Neuroprotective Potentials of Marine Algae and Their Bioactive Metabolites: Pharmacological Insights and Therapeutic Advances

Beyond their significant contribution to the dietary and industrial supplies, marine algae are considered to be a potential source of some unique metabolites with diverse health benefits. The pharmacological properties, such as antioxidant, anti-inflammatory, cholesterol homeostasis, protein clearance and anti-amyloidogenic potentials of algal metabolites endorse their protective efficacy against oxidative stress, neuroinflammation, mitochondrial dysfunction, and impaired proteostasis which are known to be implicated in the pathophysiology of neurodegenerative disorders and the associated complications after cerebral ischemia and brain injuries. As was evident in various preclinical studies, algal compounds conferred neuroprotection against a wide range of neurotoxic stressors, such as oxygen/glucose deprivation, hydrogen peroxide, glutamate, amyloid β, or 1-methyl-4-phenylpyridinium (MPP+) and, therefore, hold therapeutic promise for brain disorders. While a significant number of algal compounds with promising neuroprotective capacity have been identified over the last decades, a few of them have had access to clinical trials. However, the recent approval of an algal oligosaccharide, sodium oligomannate, for the treatment of Alzheimer’s disease enlightened the future of marine algae-based drug discovery. In this review, we briefly outline the pathophysiology of neurodegenerative diseases and brain injuries for identifying the targets of pharmacological intervention, and then review the literature on the neuroprotective potentials of algal compounds along with the underlying pharmacological mechanism, and present an appraisal on the recent therapeutic advances. We also propose a rational strategy to facilitate algal metabolites-based drug development.

Mitochondrial ROS not only a crucial early driver of acute damage but also consider as an initiator of the consequence of a series of pathological features that develop over time following the reperfusion [52]. Initially, upon reperfusion, the burst of ROS production results in oxidative damage to mitochondria, thereby disrupts ATP production [53], which ultimately initiates neuronal cell death cascades [54]. ROS-mediated mitochondrial damage further installs the inflammatory response via the activation of microglia and astrocytes as well as influx of immune cells recruited by cytokines, adhesion molecules, and chemokines across the activated cerebral blood vessels [55]. This activation of the innate immunity triggers nuclear factor-kappa-B (NF-κB)-mediated production of numerous inflammatory cytokines that contribute to I/R injury [56]. Therefore, targeting OS and inflammatory response could be imperative to develop novel therapeutic strategies for the management of stroke.

Traumatic brain injury
Traumatic brain injury (TBI), an acquired brain injury caused by an external force or shock, is also considered to be a major cause of death globally, particularly in countries with a frequent incidence of traffic accidents [57]. Despite significant medical advances in recent times, the clinical outcomes of severely head-injured patients are not satisfactory.
As in ischemic stroke, mechanisms underlying the damages to the brain tissue with TBI are categorized into two classes: primary and secondary damages. Primary damage that irreversibly involves the mechanical damage of the skull and the brain has been complicated following the brain contusions, rupturing blood vessels, axonal injuries, and intracranial hemorrhages [58]. Whereas, the secondary damage causes neuronal degeneration over time due to various biochemical changes such as OS, excitotoxicity, inflammation, and mitochondrial dysfunction [59]. Following TBI, various OS markers such as lipid peroxidation products, oxidized protein moieties and DNA damage products are accumulated in the brain while antioxidants and enzymes molecules such as glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferases (GST), superoxide dismutase (SOD) and catalase (CAT) are markedly declined (Rodriguez-Rodriguez, et al. [60]. It is suggested that treatment modalities associated with conferring neuroprotection on injured brain tissue and regeneration at the recovery stage of injured neurons have greater promise to restore at the site of brain injury following TBI.

Neuropharmacological potentials of marine algae and their metabolites: evidence from in vitro studies
Several compounds of diverse chemical classes have been reported from three major groups (brown, red, and green algae) of marine algae (Figure 1-4). Neuropharmacological properties of these compounds reported in various in vitro models are compiled (Table 1) and discussed in the following subsections. Besides bioactive compounds, macroalgae that have shown promising neuroactive potentials, and thus demand further attention are also mentioned.
In addition, a great number of marine algae have shown antioxidant activity, including Sargassum polycystum and Laurencia obtusa [71], Gelidium foliaceum and Codium duthieae [72], to mention a few.

Anticholinesterase activity
Currently prescribed anti-AD drugs are mostly based on the inhibition of cholinesterase activity. Several algal metabolites have been reported to inhibit cholinesterase activity (Table 1). For example, fucosterol and 24-hydroperoxy 24-vinylcholesterol isolated from E. stolonifera showed inhibitory activity against butyrylcholinesterase (BChE) [96]. Another study also demonstrated anticholinesterase activity of fucosterol [77]. Enzyme kinetics and computational analysis indicated a non-competitive mode of acetylcholinesterase (AChE) inhibition of fucosterol [97].

Cholesterol homeostasis and Aβ clearance activity
Some algal metabolites are known to activate LXR-β (Table 1), and thus help regulate cholesterol homeostasis and enhance Aβ clearance [48]. Fucosterol is a selective LXR-β agonist that upregulated several LXR target genes, such as ATP-binding cassette transporter A1 (ABCA1), ABCG1, and apolipoprotein E (ApoE) [109,110], suggesting that fucosterol could play a significant role in brain cholesterol homeostasis. Saringasterol, another selective LXR-β agonist isolated from S. fusiforme, activated the expression of similar LXR target genes in multiple cell lines [110]. Alginate-derived oligosaccharide isolated from marine brown algae promoted the microglial phagocytosis of Aβ, which is connected to the activation of toll-like receptor signaling [88]. As cholesterol imbalance and impaired protein clearance system significantly contribute to the pathogenesis of major neurological disorders, more efforts should, therefore, be paid to explore similar compounds that may help regulate cholesterol homeostasis and proteostasis.

Monoamine oxidase inhibition and affinity to dopaminergic receptors
Inhibition of MAO-A (monoamine oxidase-A), an enzyme that catalyzes oxidative deamination of neuroamines, such as dopamine, norepinephrine, and serotonin (5-HT), is a putative approach to raise the brain 5-HT level, thus alleviating the symptom of parkinsonism [133]. Seong and team screened the multi-target effects of three phlorotannins, i.e., phloroglucinol, phlorofucofuroeckol-A (PFF-A), and dieckol against human MAO-A and -B and various neuronal G-protein-coupled receptors (GPCRs). Of these, PFF-A exhibited a relatively higher inhibition against both hMAO isoforms, with greater selectivity toward hMAO-B (Table 1). Enzyme kinetics and computational findings indicated that PFF-A noncompetitively interacted with hMAOs and acted allosterically. In a functional assay for GPCR screening, dieckol and PFF-A showed a multi-target combination of D3R/D4R agonism and D1/5HT1A/NK1 antagonism [111].

Antiaging
Algal compounds that exhibited anti-aging effects (Table 1) could have therapeutical value for physiological as well as pathological brain aging. Sulfated oligosaccharides of Ulva lactuca and Enteromorpha prolifera, when treated in SAMP8 mice, increased the serum level of antioxidant molecules and total antioxidant capacity, and decreased the levels of malondialdehyde (MDA) and advanced glycation end products in the serum of experimental mice [87]. It has also been observed that these oligosaccharides decreased inflammatory factors, increased BDNF and choline acetyltransferase (ChAT) levels, and promoted the survival of hippocampal neurons. The underlying mechanisms involved the downregulation of p53 and FOXO1 genes and the upregulation of Sirt1 gene [87]. Caenorhabditis elegans, when treated with fucosterol (at 50 µg/mL), survived longer compared to control, indicating that this algal compound might help extend life-span and thus might protect against premature aging [112]. Antioxidant, anti-inflammatory, and immunostimulatory properties of fucosterol were supposed to be involved in its pro-survival effect [134].

Neurotrophic activity
Compounds with neuritogenic potentials are promising to reconstruct damaged neuronal network which is a characteristic feature of neurodegeneration. Several algal metabolites have shown a promising neurite outgrowth promoting potentials in cell culture conditions (Table 2). Sargachromenol from Sargassum macrocarpum promoted nerve growth factor (NGF)-dependent neuronal differentiation of PC12D cells by activating cyclic AMP-mediated protein kinase and MAPK1/2 and supported their survival by activating phosphatidylinositol-3 kinase (PI3K) [135]. Sargaquinoic acid, another metabolite from S. macrocarpum promoted neuritogenesis in PC12D cells, that involved cooperation between two independent pathways, i.e., TrkA-MAPK pathway and adenylate cyclase-PKA pathway [136]. Ina and colleagues demonstrated that the neurodifferentiation of PC12 cells by pheophytin a of Sargassum fulvellum required the presence of NGF and involved the activation of MAPK signaling pathway [137]. Vitamin B12, a chlorophyll-related analog to pheophytin a, also stimulated NGF-dependent PC12 cell differentiation by MAPK signaling pathway [138]. Dimethylsulfoniopropionate (DMSP) promoted neurite outgrowth and protected against TDAinduced cytotoxicity, involving the upregulation of Hsp32 and activation of the extracellular signalregulated kinases 1/2 (ERK1/2) [139]. Fucoxanthin has shown to exhibit neurite outgrowth activity (15.7-31% of cells to develop neurite outgrowth) at much lower concentrations (0.1-2 μM), in the absence of NGF support, indicating that this marine carotenoid could a potential neurotrophic molecule [107]. Gracilariopsis chorda and its active compound arachidonic acid modulated spine dynamics, and potentiated functional synaptic plasticity of hippocampal neurons [140].

Neuroprotective activity
Compounds that possess antioxidant, anti-inflammatory, anti-amyloidogenic, and antiaggregation, cholesterol homeostasis, and protein clearance activities are expected to show potential neuroprotective effects. Congruently, the following metabolites isolated from marine algae have been reported to confer neuroprotection against a range of toxic stimuli (Table 3).

Neuropharmacological potentials of marine algae and their metabolites: evidence from in vivo studies
The neuroprotective effects of some potential algal compounds that were reported in the in vitro conditions have successfully been translated into animal models ( Table 3), suggesting that these compounds could be potential candidates for further evaluation in the clinical trials.
Fucoidan is one of the algal compounds that has shown strong neuroprotection in several animal models. In PD model of C57/BL mice, fucoidan ameliorated MPTP-induced behavioral deficits, probably by elevating dopamine and its metabolites levels and increasing tyrosine hydroxylase expression [171]. Also, fucoidan inhibited MPTP-induced lipid peroxidation and restored antioxidant capacity [171]. Similarly, fucoidan also improved behavioral capacity, by attenuating the loss of dopaminergic neurons and inhibited the deleterious activation of microglia in the substantia nigra pars compacta in LPS-induced neurotoxicity [84]. In Aβ-induced rodent AD model, fucoidan ameliorated impaired memory, by reversing the decreased activity of ChAT, SOD, and GPx, increased activity of AChE, and rectifying the imbalance between apoptosis and prosurvival signals [181]. Fucoidan improved d-Gal-induced cognitive impairment in mice by mitigating OS and attenuating the caspase-dependent apoptosis pathway [173]. Wang and colleagues demonstrated that the supplementation of fucoidan alleviated Aβ-induced paralyzed phenotype in a transgenic C. elegans AD model [182]. Fucoidan reduced Aβ accumulation, probably by promoting proteasomal activity [182]. In another study, fucoidan-rich substances from Ecklonia cava improved trimethyltininduced cognitive dysfunction by inhibiting Aβ production and Tau hyperphosphorylation [183]. Fucoidan also attenuated transient global cerebral ischemic injury in the gerbil hippocampal CA1 area through mitigating glial activation and oxidative stress [184].
Laminarin, another polysaccharide of brown algae, has shown to protect I/R injury in gerbil models. Intraperitoneal injection of laminarin (50 mg/kg) following 5 min I/R attenuated reactive gliosis (anti-inflammatory) in the hippocampal CA1 of young gerbils [185]. A similar study following the same experimental protocol, but with aged gerbils, showed that laminarin (50 mg/kg) attenuated ischemia-induced death of pyramidal neurons in the hippocampal CA1 of aged gerbils [186]. This neuroprotective effect of laminarin is attributed to its antioxidant and anti-inflammatory properties [186]. Oligo-porphyran, a synthetic product of porphyran (Pyropia yezoensis) ameliorated behavioral deficits in 6-OHDA-induced Parkinsonian mice model by protecting dopaminergic loss and activating PI3K/Akt/Bcl-2 pathway that involved cellular signaling of anti-apoptosis and antioxidation [187]. Zhang and colleagues demonstrated that porphyran from Pyropia haitanensis improved the Aβ1-40-induced learning and memory deficits probably by elevating cerebral acetylcholine level [188].
Fucoxanthin is another significant algal metabolite that was found effective in a wide range of brain dysfunction (such as AD, ischemic stroke, and traumatic brain injury). Fucoxanthin ameliorated scopolamine-induced [106] and Aβ oligomer-induced [99] cognitive impairments in mice, possibly by inhibiting AChE activity and OS, modulating ChAT activity, and increasing BDNF expression.
Fucoxanthin alleviated cerebral ischemic/reperfusion (I/R) injury, improved the neurologic deficit score, and downregulated the expression of apoptosis-linked proteins in brain samples [158].
Fucosterol co-infusion ameliorated sAβ1-42-induced cognitive deficits in aging rats by modulating BDNF signaling [162]. Dieckol and phlorofucofuroeckol raised the brain level of acetylcholine by inhibiting AChE and reduced the inhibition of latency in ethanol-intoxicated memory-impaired mice [102]. Yang and co-investigators demonstrated that stereotaxic injection of phloroglucinol promoted synaptic plasticity and improved memory impairment in 5XFAD (Tg6799) Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 21 May 2020 doi:10.20944/preprints202005.0342.v1 mice [165]. In a later study, the same group reported phloroglucinol (orally administered)-mediated amelioration of cognitive dysfunction that involved a reduction in the amyloid β peptide burden and pro-inflammatory mediators and restoration of reduction in the dendritic spine density in the hippocampus of 5XFAD mice [203]. Phlorofucofuroeckol improved ischemic brain damage in rat MCAO model [168]. C-Phycocyanin improved the functional outcome and survival of gerbils on global cerebral I/R injury [189]. The in vitro neuroprotective effect of tramiprosate has been translated into in MCAO rat model in which it improved functional recovery following ischemic stroke [179]. Sulfated agaran, a sulfated polysaccharide from Gracilaria cornea attenuated oxidative/nitrosative stress and ameliorates behavioral deficits in rat 6-hydroxydopamine Parkinson's disease model [190]. It increased levels of dopamine, 3,4-Dihydroxyphenylacetic acid (DOPAC), GSH, and BDNF, decreased serotonin (5-HT) and thiobarbituric acid reactive substances (TBARS) levels, and decreased the expression of p65, IL-1β, and iNOS [190]. Glycoproteins isolated from Capsosiphon fulvescens ameliorated aging-induced spatial memory deficits by attenuating GSK-3β-mediated ER stress in rat dorsal hippocampus [204] and promoted probiotics-induced cognitive improvement in aged rat model [205]. Gracilariopsis chorda and its active compound arachidonic acid, given independently through oral route for 10 days, improved scopolamine-induced memory impairment in mice [140].
In addition, extracts from several marine algae have shown to either ameliorate memory impairment or enhance cognition in various in vivo models. For instance, Gelidiella acerosa attenuated Aβ25-35-induced cytotoxicity and memory deficits in mice [206], Sargassum swartzii improved memory functions in rats [207], Ishige foliacea [130] and Undaria pinnatifida [208] ameliorated scopolamine-induced memory deficits in mice. Also, some marine algae have shown to attenuate ischemic injury in stroke models. For example, Ecklonia cava ameliorated transient focal ischemia in rat MCAO model [209].

Recent progress on the development of marine algae-based neurotherapeutics
An algal oligosaccharide, sodium oligomannate, recently received conditional approval in China for improving cognitive function in patients with mild to moderate AD [26]. In preclinical studies, sodium oligomannate conferred neuroprotection against Aβ-induced neurotoxicity in human neuroblastoma cells [210] and ameliorated memory dysfunction in 5XFAD transgenic mouse model [211]. Sodium oligomannate can cross the blood-brain barrier through glucose transporter (GLUT1) and inhibits Aβ fibril formation and destabilizes the preformed fibrils into nontoxic monomers [211]. Although the complete mechanism of pharmacological actions remains unclear, sodium oligomannate harnessed neuroinflammation and thus ameliorated memory impairment by suppressing gut dysbiosis and the associated phenylalanine/isoleucine accumulation [211]. In a phase IIa pilot study in patients with AD, there was an elevation of Aβ1-42 levels in the cerebrospinal fluid (CSF) following sodium oligomannate treatment, suggesting a significant role in Aβ clearance into CSF [212]. There was a differential reduction in the cerebral glucose metabolic rate (CMRglu) in various brain regions following sodium oligomannate in clinical trials [212]. While in a phase IIa trial, the CMRglu in left orbitofrontal gyrus, left precuneus, right posterior cingulate gyrus, and right hippocampus were found to be low, in phase III trial, the lower rate was reported in superior parietal gyrus, inferior parietal gyrus, angular gyrus, and anterior wedge [212]. However, this newly approved drug lacks some advanced information like global data of effectivity and thus requires a large-scale global trial before it receives approval from the Food and Drug Administration (FDA).

Algal metabolites-based drug discovery and design
While a significant quantity of active compounds has been isolated from marine algae and added to the compound databases [213][214][215][216][217][218] every year, it is disappointing that very few of them have access to clinical trial and the success rate is also not very satisfactory. In this context, the current strategy of drug development requires a reformation with the inclusion of some modern approaches, such as virtual screening and network pharmacology. The system biology approach along with in silico study constitutes a potential computation tool that can better explain how a biologically effective compound interacts with the signal molecules of various cellular pathways.
Recent multitarget drugs have been designed by analyzing the 3D structure of already characterized compounds and crystal structure of target protein molecules. This information is focused on the virtual design of new chemical entities that include more than one biological function in a single molecule [219]. This approach is also known as target fishing, which identifies not only interacting proteins but also potential off-targets, and thus helps to understand polypharmacology, pharmacokinetics, and toxicity in the early stages of drug discovery [220]. For example, using in silico target fishing approach, Hannan and colleagues elucidated pharmacological mechanism of fucosterol-mediated neuroprotection and demonstrated that fucosterol showed interaction with potential targets, including LXR, TrKb, GR, Toll-like receptor (TLR) 2/4 and BACE1 [132]. Computational methods involving target screening are classified based on their principle including pharmacophore screening, shape screening, and reverse docking. When the target is available in the crystal structure, target fishing can be accomplished by a reverse docking approach, while in the absence, pharmacophore or shape screening can be used to find the relevant target by comparing pharmacophoric feature or shape of the compound, taking information from protein-ligand binding databases [221]. In this effort, several natural product databases containing compound target interactome are available nowadays including, SuperNatural [222], TCMID [223], TCMSP [224], and many others [225,226], however, not many are dedicated to marine algae [213][214][215]. Although algal metabolites show structural diversity and redundancy, the mentioned databases could still be available for network pharmacology to get insight into the disease-modifying mechanisms. Following this in silico approach, Vitale et al identified caulerpin as a PPAR agonist which was confirmed by both in vitro and in vivo assays [227]. In a reverse way, virtual screening through molecular docking analysis could be an alternative to find out potent hits from a large chemical library for a single target.
Compared to experimental high throughput screening, virtual screening, either by ligand or structure-based approach, can deliver the shorten cycle of hit discovery, with higher success hit rates. Furthermore, a structure-based approach consisting of molecular docking, receptor-based pharmacophore modeling together with molecular dynamics simulations and MM/PB(GB)SA approaches not only predict protein-ligand interaction but also provide a detailed binding mechanism, protein dynamics, and also highlights structure-activity relationship (SAR) for future drug design [228]. Several recent studies are adopting molecular docking techniques to analyze detailed protein-ligand interaction for marine bioactive compounds. For example, Jung et al. employed molecular docking studies to predict comparative binding interaction of monoamine oxidase (MAO) with fucoxanthin, a carotenoid from Eisenia bicyclis, where they revealed fucoxanthin as a reversible competitive hMAO inhibitor, binds strongly to the enzyme, following hydrogen bonding and hydrophobic interactions [229]. A similar approach has been applied to elucidate the interaction of fucosterol and fucoxanthin with BACE1 while analyzing BACE1 enzyme inhibition by fucosterol and fucoxanthin. Here binding interaction analysis by molecular docking identified that the presence of hydroxyl group in fucosterol and fucoxanthin is important for BACE1 inhibition; by which, both compounds interacted with Lys224 residue; Gly11 and Ala127 of the active site, respectively [105]. Interestingly, fucoxanthin was also identified as a dopamine agonist, where molecular docking study suggested that it formed H-bonding with Ser196 and Asp115 of D4 receptor, and Ser196 and Thr115 residues of D3 receptors [230]. The same group also identified some bromophenols derivatives as D3R and hD4R antagonists and studied the interaction and binding pattern by molecular docking [231].
In addition, several studies employed virtual screening to identify potent lead molecules from the database of seaweed metabolites. For instance, Florest et al. identified sigma-2 (σ2) receptor binding ligand by using both structure and ligand-based screening [232]. However, less effort has been deployed to develop marine natural product libraries, although significant studies so far have reported many compounds isolated from marine sources by large populations in the world. In this exertion, Davis  SWMD, comprising of 1110 metabolites, isolated from brown algae (266), green algae (33), and red algae (811) along with their physical and chemical properties [213]. Nevertheless, the information including experimentally-determined quantitative activity data and source information for more marine algal metabolites is still needed to facilitate computational based approaches in the exploration of marine compounds for future drug discovery.

Safety issues on marine algae-derived compounds
As a popular food material in East Asian countries, including Japan, Korea and China, seaweed are consumed without reported toxicity. However, the concern is that seaweed may sometime accumulate a considerable amount of heavy metals, such as cadmium, arsenic, mercury, and lead, and even some essential microelements such as iodine and iron [233]. It is, therefore, essential to conduct appropriate safety evaluation for seaweed. More importantly, while it is of safety concern during therapeutic development, the toxicity profile of seaweed-derived compounds needs to be thoroughly investigated. Safety information on algal metabolites is limited. However, toxicity profiles of algal polysaccharides have been reported by several studies. Observations from both in vitro and in vivo studies satisfied the non-toxic behavior of fucoidan irrespective of algal sources [234]. Fucoidan isolated from Undaria pinnatifida and Laminaria japonica was found to be safe in animal models given at very high oral doses [235][236][237][238]. Clinical studies also demonstrated the non-toxic health benefits of fucoidan in humans [239,240]. Safety evaluation studies on carrageenan suggest that sub-chronic or chronic feeding of this food-grade polysaccharide did not induce any toxic effect [241]. Moreover, dietary supplementation of carrageenan was not associated with carcinogenicity, genotoxicity, or reproductive defects [241]. Another study reported that no toxicological response was induced when iota-carrageenan was administered through the intranasal route [242]. Several studies also investigated toxicity of fucoxanthin and suggested that this carotenoid was safe and caused no visible toxicity in experimental subjects [243][244][245]. The toxicity profiles of some other marine metabolites have been recently reviewed [24]. As sufficient toxicological profiles of other potentially bioactive metabolites are lacking, they should be investigated with appropriate experimental models.

Conclusion and future perspectives
The current review highlights several neuropharmacological attributes, such as antioxidant, antiinflammatory, anti-cholinesterase, anti-amyloidogenic, antiaging, protein clearance, cholesterol homeostasis, and neuritogenic capacity of algae-derived metabolites that underlie their neuroprotective functions against a wide range of neurotoxic stimuli (Figure 1). The neuroprotective effects of marine algae and their metabolites do not necessarily depend on a single attribute, rather on the synergism of multiple of these pharmacological properties. As neurodegenerative disorders involve complex pathogenic mechanisms, they could better be managed with a single compound targeting two or more of the pathogenic mechanisms or multiple compounds with the complementary mechanism of action. In this context, algal compounds, such as fucoxanthin, fucosterol, and fucoidan that are known to target multiple pathogenic mechanisms could be potential candidates for future drug development. Besides, several metabolites, including laminarin, porphyran, saringasterol, α-bisabolol, and phlorotannins that exhibited encouraging neuroprotective roles, also deserve further attention.
have already shown neuroprotective ability as well as those that have not yet been explored, therefore, need to be screened for their ability to promote neurite extension. Despite a sizable collection of algae-based natural products with distinct neuroprotective functions, only sodium oligomannate has emerged as a successful drug for AD. This review, therefore, calls for intensive research on other potential compounds to translate the preclinical findings into clinical models. Also, the factors that are responsible for the failure of a clinical trial need to be carefully reviewed. For example, the bioavailability of a candidate drug in the brain, including its ability to cross BBB remains one of the barriers to therapeutic success. If the ADME (absorption, distribution, metabolism, and excretion) properties of a preclinically effective compound sufficiently guarantee its drug-likeliness, it is highly likely that the compound may succeed in clinical trials. That's why, the ongoing strategy requires a rational reformation incorporating modern approaches, such as virtual screening and system biology to strengthen the algae-based drug development process. The computational study will provide some crucial information on the ADME properties of potential leads and its interaction and binding affinity to molecular targets while system biology knowledge will identify the potential interaction of target molecules and cellular signaling pathways at the systemic level. With the constant discovery of new compounds, all these strategies will accelerate the designing and development of algae-based future drugs.