume. The observed neuroprotective effects included decreased oxidative stress (lower MDA and TOS levels; higher GSH, CAT, GPX, and SOD activities), attenuated inflammation (decreased TNF-α and NF-κB levels), inhibited apoptosis (downregulated p53, p53 upregulated modulator of apoptosis [PUMA], Bax, and caspase-3 expressions; upregulated Bcl-2 expression), and anti-excitotoxic actions (increased glutamate transporter-1 [GLT-1] expression) [97]. Lastly, Park et al. (2022) demonstrated that astaxanthin administration (100 mg/kg/day, i.p. for 3 days prior to transient global cerebral I/R) significantly reduced hippocampal neuronal loss in gerbils [20]. This neuroprotection was associated with decreased oxidative stress markers (8-OHdG and 4-HNE) and enhanced levels of antioxidant enzymes (SOD1 and SOD2) [20].

Collectively, these findings demonstrate astaxanthin’s potent neuroprotective efficacy against cerebral I/R injury. Its benefits, observed with oral or intraperitoneal administration (10–100 mg/kg, pre- or post-I/R), are primarily attributed to multifaceted actions, including anti-excitotoxic, antioxidant, anti-inflammatory, and anti-apoptotic mechanisms. Astaxanthin can also be obtained from algal biomass residues in aquaculture, further supporting its role as a valuable marine by-product for biomedical use.

3.2.2. Fucoxanthin

Fucoxanthin (Figure 2E), a major xanthophyll carotenoid abundant in brown algae such as Undaria pinnatifida and Laminaria japonica, has demonstrated significant neuroprotective effects in both in vitro and in vivo models of cerebral I/R. Hu et al. (2018) showed pretreatment of fucoxanthin (5, 10, and 20 μM) in rat cortical neurons exposed to OGD/R markedly reduced apoptosis (evidenced by decreased Bax and cleaved caspase-3 expression levels, and increased Bcl-2 expression) [98]. This treatment also mitigated oxidative stress (indicated by decreased ROS and MDA levels, and enhanced SOD activity) and activated the Nrf2/HO-1 signaling pathway. Consistently, in a rat model of transient focal cerebral I/R, oral administration of fucoxanthin (30, 60, and 90 mg/kg, 1 h prior to I/R) significantly improved neurological outcomes and reduced infarct volume and decreased brain edema. These beneficial effects were associated with reduced apoptosis (decreased Bax and cleaved caspase-3 expression levels; increased Bcl-2 expression), enhanced SOD activity, and activation of the Nrf2/HO-1 signaling pathway [98].

Further supporting these findings, a recent study by Qi et al. (2025) evaluated apo-9′-fucoxanthinone, a metabolite of fucoxanthin, using both OGD/R-exposed cells and a mouse model of transient focal cerebral I/R [99]. In SH-SY5Y cells subjected to OGD/R, pretreatment of apo-9′-fucoxanthinone (2.5, 5, and 10 μM) significantly suppressed apoptosis (decreased Bax and cleaved caspase-3 expression levels; increased Bcl-2 expression) through activation of the PI3K/Akt/GSK3β signaling pathway [99]. Additionally, intraperitoneal administration of apo-9′-fucoxanthinone (15 and 30 mg/kg, 2 h prior to I/R) in mice subjected to transient focal cerebral I/R significantly decreased neurological deficit scores and infarct volume. The neuroprotective effects were mechanistically linked to the suppression of inflammation (evidenced by elevated inhibitory kappa B [IκB] level; reduced IL-1β, IL-6, IκB kinase [IKK], and nuclear NF-κB levels) and apoptosis (decreased Bax and cleaved caspase-3 expression levels; increased Bcl-2 expression; fewer TUNEL-positive cells), mediated through activation of the PI3K/Akt/GSK3β signaling pathway [99].

Collectively, these studies suggest that fucoxanthin and its metabolite apo-9′-fucoxanthinone exert potent neuroprotective effects against cerebral I/R injury. These actions are primarily mediated through the modulation of apoptosis, oxidative stress, and inflammation, largely via the activation of the Nrf2/HO-1 and PI3K/Akt/GSK-3β signaling pathways. Although studies on fucoxanthin remain fewer compared to astaxanthin, existing evidence supports its efficacy when administered orally or intraperitoneally at doses ranging from 15 to 90 mg/kg, particularly during the early pre-I/R period. Fucoxanthin is typically sourced from brown algae processing residues, representing a promising example of sustainable utilization of marine by-products.

3.2.3. Lutein

Lutein (Figure 2F), a xanthophyll carotenoid, is widely recognized for its antioxidant and anti-inflammatory properties that are beneficial for neurological health [100]. While lutein has traditionally been sourced from terrestrial plants, several marine algae species, including Chlorella vulgaris and Ulva lactuca, have also been reported to contain substantial amounts of lutein [101,102], thereby justifying its inclusion in marine algae-derived bioactive compound research with neuroprotective potential.

Regarding the neuroprotective effects of lutein against cerebral I/R injury, Li et al. (2012) demonstrated that intraperitoneal administration of lutein (0.2 mg/kg at 1 h before ischemia and again 1 h after reperfusion) significantly improved survival rate and reduced infarct volume in mice subjected to transient focal cerebral I/R [103]. These neuroprotective effects correlated with reduced apoptosis (indicated by fewer TUNEL-positive cells and increased Bcl-2 expression), decreased oxidative/nitrosative stress (evidenced by reduced nitrotyrosine [NT] and poly-ADP ribose [PAR] accumulation), and suppression of inflammatory signaling (shown by decreased COX-2, phospho-IκB, and nuclear NF-κB expression levels). Additionally, lutein treatment significantly increased the expressions of Hsp70 and phospho-Akt, while reducing phospho-ERK expression, suggesting the involvement of pro-survival signaling pathways [103].

Similarly, Sun et al. (2014) reported that oral administration of lutein (7.5, 15, and 30 mg/kg/day for 7 days before I/R) in a mouse model of transient focal cerebral I/R significantly reduced neurological deficits scores and infarct volume in a dose-dependent manner [104]. These effects were mediated through anti-apoptotic properties (indicated by lower TUNEL-positive cells) and antioxidant capabilities (evidenced by an elevated GSH/oxidized glutathione [GSSG] ratio; increased SOD, GPX, and CAT activities; reduced MDA level, protein carbonyl content, and 8-OHdG-positive cells) [104].

Collectively, these studies demonstrate that lutein exerts robust neuroprotection against cerebral I/R injury by attenuating oxidative/nitrosative stress, suppressing inflammatory responses, and modulating apoptotic and pro-survival signaling pathways. Although the number of in vivo studies specifically investigating lutein from marine algae sources is limited, the available evidence supports the efficacy of lutein at doses ranging from 0.2 to 30 mg/kg/day when administered either intraperitoneally or orally prior to I/R. This strongly justifies its consideration as a potent neuroprotective agent, potentially derived or found in marine algae, for cerebral I/R injury. Notably, lutein-rich fractions from marine algae cultivation by-products may represent an underutilized yet sustainable source for neuroprotective applications.

3.2.4. Zeaxanthin

Zeaxanthin (Figure 2G), a xanthophyll carotenoid structurally similar to lutein, is widely distributed in nature, found in various fruits, vegetables, and notably in marine microalgae [105]. While extensively studied for its benefits in ocular health due to potent antioxidant properties [106], zeaxanthin has more recently been gained attention for its potential neuroprotective effects against cerebral I/R injury.

La Russa et al. (2024) evaluated the neuroprotective effects of zeaxanthin in a mouse model of transient focal cerebral I/R [107]. Zeaxanthin was orally administered at a dose of 2 mg/kg/day at 48, 24, and 1 h before I/R. This retreatment significantly reduced neurological deficit scores, infarct volume, and cerebral edema. The observed neuroprotection was associated with zeaxanthin’s potent antioxidant properties, as evidenced by increased serum biological antioxidant potential (BAP) values and reduced oxidative stress markers, including serum diacron-reactive oxygen metabolites (d-ROMs) and brain hydroperoxide levels [107].

Although the evidence is currently limited to this single in vivo study, the findings suggest that oral administration of zeaxanthin at a relatively low dose (2 mg/kg/day) during the acute pre-I/R phase can provide significant neuroprotection. This effect is primarily attributed to its potent antioxidative actions within the context of cerebral I/R injury. Zeaxanthin’s availability from microalgal by-products further reinforces its dual potential as both a nutraceutical and a neuroprotective therapeutic candidate.

Table 2. Neuroprotective activity of carotenoids found in marine algae against cerebral I/R injury.

Compound	Algal Origin (If Any)	Effective Dose	Experimental Model	Significant Findings	Signaling Pathway	Pharmacological Markers	Reference
Astaxanthin	-	0.1 mM in 20 μL	Rat model of transient focal cerebral I/R	↑Locomotor activity; ↓infarct volume; ↓oxidative stress; ↓excitotoxicity; ↓apoptosis	N/A	↓Aconitase and MDA; ↓glutamate; ↓TUNEL and Cyt c	[87]
Astaxanthin	-	50 and 80 mg/kg	Rat model of transient focal cerebral I/R	↓Neurological deficits; ↓infarct volume;	N/A	N/A	[88]
Astaxanthin	-	10, 25, 50, and 100 µM	OGD/R model in SH-SY5Y cells	↑Cell viability; ↓oxidative stress	N/A	↓Nitrite and iNOS; ↑HO-1and Hsp70↑	[89]
		30 mg/kg	Rat model of transient global cerebral I/R	↓Neuronal death; ↓apoptosis	N/A	↓PARP-1
Astaxanthin	-	5 and 10 mg/kg	Rat model of transient focal cerebral I/R	↓Neurological deficits; ↓infarct volume; ↓oxidative stress; ↓apoptosis; ↑neural regeneration	Nrf2-ARE pathway	↓MDA; ↑SOD; ↑Nrf2, HO-1, and NQO1; ↓Bax; ↑Bcl-2; ↑GFAP, MAP-2, BDNF, and GAP43	[92]
Astaxanthin	-	10 mg/kg	Mouse model of repeated cerebral I/R	↑Learning and memory; ↓neuronal death; ↓oxidative stress; ↓apoptosis	N/A	↓MDA; ↑GSH and SOD; ↓Cyt c, cleaved caspase-3, and Bax; ↑Bcl-2	[91]
Astaxanthin	-	20, 40, and 80 mg/kg	Rat model of transient focal cerebral I/R	↓Neurological deficits; ↓cerebral edema; ↓oxidative stress; ↑neurotrophic factors	N/A	↓MDA; ↑SOD, CAT, and GPX; ↑BDNF and NGF	[93]
Astaxanthin	-	30 mg/kg	Mouse model of permanent focal cerebral ischemia	↑Motor function; ↑axonal regeneration and reconnection	cAMP/PKA/CREB pathway	↑GAP43; ↑cAMP, PKA, and phospho-CREB	[94]
Astaxanthin	-	25 mg/kg	Rat model of transient focal cerebral I/R	↓Neurological deficits; ↓neuronal loss; ↓oxidative stress; ↓inflammation; ↓apoptosis	N/A	↑TAS, Nrf2, and Hsp70; ↓TOS, OSI, LPO, 8-OHdG, and AOPP; ↓MPO, TNF-α, and IL-6; ↓caspase-3, -8, and -9	[95]
Astaxanthin	-	5, 10, 20, and 40 µM	OGD/R model in SH-SY5Y cells	↑Cell viability; ↓oxidative stress; ↓apoptosis	PI3K/Akt/GSK3β/Nrf2 pathway	↓ROS and MDA; ↑SOD; ↓Bax and cleaved caspase-3; ↑Bcl-2; ↑phospho-GSK3β, phospho-AKT, nuclear Nrf2, and HO-1	[90]
Astaxanthin	-	100 mg/kg	Rat model of transient focal cerebral I/R	↓Neurological deficits; ↓brain edema; ↓infarct volume; ↓oxidative stress; ↓inflammation; ↓apoptosis	Nrf2/HO-1 pathway	↓MDA; ↑CAT, SOD, and GPX; ↓TNF-α, IL-1β, and IL-6; ↓Bax; ↑Bcl-2, ↑nuclear Nrf2 and HO-1; ↓cytosolic Nrf2	[96]
Astaxanthin	-	25, 45, and 65 mg/kg	Rat model of transient focal cerebral I/R	↓Neurological deficits; ↓infarct volume; ↓oxidative stress; ↓inflammation; ↓apoptosis; ↓excitotoxicity	N/A	↓MDA and TOS; ↑GSH, CAT, GPX, and SOD; ↓TNF-α, and NF-κB; ↓p53, PUMA, Bax, and caspase-3; ↑Bcl-2; ↑GLT-1	[97]
Astaxanthin	-	100 mg/kg	Gerbil model of transient global cerebral I/R	↓Neuronal death; ↓oxidative stress	N/A	↓8-OHdG and 4-HNE; ↑SOD1 and SOD2	[20]
Fucoxanthin	-	5, 10, and 20 µM	OGD/R model in rat cortical neurons	↓Apoptosis; ↓oxidative stress	Nrf2/HO-1 pathway	↓Bax, and cleaved caspase-3; ↑Bcl-2; ↓ROS and MDA; ↑SOD; ↑nuclear Nrf2 and HO-1	[98]
		30, 60, and 90 mg/kg	Rat model of transient focal cerebral I/R	↓Neurological deficits; ↓infarct volume; ↓brain edema ↓apoptosis; ↓oxidative stress;	Nrf2/HO-1 pathway	↓Bax, and cleaved caspase-3; ↑Bcl-2; ↑SOD; ↑nuclear Nrf2 and HO-1
Apo-9′-fucoxanthinone	Sargassum fusiforme (brown algae)	2.5, 5, and 10 µM	OGD/R model in SH-SY5Y cells	↑Cell viability; ↓apoptosis	PI3K/Akt/GSK3β pathway	↓Bax, and cleaved caspase-3; ↑Bcl-2; ↑phospho-PI3K, phospho-Akt, and phospho-GSK3β	[99]
		15 and 30 mg/kg	Mouse model of transient focal cerebral I/R	↓Neurological deficits; ↓infarct volume; ↓inflammation; ↓apoptosis	PI3K/Akt/GSK3β pathway	↓IL-1β, IL-6, IKK, and nuclear NF-κB; ↑IκB; ↓Bax, cleaved caspase-3, and TUNEL; ↑Bcl-2; ↑phospho-PI3K, phospho-Akt, and phospho-GSK3β
Lutein	-	0.2 mg/kg	Mouse model of transient focal cerebral I/R	↑Survival rate; ↓infarct volume; ↓apoptosis; ↓oxidative/nitrosative stress; ↓inflammation	PI3K/Akt, MAPK/ERK, and NF-κB pathways	↓TUNEL; ↑Bcl-2; ↓NT and PAR; ↓COX-2, phospho-IκB, and nuclear NF-κB; ↑Hsp70 and phospho-Akt; ↓phospho-ERK	[103]
Lutein	-	7.5, 15, and 30 mg/kg	Mouse model of transient focal cerebral I/R	↓Neurological deficits; ↓infarct volume; ↓apoptosis; ↓oxidative stress	N/A	↓TUNEL; ↑GSH, SOD, GPX, and CAT; ↓MDA, protein carbonyl content, and 8-OHdG	[104]
Zeaxanthin	-	2 mg/kg	Mouse model of transient focal cerebral I/R	↓Neurological deficits; ↓infarct volume; ↓brain edema; ↓oxidative stress	N/A	↑BAP; ↓d-ROMs and hydroperoxide	[107]

N/A: not applicable; -: information not available.

Table 2. Neuroprotective activity of carotenoids found in marine algae against cerebral I/R injury.

Compound	Algal Origin (If Any)	Effective Dose	Experimental Model	Significant Findings	Signaling Pathway	Pharmacological Markers	Reference
Astaxanthin	-	0.1 mM in 20 μL	Rat model of transient focal cerebral I/R	↑Locomotor activity; ↓infarct volume; ↓oxidative stress; ↓excitotoxicity; ↓apoptosis	N/A	↓Aconitase and MDA; ↓glutamate; ↓TUNEL and Cyt c	[87]
Astaxanthin	-	50 and 80 mg/kg	Rat model of transient focal cerebral I/R	↓Neurological deficits; ↓infarct volume;	N/A	N/A	[88]
Astaxanthin	-	10, 25, 50, and 100 µM	OGD/R model in SH-SY5Y cells	↑Cell viability; ↓oxidative stress	N/A	↓Nitrite and iNOS; ↑HO-1and Hsp70↑	[89]
		30 mg/kg	Rat model of transient global cerebral I/R	↓Neuronal death; ↓apoptosis	N/A	↓PARP-1
Astaxanthin	-	5 and 10 mg/kg	Rat model of transient focal cerebral I/R	↓Neurological deficits; ↓infarct volume; ↓oxidative stress; ↓apoptosis; ↑neural regeneration	Nrf2-ARE pathway	↓MDA; ↑SOD; ↑Nrf2, HO-1, and NQO1; ↓Bax; ↑Bcl-2; ↑GFAP, MAP-2, BDNF, and GAP43	[92]
Astaxanthin	-	10 mg/kg	Mouse model of repeated cerebral I/R	↑Learning and memory; ↓neuronal death; ↓oxidative stress; ↓apoptosis	N/A	↓MDA; ↑GSH and SOD; ↓Cyt c, cleaved caspase-3, and Bax; ↑Bcl-2	[91]
Astaxanthin	-	20, 40, and 80 mg/kg	Rat model of transient focal cerebral I/R	↓Neurological deficits; ↓cerebral edema; ↓oxidative stress; ↑neurotrophic factors	N/A	↓MDA; ↑SOD, CAT, and GPX; ↑BDNF and NGF	[93]
Astaxanthin	-	30 mg/kg	Mouse model of permanent focal cerebral ischemia	↑Motor function; ↑axonal regeneration and reconnection	cAMP/PKA/CREB pathway	↑GAP43; ↑cAMP, PKA, and phospho-CREB	[94]
Astaxanthin	-	25 mg/kg	Rat model of transient focal cerebral I/R	↓Neurological deficits; ↓neuronal loss; ↓oxidative stress; ↓inflammation; ↓apoptosis	N/A	↑TAS, Nrf2, and Hsp70; ↓TOS, OSI, LPO, 8-OHdG, and AOPP; ↓MPO, TNF-α, and IL-6; ↓caspase-3, -8, and -9	[95]
Astaxanthin	-	5, 10, 20, and 40 µM	OGD/R model in SH-SY5Y cells	↑Cell viability; ↓oxidative stress; ↓apoptosis	PI3K/Akt/GSK3β/Nrf2 pathway	↓ROS and MDA; ↑SOD; ↓Bax and cleaved caspase-3; ↑Bcl-2; ↑phospho-GSK3β, phospho-AKT, nuclear Nrf2, and HO-1	[90]
Astaxanthin	-	100 mg/kg	Rat model of transient focal cerebral I/R	↓Neurological deficits; ↓brain edema; ↓infarct volume; ↓oxidative stress; ↓inflammation; ↓apoptosis	Nrf2/HO-1 pathway	↓MDA; ↑CAT, SOD, and GPX; ↓TNF-α, IL-1β, and IL-6; ↓Bax; ↑Bcl-2, ↑nuclear Nrf2 and HO-1; ↓cytosolic Nrf2	[96]
Astaxanthin	-	25, 45, and 65 mg/kg	Rat model of transient focal cerebral I/R	↓Neurological deficits; ↓infarct volume; ↓oxidative stress; ↓inflammation; ↓apoptosis; ↓excitotoxicity	N/A	↓MDA and TOS; ↑GSH, CAT, GPX, and SOD; ↓TNF-α, and NF-κB; ↓p53, PUMA, Bax, and caspase-3; ↑Bcl-2; ↑GLT-1	[97]
Astaxanthin	-	100 mg/kg	Gerbil model of transient global cerebral I/R	↓Neuronal death; ↓oxidative stress	N/A	↓8-OHdG and 4-HNE; ↑SOD1 and SOD2	[20]
Fucoxanthin	-	5, 10, and 20 µM	OGD/R model in rat cortical neurons	↓Apoptosis; ↓oxidative stress	Nrf2/HO-1 pathway	↓Bax, and cleaved caspase-3; ↑Bcl-2; ↓ROS and MDA; ↑SOD; ↑nuclear Nrf2 and HO-1	[98]
		30, 60, and 90 mg/kg	Rat model of transient focal cerebral I/R	↓Neurological deficits; ↓infarct volume; ↓brain edema ↓apoptosis; ↓oxidative stress;	Nrf2/HO-1 pathway	↓Bax, and cleaved caspase-3; ↑Bcl-2; ↑SOD; ↑nuclear Nrf2 and HO-1
Apo-9′-fucoxanthinone	Sargassum fusiforme (brown algae)	2.5, 5, and 10 µM	OGD/R model in SH-SY5Y cells	↑Cell viability; ↓apoptosis	PI3K/Akt/GSK3β pathway	↓Bax, and cleaved caspase-3; ↑Bcl-2; ↑phospho-PI3K, phospho-Akt, and phospho-GSK3β	[99]
		15 and 30 mg/kg	Mouse model of transient focal cerebral I/R	↓Neurological deficits; ↓infarct volume; ↓inflammation; ↓apoptosis	PI3K/Akt/GSK3β pathway	↓IL-1β, IL-6, IKK, and nuclear NF-κB; ↑IκB; ↓Bax, cleaved caspase-3, and TUNEL; ↑Bcl-2; ↑phospho-PI3K, phospho-Akt, and phospho-GSK3β
Lutein	-	0.2 mg/kg	Mouse model of transient focal cerebral I/R	↑Survival rate; ↓infarct volume; ↓apoptosis; ↓oxidative/nitrosative stress; ↓inflammation	PI3K/Akt, MAPK/ERK, and NF-κB pathways	↓TUNEL; ↑Bcl-2; ↓NT and PAR; ↓COX-2, phospho-IκB, and nuclear NF-κB; ↑Hsp70 and phospho-Akt; ↓phospho-ERK	[103]
Lutein	-	7.5, 15, and 30 mg/kg	Mouse model of transient focal cerebral I/R	↓Neurological deficits; ↓infarct volume; ↓apoptosis; ↓oxidative stress	N/A	↓TUNEL; ↑GSH, SOD, GPX, and CAT; ↓MDA, protein carbonyl content, and 8-OHdG	[104]
Zeaxanthin	-	2 mg/kg	Mouse model of transient focal cerebral I/R	↓Neurological deficits; ↓infarct volume; ↓brain edema; ↓oxidative stress	N/A	↑BAP; ↓d-ROMs and hydroperoxide	[107]

N/A: not applicable; -: information not available.

3.3. Polyphenols

Polyphenols, naturally occurring phytochemicals recognized for their antioxidant and anti-inflammatory properties, are also abundantly found in marine algae. Among these, phlorotannins, a unique class of polyphenols exclusively present in brown algae, have garnered increasing attention due to their potent antioxidant, anti-inflammatory, and neuroprotective activities [108]. These compounds are characterized by their phloroglucinol-based oligomeric and polymeric structures, enabling them to modulate multiple cellular pathways relevant to cerebral I/R injury [109]. Among the diverse phlorotannins, dieckol and several other compounds from Ecklonia cava have shown strong neuroprotective potential in both in vitro and in vivo models. In the following sections, we summarize the experimental evidence supporting the efficacy of these marine algae-derived polyphenols in mitigating cerebral I/R injury (Table 3).

3.3.1. Dieckol

Dieckol (Figure 2H), a prominent phlorotannin isolated from the brown algae Ecklonia cava, has demonstrated promising neuroprotective effects, particularly against glutamate-induced excitotoxicity, a key contributor to the pathogenesis of cerebral I/R injury. In this regard, Cui et al. (2019) reported that pretreatment of dieckol (10, 20, 30, 40, and 50 µM) for 1 h prior to glutamate exposure significantly increased cell viability in a dose-dependent manner and ameliorated morphological deterioration in primary cortical neurons and HT22 neurons [18]. Mechanistically, dieckol markedly decreased intracellular ROS levels and attenuated mitochondrial dysfunction, as evidenced by restored ATP levels, preservation of mitochondrial membrane potential (ΔΨm), and reduced mitochondrial Ca2+ overload and ROS generation, thereby highlighting its potent antioxidant activity. Moreover, dieckol significantly upregulated the expression of cytoprotective protein HO-1 via enhanced nuclear translocation of Nrf2, indicating activation of the Nrf2/HO-1 signaling pathway [18].

Collectively, these findings suggest that dieckol exerts neuroprotective effects against excitotoxic neuronal injury primarily through ROS scavenging and activation of the Nrf2/HO-1 pathway. Although direct in vivo evidence specifically for dieckol’s efficacy against cerebral I/R injury is currently limited, these compelling mechanistic insights from in vitro studies strongly support its therapeutic potential. Further studies using animal models of cerebral I/R are warranted to fully validate its neuroprotective efficacy and assess its clinical applicability.

3.3.2. Phlorotannins from Ecklonia cava

Phlorotannin-rich extracts from the brown algae Ecklonia cava are known to contain a variety of bioactive polyphenolic compounds, including dieckol, eckol, phloroglucinol, and others. Kim et al. (2012) investigated the neuroprotective effects of an Ecklonia cava extract in a rat model of transient focal cerebral I/R [110]. The extract was administered intraperitoneally at doses of 10 and 50 mg/kg. The administration regimen involved giving half of the total dose 30 min before ischemia, and the remaining half 30 min after reperfusion. This dual-phase treatment with the extract significantly reduced neurological deficits, infarct volume, brain edema, and the number of TUNEL-positive apoptotic neurons in both the cerebral cortex and striatum [110]. While this extract represents a complex mixture of multiple polyphenolic compounds, its remarkable overall efficacy is thought to result from the synergistic action of the various phlorotannins present within it.

Collectively, these findings support the therapeutic potential of marine algae-derived polyphenols, particularly those originating from Ecklonia cava. Their neuroprotective effects are evident when administered intraperitoneally at doses ranging from 10 to 50 mg/kg, demonstrating efficacy in both pre-I/R prophylaxis and post-I/R early phase treatment. Ecklonia cava extracts are frequently obtained from algal by-products in the food industry, exemplifying the valorization of marine resources for biomedical innovation.

3.4. Sterols: β-sitosterol

Sterols, a class of lipid-derived compounds, are naturally presented in various marine algae species, including well-known examples such as fucosterol, β-sitosterol, and cholesterol of algal origin [111]. While study on marine algae-derived sterols remains comparatively limited when compared to polysaccharides, carotenoids, and polyphenols, β-sitosterol (Figure 2I), a phytosterol abundantly found in marine algae such as Undaria pinnatifida and Ulva lactuca [112], has recently emerged as a promising compound for its neuroprotective potential against cerebral I/R injury (Table 3). In this regard, Tang et al. (2024) reported the neuroprotective effects of β-sitosterol in both in vitro and in vivo models of cerebral I/R [113]. In their in vitro study using primary cortical neurons subjected to OGD/R, pretreatment of β-sitosterol (0.1, 1, and 10 µM for 24 h) significantly preserved neuronal activity and reduced LDH release and the proportion of apoptotic cells. Additionally, in a mouse model of transient focal cerebral I/R, intraperitoneal administration of β-sitosterol (2, 10 and 50 mg/kg at 30 min after I/R) significantly reduced infarct volume, brain edema, and neurological deficits. These beneficial effects were mechanistically linked to several actions: decreased components of endoplasmic reticulum stress (e.g., glucose-regulated protein 78 [GRP78]/binding immunoglobulin protein [Bip] and caspase-12 expression), attenuated apoptosis (decreased caspase-3 and Bax expression levels; increased Bcl-2 expression), and inhibition of phospho-JNK2 and phospho-signal transducer and activator of transcription 3 (STAT3). Furthermore, β-sitosterol demonstrated the ability to downregulate Niemann-Pick C1 like 1 (NPC1L1, a key cholesterol transporter) and reduce cholesterol accumulation in the ischemic brain [113].

Collectively, these findings support the neuroprotective potential of β-sitosterol as a marine algae-derived sterol for mitigating cerebral I/R injury, suggesting its involvement in ER stress modulation, apoptosis inhibition, JNK/STAT3 pathway regulation, and cholesterol homeostasis. As β-sitosterol can be isolated from algal processing by-products, its study highlights the translational and sustainable use of marine-derived resources.

Table 3. Neuroprotective activity of polyphenols and β-sitosterol found in marine algae against cerebral I/R injury.

Compound	Algal Origin (If Any)	Effective Dose	Experimental Model	Significant Findings	Signaling Pathway	Pharmacological Markers	Reference
Dieckol	Ecklonia cava (brown algae)	10, 20, 30, 40, and 50 µM	Glutamate excitotoxicity model in primary cortical neurons and HT22 neurons	↑Cell viability; ↓morphological deterioration; ↓oxidative stress; ↓mitochondrial dysfunction	Nrf2/HO-1 pathway	↓Intracellular ROS; ↑ATP and ΔΨm; ↓mitochondrial Ca2+ overload and ROS generation; ↑nuclear Nrf2 and HO-1	[18]
Phlorotannin-rich extract	Ecklonia cava (brown algae)	10 and 50 mg/kg	Rat model of transient focal cerebral I/R	↓Neurological deficits; ↓infarct volume; ↓brain edema; ↓apoptosis	N/A	↓TUNEL	[110]
β-sitosterol	-	0.1, 1, and 10 µM	OGD/R model in primary cortical neurons	↑Neuronal activity; ↓LDH release; ↓apoptosis	N/A	↓LDH; ↓Annexin V	[112]
		2, 10, and 50 mg/kg	Mouse model of transient focal cerebral I/R	↓Neurological deficits; ↓infarct volume; ↓brain edema; ↓endoplasmic reticulum stress; ↓cholesterol-induced apoptosis	cholesterol overload/endoplasmic reticulum stress/apoptosis pathways	↓TUNEL; ↓GRP78/Bip, caspase-12, and caspase-3; ↓Bax; ↑Bcl-2; ↓phospho-JNK2, phospho-STAT3, NPC1L1, and cholesterol

N/A: not applicable; -: information not available.

Table 3. Neuroprotective activity of polyphenols and β-sitosterol found in marine algae against cerebral I/R injury.

Compound	Algal Origin (If Any)	Effective Dose	Experimental Model	Significant Findings	Signaling Pathway	Pharmacological Markers	Reference
Dieckol	Ecklonia cava (brown algae)	10, 20, 30, 40, and 50 µM	Glutamate excitotoxicity model in primary cortical neurons and HT22 neurons	↑Cell viability; ↓morphological deterioration; ↓oxidative stress; ↓mitochondrial dysfunction	Nrf2/HO-1 pathway	↓Intracellular ROS; ↑ATP and ΔΨm; ↓mitochondrial Ca2+ overload and ROS generation; ↑nuclear Nrf2 and HO-1	[18]
Phlorotannin-rich extract	Ecklonia cava (brown algae)	10 and 50 mg/kg	Rat model of transient focal cerebral I/R	↓Neurological deficits; ↓infarct volume; ↓brain edema; ↓apoptosis	N/A	↓TUNEL	[110]
β-sitosterol	-	0.1, 1, and 10 µM	OGD/R model in primary cortical neurons	↑Neuronal activity; ↓LDH release; ↓apoptosis	N/A	↓LDH; ↓Annexin V	[112]
		2, 10, and 50 mg/kg	Mouse model of transient focal cerebral I/R	↓Neurological deficits; ↓infarct volume; ↓brain edema; ↓endoplasmic reticulum stress; ↓cholesterol-induced apoptosis	cholesterol overload/endoplasmic reticulum stress/apoptosis pathways	↓TUNEL; ↓GRP78/Bip, caspase-12, and caspase-3; ↓Bax; ↑Bcl-2; ↓phospho-JNK2, phospho-STAT3, NPC1L1, and cholesterol

N/A: not applicable; -: information not available.

4. Future Perspectives

Despite the extensive preclinical evidence supporting the neuroprotective effects of bioactive compounds found in marine algae against cerebral I/R injury, several key challenges and critical considerations remain to be addressed before their successful clinical translation.

One major challenge lies in the limited and often incomplete understanding of the precise molecular mechanisms by which these compounds exert their effects. While many studies have identified broad anti-excitotoxic, antioxidant, anti-inflammatory, and anti-apoptotic properties, the complex upstream and downstream signaling pathways involved, as well as multi-target interactions, remain incompletely defined. Therefore, future investigations should prioritize dissecting these intricate molecular mechanisms through advanced omics technologies and targeted pathway analyses. Such detailed mechanistic insights are crucial for rational drug development and optimization.

Moreover, the majority of existing research has been confined to in vitro systems or rodent models, often employing acute treatment paradigms (e.g., pre-treatment or single-dose post-treatment). To substantially enhance their translational relevance, long-term preclinical studies using more clinically applicable models should be prioritized. These include comorbid animals (e.g., diabetic, hypertensive), aged rodents, or even larger animal models, which better mimic the human ischemic stroke condition. Such comprehensive studies would be instrumental in determining not only efficacy but also optimal dosing regimens, bioavailability, therapeutic time windows, and potential side effects in complex biological systems. In addition, while many bioactive compounds found in marine algae demonstrate significant neuroprotective effects when administered alone, their potential to provide synergistic benefits when used in combination with existing standard therapies, such as thrombolytics or neurorehabilitative agents, remains largely unexplored. Exploring such rational combinatorial strategies could yield more robust and clinically superior therapeutic outcomes.

Equally important is the imperative need to validate the pharmacokinetics, pharmacodynamics, BBB permeability, and long-term safety and toxicity profiles of these compounds, particularly for those with low solubility or stability. This is particularly crucial for those compounds exhibiting low solubility or inherent stability issues. To overcome challenges related to bioavailability and targeted delivery, developing novel and advanced drug delivery systems, such as nanoparticle-based formulations or targeted drug carriers, could significantly improve their therapeutic efficacy and enhance brain penetration.

Finally, while many individual marine algae-derived bioactive compounds have been identified and studied in isolation, the broader and perhaps more holistic potential of whole algal extracts or specific fractions rich in multiple active constituents remains underexplored. Investigating the synergistic and pleiotropic actions of multi-component extracts may offer a more comprehensive and effective approach to neuroprotection against cerebral I/R injury. Integrating these research directions and adopting a more holistic approach will be essential for successfully advancing marine algal bioactive compounds from experimental findings toward tangible clinical applications in cerebral I/R therapy. Simultaneously, marine by-products, through their sustainable utilization as renewable sources of bioactive agents, demonstrate significant dual potential, serving as both promising neuroprotective therapeutics and valuable contributors to marine resource valorization.

From my perspective, despite these promising directions, several limitations remain evident. The lack of standardized extraction methods and dosing protocols makes it difficult to directly compare outcomes across studies, and the predominance of young, healthy animal models limits translational relevance. I believe that addressing these methodological issues and incorporating comorbid or aged models will be essential for bridging the gap between experimental findings and clinical application.

5. Conclusions

Marine algae represent a rich and underexplored source of structurally diverse bioactive compounds with significant neuroprotective potential in experimental models of cerebral I/R injury. Our comprehensive review has highlighted the multifaceted therapeutic efficacy of various classes of these compounds. Specifically, polysaccharides such as fucoidan, laminarin, and porphyran; carotenoids, including astaxanthin, fucoxanthin, lutein, and zeaxanthin; polyphenols such as dieckol and other phlorotannins; and the sterol, including β-sitosterol, have consistently demonstrated significant efficacy. Their beneficial actions include reducing neuronal death, suppressing excitotoxicity and inflammation, mitigating oxidative stress, and protecting the BBB integrity in cerebral I/R injury.

Importantly, marine algae and their by-products constitute sustainable and renewable resources that can be valorized for biomedical applications. These marine algae-derived bioactive compounds not only exhibit pleiotropic actions by targeting multiple interconnected pathological pathways but also illustrate how underutilized marine by-products can be transformed into valuable neuroprotective agents. While current preclinical evidence is highly promising, further rigorous research is essential to overcome translational barriers and establish clinical applicability. Nevertheless, the utilization of marine by-products for the development of novel therapeutic strategies represents a promising frontier in neuroprotection research, offering both biomedical and sustainability-driven value for the prevention and treatment of cerebral I/R injury.

In my view, the true potential of these compounds lies not only in their multi-targeted neuroprotective effects but also in their sustainable sourcing from marine by-products. This dual advantage highlights their importance as both therapeutic candidates and contributors to resource valorization. I consider the integration of pharmacological research with marine biotechnology essential for advancing these compounds toward clinical application.