Mitochondrial dysfunction in brain disorders

The brain requires a substantial amount of energy to maintain electrophysiological activities; therefore, the generation of ATP through oxidative phosphorylation by mitochondria is critical for brain health. Since the brain lacks sufficient long-term energy storage capacity, neurones are vulnerable to impaired energy metabolism,^{(Reference Wang, Zhao and Ma9)} which commonly occurs in brain disorders that are associated with mitochondrial dysfunction. For example, the lack of blood flow to the brain disrupts the function of the electron transport chain (ETC), leading to energy failure in cases of cerebral ischaemia.^{(Reference Qin, Yang and Chu10)} Furthermore, impaired energy metabolism has been reported in neurodegeneration models. The aggregation of α-synuclein inhibits the function of complex I in the ETC, which causes ATP depletion.^{(Reference Reeve, Ludtmann and Angelova11)} Impaired ETC functioning has been reported in the brains of AD patients.^{(Reference Maurer, Zierz and Möller12)}

ATP depletion impairs the ATP-dependent Na⁺/K⁺ and Ca²⁺ pumps, which leads to ionic imbalance in the cytosol, where increased Ca²⁺ ions activate cellular responses that cause neuronal damage. Ca²⁺ triggers the release of neurotransmitters into the extracellular space, including glutamate, which then activates N-methyl-D-aspartate receptors causing a large influx of Ca²⁺ and excitotoxicity. In addition, Ca²⁺ activates the opening of the mitochondrial permeability transition pore (mPTP),^{(Reference Robinson, Lee and DaSilva13,Reference Abramov and Duchen14)} which is a large non-selective channel that triggers cell death. Once opened, mitochondrial membrane depolarization, ATP depletion, and mitochondrial swelling occur, ultimately leading to cell death. Research has shown that excitotoxicity triggers the dissociation of the F₁ subcomplex from the Fo component of F₁Fo ATP synthase, which results in the opening of a leak channel.^{(Reference Bonora, Morganti and Morciano15,Reference Mnatsakanyan, Park and Wu16)} A rodent model of focal cerebral ischaemia showed a decreased mitochondrial membrane potential in isolated mitochondria when compared with the control model.^{(Reference Li, Ma and Yu17)} An ischaemia-reperfusion model revealed that the loss of mitochondrial membrane potential was prevented by treatment with cyclosporine A, which inhibits mPTP.^{(Reference Liu, Wang and Zhang18)} The neuroprotective properties of cyclosporine A were also observed in rodent TBI models.^{(Reference Sullivan, Thompson and Scheff19)} In addition, amyloid-β (Aβ) peptide can trigger mPTP opening by causing the translocation of cyclophilin D.^{(Reference Du and Yan20)} A deficiency in cyclophilin D could maintain mitochondrial membrane potential and improve cognitive function in AD mice, thereby indicating the involvement of mPTP in AD pathology.^{(Reference Du, Guo and Fang21)} In a PD model, α-synuclein aggregates caused the loss of mitochondrial membrane potential and induced the activity of a leak channel similar to mPTP.^{(Reference Ludtmann, Angelova and Horrocks22)}

Mitochondria are critical for the functioning of apoptotic pathways. Oligomerization of pro-apoptotic Bcl-2 family proteins such as Bax and Bak in the mitochondrial membrane promotes the release of cytochrome c from the mitochondria. This cytochrome c then binds to apoptotic protease-activating factor-1 and activates caspases,^{(Reference Kim, Du and Fang23)} which causes the proteolysis of structural and functional proteins, leading to cell death. This apoptotic pathway can be inhibited by anti-apoptotic Bcl-2 family members, such as Bcl-2 and Bcl-xL, which sequester pro-apoptotic proteins. Maintaining a balance between pro- and anti-apoptotic Bcl-2 family proteins is critical for cell survival, and alterations in these protein levels are evident in brain tissues of humans and animals with brain disorders. Postmortem studies have identified increased levels of pro-apoptotic Bax proteins in the brain tissues of PD patients.^{(Reference Tatton24)} Similarly, mouse PD models have shown increased pro-apoptotic Bax protein and mRNA levels and decreased anti-apoptotic Bcl-2 protein levels in dopaminergic neurones.^{(Reference Vila, Jackson-Lewis and Vukosavic25)} In addition, genetically modified Bax-deficient PD mice were revealed to be resistant to the loss of dopaminergic neurones.^{(Reference Vila, Jackson-Lewis and Vukosavic25)} The Aβ peptide, which is a hallmark of AD, can decrease Bcl-2 and increase Bax, thereby potentially contributing to neuronal apoptosis and neurodegeneration.^{(Reference Paradis, Douillard and Koutroumanis26)} Increased levels of Bax and decreased levels of Bcl-2 and Bcl-xL have been observed in a rodent model of cerebral ischaemia,^{(Reference Zhang and Wang27)} and treatment with pro-apoptotic protein inhibitors reversed excitotoxicity-associated neuronal death.^{(Reference Park, Licznerski and Mnatsakanyan28)}

Mitochondria are major contributors to cellular ROS, which are by-products of oxidative phosphorylation.^{(Reference Lin and Beal29)} ETC impairment can cause excessive ROS production, which overwhelms the antioxidant defence system and promotes oxidative stress. Increases in oxidative stress markers that indicate lipid peroxidation and DNA oxidation have been observed in the brain during neurodegeneration^{(Reference Butterfield and Halliwell30,Reference Su, Wang and Nunomura31)} and the depletion of antioxidant enzymes such as glutathione peroxidase and superoxide dismutase (SOD) has been identified in neurodegenerative diseases. In AD, Aβ plaques accumulate in the brain and disrupt the activities of ETC complexes, which causes an overproduction of ROS.^{(Reference Maurer, Zierz and Möller12)} Moreover, oligomeric or fibrillar α-synuclein inhibits the function of the mitochondrial respiratory chain, resulting in increased ROS production in PD cases.^{(Reference Reeve, Ludtmann and Angelova11)} Oxidative stress can activate the NLRP3 inflammasome, which is a multiprotein complex that triggers the processing and secretion of pro-inflammatory cytokines.^{(Reference Sorbara and Girardin32)} Elevated levels of ROS and ROS-mediated cellular damage in neurodegenerative diseases trigger inflammatory responses that cause immune cell recruitment and additional ROS production. Extracellular accumulation of Aβ plaques can activate microglia, which release pro-inflammatory cytokines.^{(Reference Wang, Tan and Yu33)} In cerebral ischaemia, both hypoxia and reperfusion trigger inflammatory responses that activate macrophages and release pro-inflammatory cytokines, including TNF alpha (TNF-α), IL-1, IL-6, and IL-8.^{(Reference Qin, Yang and Chu10)} These inflammatory cytokines induce the production of adhesion molecules on endothelial cells that promote neutrophil adhesion; these activated neutrophils then generate additional ROS.^{(Reference Kawabori and Yenari34)}

Mitochondrial DNA has been implicated in the pathogenesis of neurodegenerative disorders because of its predisposition to oxidative damage due to its proximity to the ETC and the lack of a proper DNA repair mechanism.^{(Reference Chen, Turnbull and Reeve35)} Furthermore, mutations in genes associated with mitochondrial function have been linked to neurodegeneration, such as the PARK genes, which are critical for mitochondrial function and have been implicated in the pathogenesis of PD. Mutations in the PINK1 and Parkin genes have been associated with decreased ETC enzyme activity and ATP depletion.^{(Reference Chen, Turnbull and Reeve35)} These mutations disrupt the balance of mitochondrial fission, fusion, and mitophagy, leading to an increased number of fragmented mitochondria. Mutations in the DJ1 and LRRK2 genes are associated with decreased mitochondrial membrane potential, increased oxidative stress, decreased complex I function, and increased mitochondrial fragmentation.^{(Reference Lev, Roncevich and Ickowicz36,Reference Martin, Kim and Dawson37)}

Neuroprotective effects of fucoxanthin

Fucoxanthin (C₄₂H₅₈O₆) is a carotenoid marine xanthophyll that is found in brown seaweed such as Undaria pinnatifida and Laminaria japonica.^{(Reference Wang, Wang and Zhang38,Reference Fung, Hamid and Lu39)} It has a strong antioxidant capacity because of the presence of multiple double bonds, including a conjugated carbonyl group. Fucoxanthin has a radical scavenging effect when treated with 1,1-diphenyl-2-picrylhydrazyl and 2,2′-Azinobis-3-ethylbenzo thiazoline-6-sulfonate^{(Reference Nomura, Kikuchi and Kubodera40–Reference Sachindra, Sato and Maeda43)} and exhibits a stronger hydroxyl radical quenching activity than other antioxidants.^{(Reference Sachindra, Sato and Maeda43)} In addition to its direct scavenging effect, fucoxanthin regulates the gene expression of antioxidant enzymes such as SOD and catalase to help support cellular redox homeostasis.^{(Reference Xiang, Liu and Lin44)}

Although epidemiological data demonstrating the direct effect of fucoxanthin on brain disorders are limited, a high intake of seaweed has been reported to lower the risk of PD^{(Reference Okubo, Miyake and Sasaki45)} and stroke-mediated mortality in humans.^{(Reference Kishida, Yamagishi and Muraki46)} Pharmacokinetic studies using human plasma detected fucoxanthinol, a metabolite of fucoxanthin, after a single oral administration of kombu (Laminaria japonica) extract containing fucoxanthin (31 mg)^{(Reference Hashimoto, Ozaki and Mizuno47)} or a 1-week dose of dried wakame (Undaria pinnatifida) containing 6.1 mg of fucoxanthin.^{(Reference Asai, Yonekura and Nagao48)} Quantitative analyses of fucoxanthin in human tissues other than blood have not been conducted; however, Hashimoto et al. observed its distribution and that of its metabolites such as fucoxanthinol and amarouciaxanthin A in tissues after oral administration in a mouse model.^{(Reference Hashimoto, Ozaki and Taminato49)} Although the brain was not analysed in that study, fucoxanthin was present in other lipid-rich organs such as the adipose and liver. While the neuroprotective potential of fucoxanthin has been documented in in vivo animal models, its ability to cross the blood-brain barrier (BBB) remains unconfirmed. However, since other carotenoids from the xanthophyll family, such as astaxanthin, lutein, and zeaxanthin, can permeate the BBB, fucoxanthin has the potential for uptake into brain tissue.^{(Reference Manabe, Komatsu and Seki50,Reference Vishwanathan, Neuringer and Snodderly51)}

Alzheimer’s disease

Alzheimer’s disease is a progressive neurodegenerative disorder that is characterised by cognitive impairment, memory decline, and behavioral and personality changes. It is the most common cause of dementia in older adults and affects one in nine US residents aged 65 and older.⁽⁵²⁾ The complex neuropathology of AD involves the extracellular aggregation of Aβ into plaques and the intracellular accumulation of hyperphosphorylated tau protein into neurofibrillary tangles. These processes accompany and affect significant mitochondrial dysfunction in AD models. Aβ can impair the functioning of ETC, cause the loss of mitochondrial membrane potential, increase ROS production, and disrupt Ca²⁺ homeostasis.^{(Reference ME53–Reference Kuchibhotla, Goldman and Lattarulo56)} In addition to mitochondrial dysfunction, Aβ induces neuroinflammation and impairs neurotransmission.

Fucoxanthin has been suggested to protect mitochondria against AD-associated pathologies.^{(Reference Xiang, Liu and Lin44,Reference Lin, Yu and Zhao57,Reference Lee, Youn and Yoon58)} Treatment with fucoxanthin prevents the loss of cell viability against Aβ-induced cytotoxicity.^{(Reference Lin, Yu and Zhao57,Reference Lee, Youn and Yoon58)} In particular, fucoxanthin-treated cells were resistant to apoptotic death, thereby indicating mitochondrial protection,^{(Reference Lin, Yu and Zhao57,Reference Lee, Youn and Yoon58)} and fucoxanthin-modified Aβ1-42 oligomers have been reported to be less toxic than Aβ1-42 oligomers to SH-SY5Y cells.^{(Reference Xiang, Liu and Lin44)} Furthermore, fucoxanthin may directly prevent the formation of Aβ plaques and neurofibrillary tangles. Xiang et al. showed the binding of fucoxanthin to Aβ1-42 peptides, where it inhibited the formation of Aβ fibrils and oligomers^{(Reference Xiang, Liu and Lin44)} and prevented Aβ-mediated mitochondrial dysfunction.^{(Reference Itoh, Wakabayashi and Katoh59–Reference Dickson62)} Similarly, Jung et al. reported the binding of fucoxanthin and inhibition of β-site amyloid precursor protein cleaving enzyme 1, which cleaves the amyloid precursor protein to produce Aβ.^{(Reference Jung, Ali and Choi63)} Fucoxanthin may inhibit the production and aggregation of Aβ through interaction with two hydroxyl groups.^{(Reference Jung, Ali and Choi63)} In addition, co-incubation of Aβ monomers with fucoxanthin resulted in a dose-dependent decrease in Aβ oligomer formation through hydrophobic interactions. Lee et al. reported that fucoxanthin reversed the loss of mitochondrial membrane potential in Aβ-treated PC12 cells.^{(Reference Lee, Youn and Yoon58)} In that study, 5 μM fucoxanthin was as effective as 50 μM resveratrol, an antioxidant with neuroprotective function, indicating a strong mitochondrial protection capacity. Fucoxanthin inhibits Aβ-mediated upregulation of Bax, thereby helping to maintain the integrity of the mitochondrial membrane.^{(Reference Lee, Youn and Yoon58)} Those authors also showed that treatment with fucoxanthin prevented the increase of intracellular Ca²⁺, as measured by fluo3-AM. Although mPTP was not primarily discussed in that study, the data suggests that fucoxanthin has a role in inhibiting the opening of the mPTP.

Fucoxanthin protects cells from oxidative damage associated with AD.^{(Reference Lin, Yu and Zhao57,Reference Lee, Youn and Yoon58)} Treatment with fucoxanthin was shown to increase nuclear Nrf2 expression, whereas co-treatment with a PI3K inhibitor attenuated this increase, suggesting that fucoxanthin mediated this increased expression through the Akt/GS3K signalling pathway.^{(Reference Lee, Youn and Yoon58)} Similarly, treatment with fucoxanthin increased the activation of the pro-survival PI3K/Akt pathway in Aβ SH-SY5Y cells.^{(Reference Lin, Yu and Zhao57)} Nrf2 is an important regulator of cellular antioxidants that is normally sequestered in the cytosol by Keap1.^{(Reference Itoh, Wakabayashi and Katoh59)} Oxidative stress induces the translocation of Nrf2 to the nucleus, where pFyn eventually stimulates its export. Fucoxanthin may increase nuclear Nrf2 by preventing the phosphorylation of Fyn and Nrf2 by GS3K, thereby decreasing the degradation and export of Nrf2 from the nucleus.^{(Reference Lee, Youn and Yoon58)} Similarly, fucoxanthin regulated redox homeostasis in in vivo models of AD and was shown to attenuate the decrease in SOD, catalase, and glutathione in AD mice.^{(Reference Xiang, Liu and Lin44)} The BV2 cells treated with the poly lactic-co-glycolic acid-block-polyethylene glycol (PLGA-PEG)-fucoxanthin nanoparticle prevented Aβ-induced NF-κB, TNF-α, and IL-1β induction compared with the BV2 cells treated with only Aβ oligomers, indicating that fucoxanthin prevented Aβ-induced neuroinflammation.^{(Reference Yang, Jin and Wu60)} Furthermore, fucoxanthin has anticholinesterase and antibutyrylcholinesterasic activity,^{(Reference Kawee-ai, Kuntiya and Kim61)} and since acetylcholine is considerably depleted in the AD pathology, fucoxanthin may help maintain acetylcholine levels in the brain.^{(Reference Kawee-ai, Kuntiya and Kim61)}

Parkinson’s disease

Parkinson’s disease is a progressive neurodegenerative disorder caused by the loss of dopaminergic neurones in the substantia nigra that leads to a deficiency of dopamine, which is a neurotransmitter that controls movement, pleasure, and motivation.^{(Reference Dickson62)} The common symptoms of PD include tremors, rigidity, akinesia, and postural instability,^{(Reference Dickson62)} while non-motor symptoms such as depression, anxiety, and cognitive impairments can also occur.^{(Reference Dickson62)} In 2019, over 8.5 million individuals worldwide were estimated to be living with PD.⁽⁶⁴⁾ A 2022 study stated that close to 90,000 people are diagnosed with PD every year in the United States, representing a 50% increase from the previously estimated number of 60,000 annually.⁽⁶⁵⁾ Currently, patients with PD are treated with levodopa (L-DA) to alleviate symptoms, although this treatment may cause neurotoxicity in the long term.^{(Reference Tambasco, Romoli and Calabresi66)}

The degradation of dopaminergic neurones is associated with the accumulation of misfolded α-synuclein proteins. Oligomeric and fibrillar α-synucleins inhibit the function of ETC and impair ATP production. Postmortem studies have shown decreases in complexes I and II in the PD brain.^{(Reference Grünewald, Rygiel and Hepplewhite67)} Furthermore, the α-synuclein aggregate interacts with F₁Fo ATP synthase in the respiratory chain, which causes the opening of the mPTP,^{(Reference Ludtmann, Angelova and Horrocks22)} and disruption of the respiratory chain leads to the overproduction of ROS that damages the mitochondria. Increased oxidative stress also impairs the function of the ubiquitin-proteasome system, thereby inhibiting the clearance of these misfolded proteins and leading to their accumulation in neurones.^{(Reference Moon and Paek68)} Degradation of dysfunctional mitochondria is important for maintaining a healthy pool of neuronal mitochondria. Mutations in the PINK1 and Parkin genes in the PD brain impair the mitophagy process resulting in the accumulation of dysfunctional mitochondria.^{(Reference Pickrell and Youle69)} Similarly, DJ1 and LRRK2 gene mutations are associated with loss of mitochondrial membrane potential and morphology.^{(Reference Lev, Roncevich and Ickowicz36,Reference Martin, Kim and Dawson37)} DJ1 binds to the β-subunit of the F1Fo ATP synthase enhancing ATP production. In contrast, a DJ1 mutant fails to close the mitochondrial inner membrane leak, thereby altering energy metabolism.^{(Reference Chen, Park and Mnatsakanyan70)} The aggregation of α-synuclein can also affect mitochondrial fragmentation^{(Reference Nakamura, Nemani and Azarbal71)} and movement, which alters the mitochondrial distribution in axonal regions that have high energy demands.^{(Reference Thorne and Tumbarello72)}

In vitro and in vivo studies have suggested the mitochondrial protective effects of fucoxanthin in PD pathology. Treatment with fucoxanthin prevented the loss of mitochondrial membrane potential in PC12 cells challenged with 6-hydroxydopamine (6-OHDA) or a combination of 6-OHDA and L-DA.^{(Reference Wu, Han and Liu73,Reference Liu, Lu and Tang74)} Although the levels of ATP production and oxygen consumption were not directly measured in those models, maintaining mitochondrial membrane potential is critically important to power F₁Fo ATP synthase. Thus, fucoxanthin may help maintain mitochondrial energy metabolism. In addition, annexin V and propidium iodide co-staining showed that fucoxanthin prevented PD-associated apoptotic cell death,^{(Reference Wu, Han and Liu73,Reference Liu, Lu and Tang74)} suggesting that fucoxanthin is involved in the protection of mitochondrial membrane integrity. The direct role of fucoxanthin on mitochondrial quality control in the PD brain is unknown. Lian et al. showed that treatment with fucoxanthin increased the ratio of LC3-II to LC3-I, the protein level of Parkin, and the number of autophagosomes and mitophagosomes in retinal ganglion cells challenged with excitotoxicity,^{(Reference Lian, Hu and Zhang75)} suggesting that fucoxanthin has a role in regulating mitophagy. Those authors further showed that fucoxanthin prevented the loss of mitochondrial membrane potential during excitotoxicity and helped protect from apoptotic death by lowering Bax and increasing Bcl-2.

The loss of mitochondrial membrane integrity and inefficient operation of ETC increases ROS production. PC12 cells challenged with 6-OHDA or a combination of 6-OHDA and L-DA showed increased DCF signals indicating increased intracellular ROS,^{(Reference Wu, Han and Liu73,Reference Liu, Lu and Tang74)} whereas fucoxanthin-treated PC12 cells were resistant to ROS production in a dose-dependent manner. In addition to its radical scavenging properties,^{(Reference Nomura, Kikuchi and Kubodera40–Reference Yan, Chuda and Suzuki42)} fucoxanthin increased antioxidant enzyme expression in PD models.^{(Reference Wu, Han and Liu73,Reference Liu, Lu and Tang74)} Fucoxanthin binds to a hydrophobic site on Keap1 where it decreases the affinity of Keap1 to Nrf2-binding in a dose-dependent manner.^{(Reference Wu, Han and Liu73)} Therefore, fucoxanthin increased the nuclear expression of Nrf2 and the downstream genes that encode antioxidant enzymes such as haem oxygenase-1, the glutamate-cysteine ligase modifier subunit, and the glutamate-cysteine ligase catalytic subunit in 6-OHDA-treated PC12 cells.^{(Reference Wu, Han and Liu73)} In addition, PD mice that underwent intragastric administration of fucoxanthin (50, 100, or 200 mg/kg/day) for 28 d improved pole climbing, swimming, and suspension experiment scores, indicating improved motor function.^{(Reference Liu, Lu and Tang74)} Similarly, zebrafish larvae treated with different concentrations of fucoxanthin for 4 d showed improved swimming abilities after exposure to 6-OHDA.^{(Reference Wu, Han and Liu73)}

Cerebral ischaemia

Cerebral ischaemia is a condition that commonly occurs during cardiovascular events such as stroke or cardiac arrest and involves reduced blood flow to the brain. This condition impairs mitochondrial energy metabolism through the deprivation of oxygen and essential nutrients to the brain.^{(Reference Sims and Mitochondria76,Reference Yang, Mukda and Chen77)} Dysfunctional mitochondria cause the production of excessive ROS, which damage various cellular components and trigger apoptotic pathways, including the oligomerization of pro-apoptotic proteins in the mitochondrial membrane and the release of cytochrome c, leading to programmed cell death.^{(Reference Broughton, Reutens and Sobey78)} In addition, ischaemia-mediated energy depletion causes the failure of the ATP-dependent ionic pump, thereby altering intracellular ionic homeostasis. Furthermore, excessive cellular Ca²⁺ concentrations cause the opening of mPTP,^{(Reference Li, Park and Jonas79,Reference Baumgartner, Gerasimenko and Thorne80)} which exacerbates the energy crisis and leads to neuronal death.

Ikeda et al. showed that treatment with fucoxanthin isolated from wakame (Undaria pinnatifida) promoted the release of lactate dehydrogenase in hypoxia-exposed primary cortical neurones,^{(Reference Ikeda, Kitamura and Machida81)} which suggests that fucoxanthin reduces cytotoxicity during oxygen depletion. Those authors performed an in vivo study using stroke-prone spontaneously hypertensive rats, which were characterised by severe spontaneous hypertension and the development of cerebrovascular diseases. Supplementation with 5% wakame powder delayed the development of stroke and increased the lifespan of the rats. Hu et al. further investigated the cellular mechanisms of fucoxanthin-mediated neuroprotection^{(Reference Hu, Chen and Tian82)} by intragastrically administering 30, 60, and 90 mg/kg of fucoxanthin to Wistar rats 1 h before middle cerebral artery occlusion (MCAO). The results showed that rats treated with fucoxanthin exhibited a dose-dependent reduction of MCAO-induced brain injury. Treatment with fucoxanthin increased the ratio of Bcl-2/Bax and decreased the cleaved caspase 3 protein level, indicating inhibition of mitochondria-mediated apoptosis during cerebral ischaemia. Consistent with in vivo data, rat cortical neurones treated with fucoxanthin showed anti-apoptotic properties in response to oxygen-glucose deprivation and reoxygenation challenges.^{(Reference Hu, Chen and Tian82)} Furthermore, the study suggested that fucoxanthin increased antioxidant proteins such as SOD^{(Reference Hu, Chen and Tian82)} via the activation of Nrf2,^{(Reference Wang, Zhang and Lu83)} thereby protecting neurones from oxidative stress. Wang et al. used PLGA-PEG nanoparticles to increase fucoxanthin bioavailability in the brains of MCAO-induced rats.^{(Reference Wang, Zhang and Lu83)} PLGA-PEG encapsulation improves fucoxanthin stability in the body and allows for its extended release and enhanced penetration into the central nervous system. The results of that study showed that the intravenous administration of PLGA-PEG fucoxanthin nanoparticles (20 and 40 mg/kg) half an hour before MCAO reduced the behavioural deficits associated with cerebral ischaemia in the rats. In addition, the infarct volumes and brain oedema extents were decreased in rats receiving the nanoparticle treatment.^{(Reference Wang, Zhang and Lu83)} Furthermore, PLGA-PEG fucoxanthin nanoparticles prevented the loss of glutathione peroxidase, SOD, and catalase activity in the ischaemic brain indicating the roles of these compounds in regulating antioxidant defence. Fucoxanthin nanoparticles exhibit anti-inflammatory properties through the inactivation of the NF-κB pathway.

Depression and anxiety

Depression is characterised by a pervasive lack of interest in daily activities that can lead to a profound sense of hopelessness or self-harm, while anxiety involves excessive worry and enduring fear. Depression and anxiety frequently co-occur, possibly due to overlapping cellular mechanisms, with 41.6% of individuals diagnosed with a depressive episode presenting with anxiety within 12 months of the diagnosis,^{(Reference Kalin84)} demonstrating a substantial comorbidity between the two conditions. Although the neurological pathways that affect these disorders are not fully understood, a growing body of studies suggests an association with mitochondrial dysfunction.^{(Reference Fox and Lobo85,Reference Hollis, Pope and Gorman-Sandler86)} Cellular energy metabolism is dysregulated in patients with depression.^{(Reference Li, Su and Wang87)} Similarly, a proteomic analysis of mice challenged with chronic corticosterone, a stress hormone associated with depression and anxiety, showed that oxidative phosphorylation-related protein expression was decreased in these mice.^{(Reference Gong, Yan and Lei88)} Treatment with ATP reversed the impaired synaptic transmission and excitability in neurones in depression mouse models.^{(Reference Lin, Huang and Luo89)} Moreover, repeated unpredictable stress downregulated anti-apoptotic genes such as Bcl-2 and Bcl-xL in rat brains,^{(Reference Kosten, Galloway and Duman90)} whereas approaches that improved the anti-apoptotic/pro-apoptotic Bcl-2 protein ratio alleviated the depression-associated behaviours.^{(Reference Wang, Xie and Zhang91)}

Although the risk factors for behavioural disorders are complex, studies have demonstrated that the consumption of a healthy diet lowers the risk of depression.^{(Reference Kris-Etherton, Petersen and Hibbeln92,Reference Molendijk, Molero and Sánchez-Pedreño93)} A prospective cohort study with Japanese adults, which was adjusted for biological, socio-economic, and dietary factors, reported that high seaweed intake was negatively associated with depressive symptoms.^{(Reference Guo, Huang and Cui94)} In animal models, treatment with extract from the brown seaweed Sargassum horneri (500 mg/kg) for 3 weeks prevented the loss of neurotransmitters such as serotonin, dopamine, and norepinephrine in the mouse brain, as well as improvements in depressive-live behaviours caused by an intraperitoneal injection of corticosterone.^{(Reference Park, Kim and Kim95)} The authors performed a quantitative analysis and verified the presence of fucoxanthin in the extract. That study further revealed that the underlying mechanism involved the activation of the ERK-CREB-BDNF pathways by the brown seaweed extract. Although the role of Sargassum horneri in mitochondrial protection was not intensively featured in that study, the BDNF has been previously shown to increase anti-apoptotic Bcl-xL^{(Reference Chao, Ma and Lee96)} where the depletion of Bcl-xL impairs the maturity of BDNF.^{(Reference Park, Crowe-White and Ciesla97)} Thus, treatment with fucoxanthin may promote the development and growth of neurones by preventing the mitochondrial dysfunction associated with depression. In addition, the intragastric administration of fucoxanthin (0, 50, 100, and 200 mg/kg) improved Lipopolysaccharide (LPS)-induced anxiety behaviours in mice.^{(Reference Jiang, Wang and Lin98)} Treatment with fucoxanthin regulates the AMPK-NF-κB pathways and prevents the accumulation of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, and iNOS and COX-2 in the hippocampus, cortex, and hypothalamus.

Brain aging

The cumulative impact of oxidative damage on neurones contributes to the process of brain aging.^{(Reference Harman99,Reference Paradies, Petrosillo and Paradies100)} This oxidative damage results from the generation of free radicals through environmental exposure, inflammation, immune responses, and infection.^{(Reference Harman99,Reference Paradies, Petrosillo and Paradies100)} Postmortem analyses of aged human brain tissues, particularly in the hippocampus and cortical regions, revealed elevated ROS levels and a decrease in antioxidant enzymes such as SOD and catalase.^{(Reference Venkateshappa, Harish and Mahadevan101)} The accumulation of dysfunctional mitochondria in aged brains is associated with brain atrophy and neuronal apoptosis,^{(Reference Boveris and Navarro102)} and the mitochondria isolated from the brains and other tissues of aged rodents demonstrated decreased ETC activity. Specifically, ETC complexes I and IV exhibit reduced activity in the aging brain, which can be attributed to increased oxidative stress.^{(Reference Boveris and Navarro102)}

The diet patterns in Okinawa, a blue zone region with a high life expectancy, include nutrient-dense foods such as lean meat, fish, and vegetables, including seaweed.^{(Reference Willcox and Willcox103)} Fucoxanthin is abundant in brown seaweed, which is a common part of the Okinawan diet. In the 1990s, Okinawan people had the lowest mortality rate from age-associated diseases in the Japanese and US populations.^{(Reference Willcox, Willcox and Todoriki104)} Research investigating the direct role of fucoxanthin in brain aging is still limited; however, oxidative stress and inflammation are the main risk factors for age-associated cognitive decline,^{(Reference Baierle, Nascimento and Moro105,Reference Ownby106)} and the antioxidant effects of fucoxanthin have been determined.^{(Reference Nomura, Kikuchi and Kubodera40–Reference Yan, Chuda and Suzuki42)} Chen et al. reported that the administration of 100–200 mg/kg of fucoxanthin for 7 d post-laparotomy surgery improved cognitive function in 12–14-month-old mice.^{(Reference Chen, Dong and Gong107)} This treatment also decreased neuroinflammation and oxidative stress by activating the Akt and Nrf2 pathways, decreasing the levels of pro-inflammatory cytokines such as TNF-α and IL-1β, and increasing the antioxidant enzymes in the hippocampal tissue.^{(Reference Chen, Dong and Gong107)}

Fucoxanthin increased the lifespan and resilience of Caenorhabditis elegans (C. elegans) and Drosophila melanogaster models to starvation and thermal and oxidative stress. Two carotenoids, fucoxanthin and β-carotene, were tested in that study, and lifespan extensions in C. elegans were only observed in the fucoxanthin-treated group.^{(Reference Lashmanova, Proshkina and Zhikrivetskaya108)} Additionally, transcriptome analysis showed that fucoxanthin regulates the pathways involved in longevity, Wnt, and autophagy.^{(Reference Moskalev, Shaposhnikov and Zemskaya109)} In particular, the Wnt signalling pathway controls mitochondrial function, including metabolism, biogenesis, and dynamics in cancer and non-transformed cells. Increased Wnt signalling activates mitophagy by increasing ROS production, which in turn decreases the number of damaged mitochondria and increases the quantity of working mitochondria through biogenesis. The Wnt signalling pathway is important for maintaining mitochondrial homeostasis; therefore, fucoxanthin-mediated upregulation of genes associated with the Wnt pathway could lead to mitochondrial protection. In addition, autophagy is an important quality control mechanism to remove damaged organelles such as dysfunctional mitochondria. Dysregulated autophagy promotes protein aggregation, which is associated with neurodegeneration such as that of PD. Furthermore, this study also showed that oxidative phosphorylation and apoptosis were one of the major targets of fucoxanthin, suggesting its role in regulating mitochondrial function.