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Astaxanthin as a Potential Neuroprotective Agent for Neurological Diseases

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Neurological diseases, which consist of acute injuries and chronic neurodegeneration, are the leading causes of human death and disability. However, the pathophysiology of these diseases have not been fully elucidated, and effective treatments are still lacking. Astaxanthin, a member of the xanthophyll group, is a red-orange carotenoid with unique cell membrane actions and diverse biological activities. More importantly, there is evidence demonstrating that astaxanthin confers neuroprotective effects in experimental models of acute injuries, chronic neurodegenerative disorders, and neurological diseases. The beneficial effects of astaxanthin are linked to its oxidative, anti-inflammatory, and anti-apoptotic characteristics. In this review, we will focus on the neuroprotective properties of astaxanthin and explore the underlying mechanisms in the setting of neurological diseases.
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Mar. Drugs 2015, 13, 1-x manuscripts; doi:10.3390/md130x000x
marine drugs
ISSN 1660-3397
Astaxanthin as a Potential Neuroprotective Agent for
Neurological Diseases
Haijian Wu 1, Huanjiang Niu 1, Anwen Shao 2, Cheng Wu 1, Brandon J. Dixon 3,
Jianmin Zhang 2, Shuxu Yang 1,* and Yirong Wang 1,*
1 Department of Neurosurgery, Sir Run Run Shaw Hospital, School of Medicine,
Zhejiang University, Hangzhou, 310016, China; E-Mails: (H.W.); (H.N.); (C.W.)
2 Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University,
Hangzhou, 310009, China; E-Mails: (A.S.); (J.Z.)
3 Department of Physiology and Pharmacology, School of Medicine, Loma Linda University,
Loma Linda, CA, 92350, USA.; E-Mail: (B.D.)
* Authors to whom correspondence should be addressed; E-Mails: (S.Y.),
Tel./Fax: +86-571-8600-6166; (Y.W.), Tel./Fax: +86-571-8600-6166.
Academic Editor: George Perry
Received: 6 June 2015 / Accepted: 7 September 2015 / Published:
Abstract: Neurological diseases, which consist of acute injuries and chronic
neurodegeneration, are the leading causes of human death and disability. However, the
pathophysiology of these diseases have not been fully elucidated, and effective treatments
are still lacking. Astaxanthin, a member of the xanthophyll group, is a red-orange
carotenoid with unique cell membrane actions and diverse biological activities. More
importantly, there is evidence demonstrating that astaxanthin confers neuroprotective
effects in experimental models of acute injuries, chronic neurodegenerative disorders, and
neurological diseases. The beneficial effects of astaxanthin are linked to its oxidative,
anti-inflammatory, and anti-apoptotic characteristics. In this review, we will focus on the
neuroprotective properties of astaxanthin and explore the underlying mechanisms in the
setting of neurological diseases.
Keywords: astaxanthin; oxidative stress; inflammation; apoptosis; neuroprotection;
neurological diseases
Mar. Drugs 2015, 13 2
1. Introduction
Neurological diseases, exemplified by acute injuries (e.g., stroke and traumatic brain injury) and
chronic neurodegeneration (e.g., Alzheimer’s d isease, Parkinson’s disease, and Huntington’s disease),
are common causes of human death and disability [1,2]. Oxidative stress, inflammation, and apoptosis
are some of the mechanisms involved in the pathogenesis of these diseases [3,4]. For example, highly
insoluble amyloid beta peptide deposits and neurofibrillary tangles provide obvious stimuli for
oxidative stress and inflammation in a brain with Alzheimer’s disease (AD), which significantly
contributes to neuronal death in this disease [57]. In addition, there is evidence demonstrating that
mitochondrial deficits, oxidative and nitrosative stress, accumulation and aggregation of aberrant or
misfolded proteins (i.e., α-synuclein), and dysfunction of ubiquitin-proteasome system represents the
principal molecular events that commonly underlie the pathogenesis of familial and sporadic forms
of Parkinson’s disease (PD) [8,9]. Additionally, highly polymorphic CAG tri-nucleotide repeat
expansions in exon-1 of the huntingtin gene encodes an abnormally long poly-glutamine repeat, which
is associated with Huntington’s d isease (HD)-related brain pathology [10]. Poly-glutamine expansion
causes huntingtin to aggregate and accumulate in the nucleus. This leads to abnormal interactions with
other proteins, which results in intra-nuclear accumulation of mutant huntingtin and the formation of
neuropil aggregates that may ultimately lead to neuronal cell death [11]. Therefore, multi-targeted
pharmacological agents may be effective for the treatment of these devastating diseases.
Astaxanthin, a unique member of the xanthophylls, is a deep red-colored phytonutrient that can be
synthesized by a microalgae called Haematococcus pluvialis [12]. Distinct from other members of the
xanthophylls, astaxanthin has two hydroxyl groups [13]. Astaxanthin spans the bi-lipid layer and is
long enough that the two hydroxyl groups jut into the fluid phase near the membrane, and that when
electrons are extracted from these hyroxyl groups by free radicals, the molecule is resonance
stabilized. As a consequence, these properties allow astaxanthin to do a lot in the body. For instance,
astaxanthin can dramatically decrease the risk of cardiovascular disease [14]. A diet supplemented
with astaxanthin (75 or 200 mg/kg body weight per day) for 8 weeks has been shown to improve
endothelium-dependent vasodilatation in resistance vessels, reduce systolic blood pressure, and
improve cardiovascular remodeling in spontaneously hypertensive rats [15]. In addition, astaxanthin
(100 and 500 mg/100 g) for 60 days protects against serum protein oxidation in hyper-cholesterolemic
rabbits [16]. Studies have also demonstrated that astaxanthin can easily cross the BBB to protect the
brain from acute injury and chronic neurodegeneration [17,18]. The neuroprotective properties of this
molecule involves anti-oxidation, anti-inflammation, and anti-apoptotis [1921]. Thus, this review
article will focus on the beneficial effects of astaxanthin and explore the underlying mechanisms
observed in experimental models of neurological diseases. We also propose that further studies
involving astaxanthin are needed, in order to evaluate its potential application in the treatment of
neurological disorders.
2. Astaxanthin: Source, Biochemistry, Bioavailability, and Safety
Xanthophyll is a class of oxygen-containing carotenoid pigments whose biosynthesis in plants derives
from the lycopene. Astaxanthin is a reddish pigment which belongs to the xanthophyll family [22].
Mar. Drugs 2015, 13 3
This compound naturally exists in a wide variety of living organisms which includes microalgae,
complex plants, and seafood [23]. The commercial form of astaxanthin is mainly synthesized from the
algae Haematococcus pluvialis and the yeast Phaffia rhodozyma. As a member of the xanthophyll
group, astaxanthin is closely related to other carotenoids suc h as β-carotene, lutein, and zeaxanthin.
As a member of the xanthophyll group, astaxanthin is closely related to other carotenoids such as
β-carotene, lutein, and zeaxanthin [24]. Similarly, they share many of the physiological and metabolic
functions attributed to carotenoids [25]. Unlike β-carotene, astaxanthin does not have pro-vitamin A
activity in the human body [26].
The molar mass of astaxanthin is 596.84 g/mol and the molecular formula is C40H52O4. It is a
symmetric molecule consisting of two terminal rings joined by a short polyene ring [22]. The hydroxyl
group at the end of the molecule enables it to esterify fatty acids to form mono-esters or di-esters [13].
Natural astaxanthin mainly exists in an esterified form, while the synthetic form is produced in a free
form [27]. Astaxanthin also contains conjugated double bonds, giving this molecule strong anti-oxidant
properties by donating electrons and reacting with free radicals to terminate free radical chain reactions
within cells [25,28].
Astaxanthin has both lipophilic and hydrophilic properties, since it is fat-soluble and can be carried
by fat molecules directly to tissues and organs that need it the most, like the brain, retina, and skeletal
muscle [22]. Astaxanthin is first absorbed into enterocytes through passive diffusion and undergoes
facilitated diffusion in the presence of lipids [29]. The unesterified forms are incorporated into
chylomicrons and are transported into the liver via the lymphatic system [30]. The liver does not
biochemically convert these molecules into vitamin A [31]. Instead, it is incorporated into lipoproteins
that are transported into organs and tissues via the circulation [32].
Astaxanthin is safe to consume with food and contains no reports of side effects [33,34].
One randomized clinical trial found that 6 mg/day of astaxanthin can be safely consumed by healthy
adults [35]. In addition, numerous human clinical trials have shown that the astaxanthin rich extract,
Haematococcus pluvialis, is safe as well [36,37]. Hoffman-La Roche confirmed the safety of astaxanthin
with acute, mutagenicity, teratogenicity, embryotoxicity, and reproductive toxicity tests [38]. In addition,
the United States Food and Drug Administration approved the use of astaxanthin as a dietary
supplement in 1999 [25].
3. Neuroprotective Properties of Astaxanthin in Neurological Diseases
There have been numerous studies concerning the beneficial effects of astaxanthin.
Astaxanthin-mediated neuroprotection in experimental models of neurological disorders involves
anti-oxidantion, anti-inflammation, and anti-apoptotic mechanisms [17,39]. The following sections
will delve into these molecular mechanisms and their potential as treatments for neurological diseases.
3.1. Anti-Oxidant Effects
Oxidative stress is a key mediator in the pathology of neurological diseases [4042]. Disturbance of
the equilibrium status of pro-oxidant/anti-oxidant reactions in cells can lead to oxidative stress, which
causes generation of reactive oxygen species (ROS) and free radicals [43]. When produced in excessive
amounts, ROS like the superoxide anion radical (O2) and its dismutation product, hydrogen peroxide
Mar. Drugs 2015, 13 4
(H2O2), are detrimental to metabolic functions [44,45]. The O2 radical can oxidize the [4Fe-4S] clusters
of dehydratases, such as aconitase, causing inactivation and release of Fe2+ [46,47]. Thereafter, Fe2+
reacts with H2O2 to yield the potent oxidizing free radical species hydroxyl radical (OH). These
substances further react with key organic substrates, such as DNA, proteins, and lipids, to disturb cell
function and cause cell death [48]. It is worth mentioning that astaxanthin can act as a safeguard
against oxidative damage through various mechanisms, by quenching of singlet oxygen, scavenging of
radicals, inhibiting lipid peroxidation, and regulating gene expression related to oxidative stress [4952].
For example, astaxanthin exerts beneficial effects against HgCl2-induced acute renal failure by
preventing lipid and protein oxidation [53]. In an in vivo murine model, astaxanthin administration
prevented N-Methyl-D-aspartate (NMDA)-triggered retinal damage, which is associated with
decreasing lipid peroxidation and oxidative DNA damage [54]. Astaxanthin treatment ameliorates
cyclophosphamide-induced oxidative stress and the subsequent DNA damage in rat hepatocytes [55].
The protective effect of this molecule is attributed to the activation of nuclear erythroid 2-related factor 2
(Nrf2) antioxidant response element (ARE) pathway, which eventually facilitates Nrf2-dependent gene
expression of heme oxygenase-1 (HO-1) and NAD(P)H: quinine oxidoreductase-1 (NQO-1) [55]. In
the human retinal pigment epithelial (RPE) cell line ARPE-19, astaxanthin inhibited the intracellular
production of ROS and prevented H2O2-induced decrease in retinal pigment epithelial cell viability [56].
Astaxanthin also increased the nuclear translocation of Nrf2 and enhanced the expression of phase II
anti-oxidant enzymes through the activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway,
which eventually provided protection against H2O2-induced oxidative stress in ARPE-19 cells [56].
The anti-oxidative effects of astaxanthin have also been investigated in experimental models of
acute neurological conditions (Figure 1). Lee et al. reported that astaxanthin provides neuroprotective
effects against oxidative stress induced by oxygen-glucose deprivation in SH-SY5Y cells and 10-min
global cerebral ischemia in rats [57]. In a murine model of ischemic stroke, pre-treatment with
astaxanthin decreased ROS production and alleviated lipid peroxidation in the ipsilateral brain of rats
subjected to middle cerebral artery occlusion (MCAO) [17]. Simultaneously, astaxanthin reduced
cerebral infarction and promoted locomotor function recovery following MCAO [17]. Zhang et al.,
found that administration of astaxanthin had the potential of alleviating early brain injury (EBI) after
subarachnoid hemorrhage (SAH) through its anti-oxidative properties [19]. Treatment with astaxanthin
is believed to confer protective effects by restoring endogenous anti-oxidant enzymes of glutathione
(GSH) and superoxide dismutase (SOD) following SAH [19]. Wu et al. reported that post-SAH
treatment of astaxanthin facilitated the Nrf2-ARE pathway and ameliorated EBI in a prechiasmatic
cistern model of SAH [58]. Astaxanthin activated the Nrf2-ARE signaling pathway to up-regulate the
expression of Nrf2-regulated enzymes like HO-1, NQO-1 and glutathione-S-transferase-α1 (GST-α1)
to resist oxidative stress [58].
Astaxanthin also plays a role in preventing the development of chronic neurodegeneration.
It boosted the expression of HO-1 and protected neurons against -induced cytotoxicity [59,60].
Astaxanthin-stimulated activation of extracellular regulated protein kinase (ERK) signaling pathway
facilitated the dissociation of Nrf2 from Keap1, promoting the nuclear translocation and DNA-binding
activity of Nrf2 leading to up-regulation of HO-1 expression and protection against -induced
neurotoxicity [59]. In a cellular model of PD, astaxanthin reduced the generation of intracellular
ROS and provided cytoprotective effects against 1-methyl-4-phenylpyridinium (MPP+)-induced
Mar. Drugs 2015, 13 5
cytotoxicity [61]. In addition, astaxanthin enhanced HO-1 expression and limited NADPH oxidase 2
(NOX2)-mediated oxidative damage in MPP+-treated PC12 cells [62]. Astaxanthin antagonized
MPP+-induced oxidative stress through the regulation of specificity protein 1 (Sp1) and NMDA
receptor subunit 1 (NR1) signaling pathway [63]. Pre-treatment with astaxanthin markedly inhibited
the up-regulation and nuclear transfer of Sp1, thereby alleviated MPP+-induced production of
intracellular ROS and cytotoxicity in PC12 cells [63]. Thus, astaxanthin provides protection against
oxidative attacks in experimental neurological diseases.
Figure 1. The anti-oxidative effects of astaxanthin in neurological diseases. Astaxanthin
facilitates the dissociation and nuclear translocation of nuclear erythroid 2-related factor
(Nrf2), through activation of the PI3K/Akt and ERK signaling pathways, which contributes
to increased expression of Nrf2-regulated enzymes like HO-1, NQO-1, and GST-α1 that
resist oxidative stress. In addition, astaxanthin negatively regulates Sp1/NR1 signaling
pathway, alleviating the production of intracellular ROS and oxidative stress.
3.2. Anti-Inflammatory Effects
Inflammation is defined as series of complex immune responses that biologically occurs as a
reaction to injuries of the body. It functions as a host defense mechanism to clear out damaged tissue
from the original insult and initiates the tissue repair process [64]. However, excessive or uncontrolled
inflammation is detrimental to the host and can cause da mage to the host’s cells and tissues [65]. In the
central nervous system (CNS), inflammation has a critical role in both acute conditions (i.e., stroke and
traumatic injury) and chronic neurodegenerative conditions (e.g., AD, PD, and HD) [66]. Interestingly,
Mar. Drugs 2015, 13 6
astaxanthin exhibits anti-inflammatory effects in lipopolysaccharide-induced uveitis by directly blocking
the activity of inducible nitric oxide synthase (NOS) (Figure 2) [67]. In addition, astaxanthin
suppressed gene expression of inflammatory mediators (i.e., TNF-α and IL-) and alleviated
endotoxin-induced uveitis by blocking the NF-κB-dependent signaling pathway [68]. Under normal
conditions NF-κB, a heterodimer composed of p50 and p65 subunits, interacts with inhibitor of NF-κB
(IκB) and remains inactive in the cytosol [69]. Upon stimulation, IκB undergoes phosphorylation by IκB
kinase β (IKKβ) and is degraded via the ubiquitin proteasome pathway [70,71]. Dissociation of IκB
from the p50/p65 heterodimer exposes the nuclear localization signal on NF-κB, which subsequently
leads to the translocation of NF-κB (p65) into the nucleus to regulate the transcription of inflammatory
genes [72]. Astaxanthin treatment effectively alleviated NF-κB-related inflammation in the liver of
mice subjected to a high fructose and high fat diet by suppressing IKKβ phosphorylation and nuclear
translocation of NF-κB (p65) subunit [73]. Astaxanthin also suppressed ROS-induced nuclear
expression of NF-κB (p65) and reduced the downstream production of pro-inflammatory cytokines
(i.e., IL-1β, IL-6 and TNF-α) in U937 mononuclear cells by restoring the physiological levels of
protein tyrosine phosphatase-1 (SHP-1) [74]. In a mouse model of experimental choroidal
neovascularization, Izumi-Nagai demonstrated that astaxanthin treatment led to significant inhibition of
macrophage infiltration into choroidal neovascularization [75]. Furthermore, astaxanthin suppressed
IκB-α degradation and NF-κB nuclear translocation, resulting in subsequent down-regulation of
inflammatory molecules (i.e., IL-6, vascular endothelial growth factor (VEGF), intercellular adhesion
molecule-1 (ICAM-1), and monocyte chemotactic protein 1 (MCP1) [75]. Astaxanthin also decreased
gastric inflammation in mice infected with Helicobacter pylori, shifting the T-lymphocyte response
from a Th1 response to a Th1/Th2 response [76]. Additionally, astaxanthin decreased nitric oxide
(NO) production and inducible nitric oxide synthase (iNOS) activity in macrophages, resulting in
inhibition of cyclooxygenase and
down-regulation of prostaglandin E2 (PGE2) and TNF-α in mice [67]. Dietary administration of
astaxanthin significantly suppressed aberrant NF-κB activation in co lonic mucosa, lowering gene
expressions of IL-1β, IL-6, and COX-2, which contributes to attenuation of dextran sulfate sodium
(DSS)-induced colitis [77]. Lee and colleagues discovered that astaxanthin prevented inflammatory
processes by suppressing the activation of NF-κB signaling and the production of pro-inflammatory
cytokines (e.g., TNF-α and IL-1β) using both in vitro and in vivo models [78]. In human keratinocytes,
Terazawa et al. demonstrated that astaxanthin interrupts the auto-phosphorylation and self-activation
of mitogen- and stress-activated protein kinase-1 (MSK1), which results in decreased phosphorylation
of NF-κB (p65) and deficiency of NF-κB DNA binding activity [79]. As a consequence, UVB-induced
expression and secretion of PGE2 and IL-8 were down-regulated in these human keratinocytes [79].
In a prechiasmatic cistern SAH model, astaxanthin provides neuroprotection against EBI through
suppression of cerebral inflammation [20]. Post-treatment with astaxanthin after SAH reduced neutrophil
infiltration, suppressing the activity of NF-κB, decreasing the protein and mRNA levels of inflammatory
mediators IL-1β, TNF-α, and ICAM-1, and dramatically reversed brain inflammation [20]. As a result
secondary brain injury cascades, neuronal degeneration, BBB disruption, cerebral edema, and
neurological dysfunction, were all alleviated after astaxanthin administration [20]. However, there is
still a lack of research documenting the anti-inflammatory effects of astaxanthin on the treatment of
neurological disorders. Several studies have reported that astaxanthin can enhance both humoral and
Mar. Drugs 2015, 13 7
cell-mediated immune responses [26,8083]. Dietary supplement of astaxanthin can stimulate T cell
and B cell mitogen-induced lymphocyte proliferation, increase the cytotoxic activity of natural killer
cell, and enhance IFN-γ and IL-6 production in young healthy adult female human subjects [84].
Additionally, Balietti et al. showed gender-related differences in the anti-inflammatory effects of
astaxanthin on the aging rat brain [85]. However, it is still unknown if this molecule exerts different
anti-inflammatory effects in female and male brains under pathological conditions. Therefore, there is
a need for future studies elucidating the inflammatory regulation mechanisms of astaxanthin.
Figure 2. The anti-inflammatory effects of astaxanthin in neurological diseases. Through
suppression of IκB-α degradation and NF-κB nuclear translocation, astaxanthin inhibits the
expression of inflammatory molecules IL-6, ICAM-1, and MCP1. Astaxanthin also suppresses
nuclear expression of NF-κB and reduces downstream production of pro-inflammatory
cytokines by restoring physiological levels of SHP-1.
3.3. Anti-Apoptotic Effects
Apoptosis is a highly sophisticated energy-dependent process of programmed cell death [86].
Morphologically, it is characterized by shrinkage of the cell, membrane blebbing, nuclear fragmentation
and chromatin condensation [87]. Under normal physiological conditions, apoptosis is vital for
embryonic development and tissue homeostasis [88]. Under pathological conditions, uncontrolled
apoptosis is harmful and contributes to the pathogenesis of a variety of human diseases including
neurological disorders [89]. Kim et al. demonstrated that astaxanthin provided protection against
H2O2-mediated apoptosis in a mouse neural progenitor cell culture model [90]. Astaxanthin is believed
Mar. Drugs 2015, 13 8
to inhibit H2O2-mediated apoptotic cell death by maintaining mitochondria integrity, reducing
cytochrome c release from the mitochondria, and inhibiting caspase activation in astaxanthin
pre-treated cells through the modulation of p38 and mitogen-activated protein kinase kinase (MEK)
signaling pathways in neural progenitor cells from mice [90]. Dong et al. reported that astaxanthin
significantly reduced apoptotic death of retinal ganglion cells and alleviated diabetic retinopathy
by oxidative stress inhibition [91]. In addition, astaxanthin administration increased Akt, enhanced Bad
phosphorylation, and down-regulated the activation of downstream pro-apoptotic proteins
(e.g., cytochrome c and caspase-3/9), leading to the amelioration of mitochondrial-related apoptosis
and the attenuation of early acute kidney injury following severe burns [92].
Astaxanthin exerts a protective effect against neuronal apoptosis in the setting of neurological
diseases as well (Figure 3). For example, astaxanthin mediated the activation of the PI3K/Akt survival
pathway, promoted the phosphorylation-dependent inactivation of Bad, and decreased caspase-
dependent neuronal apoptosis after SAH [21]. As a result, secondary brain injury in the early period of
SAH, BBB disruption, cerebral edema, neurological deficits were all alleviated after treatment with
astaxanthin [21]. Intra-cerebroventricular administration of astaxanthin antagonized
ischemia/reperfusion-induced translocation of cytochrome c from the mitochondria to the cytoplasm,
and prevented apoptosis in a transient MCAO model of ischemic stroke [17]. Lu et al. In addition,
reported similar findings demonstrating that astaxanthin exhibits noticeable neuroprotection against
cerebral ischemia-reperfusion insults through its anti-apoptotic actions [93]. In addition, pre-treatment
with astaxanthin also significantly restored the mitochondrial membrane potential, prevented H2O2-
induced neuronal apoptosis, decreased cerebral infarct volume, and improved neurological function
after MCAO [93].
In an in vitro model of PD, Ikeda et al. demonstrated that astaxanthin attenuates 6-hydroxydopamine
(6-OHDA)-induced apoptosis in human neuroblastoma SH-SY5Y cells [94]. Pre-treatment with
astaxanthin significantly inhibits ROS generation and subsequent phosphorylation of p38 MAPK,
ameliorates mitochondrial dysfunction, increases ΔΨm, reduces cytochrome c release, caspase
activation, and rescues the cell from 6-OHDA-induced apoptosis [94,95]. Lee and coworkers found that
astaxanthin treatment prevents MPP+-induced up-regulation of Bax and down-regulation of Bcl-2,
alleviating ΔΨ m collapse in SH-SY5Y cells and protects the neuron against MPP+-induced
mitochondrial damage and apoptosis [96]. Liu et al. demonstrated that astaxanthin has protective
effects on 6-OHDA-induced cellular toxicity and apoptotic death of dopaminergic SH-SY5Y cells by
inhibiting intracellular ROS generation, the decrease of mitochondrial membrane potential, the release
of mitochondrial cytochrome c [97].
Intrestingly, it has been shown that astaxanthin induces cancer cell apoptosis through a
mitochondrial-dependent pathway [98]. Astaxanthin mediates the inhibition of the Janus kinase 1
(JAK1)/STAT3 (signal transducer and activator of transcription 3) signaling pathway in hepatocellular
carcinoma CBRH-7919 cells which down-regulates the anti-apoptotic gene expression of Bcl-2 and
Bcl-xl, while also enhancing the pro-apoptotic gene expression of Bax resulting in apoptosis [99].
Another study also reported that astaxanthin induces caspase-mediated mitochondrial apoptosis by
down-regulating the expression of anti-apoptotic Bcl-2 and survivin while up-regulating pro-apoptotic
Bax and Bad [100]. It has also been reported that astaxanthin can induce the intrinsic apoptotic
pathway in a hamster model of oral cancer through the inactivation of ERK/MAPK and PI3K/Akt
Mar. Drugs 2015, 13 9
cascades which leads to the inhibition of NF-κB and Wnt/β-catenin [100]. Thus, depending on the
pathological condition, astaxanthin may exert either anti-apoptotic or pro-apoptotic effects.
Figure 3. The anti-apoptotic effects of astaxanthin in neurological diseases. Astaxanthin
induces the activation of PI3K/Akt survival pathway, promoting the phosphorylation-dependent
inactivation of Bad, which leads to a decrease in caspase-dependent neuronal apoptosis.
Astaxanthin also maintains mitochondria integrity through modulation of p38 and MEK
signaling pathways, which reduces cytochrome c release and inhibits caspase-dependent
apoptotic cell death.
4. Conclusions and Perspective
Astaxanthin confers multiple neuroprotective effects in various experimental models of neurological
diseases, which includes both acute injuries and chronic neurodegenerative disorders. The protective
effects of astaxanthin are associated with its anti-oxidative, anti-inflammatory, anti-apoptotic effects.
Astaxanthin is a safe nutrient, with no toxic effects when it is consumed with food. Furthermore, as a
fat-soluble compound, astaxanthin is able to effectively pass through the BBB. Therefore, astaxanthin
is an excellent candidate for treating neurological diseases. It is essential that there continues to be
further evaluations of the protective properties and underlying mechanisms of astaxanthin, which may
eventually lead to astaxanthin becoming a novel neuroprotective agent.
Although the neuroprotective effects of astaxanthin have been examined in several experimental
models of neurological disorders, there is a lack of research in some areas. Future studies should focus
on the pharmaceutical potential and effects of astaxanthin esters in the treatment of neurological
Mar. Drugs 2015, 13 10
disorders, especially since astaxanthin diesters can be easily absorbed into the metabolism and may
increase biological activity more effectively than its free form [13]. Furthermore, it is important to note
that a lot of the current data concerning astaxanthin-mediated neuroprotection mainly comes from
ischemic stroke, SAH, AD, and PD. There is minimal evidence available regarding other neurological
diseases such as traumatic brain injury, intracerebral hemorrhage, and HD. Therefore, future
investigations should include these neurological disease models. The therapeutic time window,
reliability of drug administration routes, and the optimal dosages of astaxanthin are other areas that
need to be explored and determined. Most importantly, the development of clinical trials to assess
astaxanthin as treatment of neurological diseases is warranted since there are a number of promising
general safety results, neurological experimental model studies, and clinical trials in other diseases.
This study was supported by National Natural Science Foundation of China (Grant. 81171096 and
81371433), Public Technology Application Research Project of Zhejiang Province (2014C33G2010288).
Authors Contribution
H.W. and H.N. collected the data and wrote the manuscript. A.S. and C.W. checked the data for accuracy.
B.D. and J.Z. polished the language. Y.S. and Y.W. designed the review study.
Conflicts of Interest
The authors declare no conflicts of interest.
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... Previous studies have identified the health benefits of AST against neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), cerebral ischemia/reperfusion (IR), subarachnoid hemorrhage (SAH) and cognitive disorders (24,25). Therefore, the present review focused on the biological activities and neurological functions of AST. ...
... The two pathways facilitate the dissociation of nuclear factor erythroid 2-related factor 2 (Nrf2) from Kelch-like ECH-associated protein 1. Nrf2 is translocated to the nucleus and activates the Nrf2 antioxidant response element (ARE) signaling pathway (33). The PI3K/Akt pathway upregulates the expression of HO-1, NAD(P)H quinone oxidoreductase-1 (NQO-1), glutathione-S-transferase-α1, the glutamate-cysteine ligase modifier subunit and the glutamate-cysteine ligase catalytic subunit, which provide protection against OS both in vitro and in vivo (24,(34)(35)(36). In addition, it has been reported that rats fed AST show elevated levels of other antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT) (37,38), thiobarbituric acid reactive substances and peroxidase, in the liver and plasma (24,39). ...
... The PI3K/Akt pathway upregulates the expression of HO-1, NAD(P)H quinone oxidoreductase-1 (NQO-1), glutathione-S-transferase-α1, the glutamate-cysteine ligase modifier subunit and the glutamate-cysteine ligase catalytic subunit, which provide protection against OS both in vitro and in vivo (24,(34)(35)(36). In addition, it has been reported that rats fed AST show elevated levels of other antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT) (37,38), thiobarbituric acid reactive substances and peroxidase, in the liver and plasma (24,39). ...
Astaxanthin is a lipid‑soluble carotenoid produced by various microorganisms and marine animals, including bacteria, yeast, fungi, microalgae, shrimps and lobsters. Astaxanthin has antioxidant, anti‑inflammatory and anti‑apoptotic properties. These characteristics suggest that astaxanthin has health benefits and protects against various diseases. Owing to its ability to cross the blood‑brain barrier, astaxanthin has received attention for its protective effects against neurological disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, cerebral ischemia/reperfusion, subarachnoid hemorrhage, traumatic brain injury, spinal cord injury, cognitive impairment and neuropathic pain. Previous studies on the neurological effects of astaxanthin are mostly based on animal models and cellular experiments. Thus, the biological effects of astaxanthin on humans and its underlying mechanisms are still not fully understood. The present review summarizes the neuroprotective effects of astaxanthin, explores its mechanisms of action and draws attention to its potential clinical implications as a therapeutic agent.
... Resveratrol has been recently tested showing significant clinical efficacy in combination with donepezil hydrochloride in Alzheimer's disease patients by improving their inflammatory parameters, such as TNF-alpha and interleukine-6, as well as cognitive function estimated by minimental state examination and Alzheimer's disease assessment scale cognitive subscale and prognosis (ADAS-Cog) during 2 months of treatment (Table 2) [48]. Beyond polyphenols, carotenoids have been widely described as neuroprotective agents for neurological diseases [49]. Among others, they have been described to play a role in amelioration of clinical symptoms (neurocognitive performance and prognosis) derived from neurodegeneration in Alzheimer's disease [50]. ...
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The distinguishing pathogenic features of neurodegenerative diseases include mitochondrial dysfunction and derived reactive oxygen species generation. The neural tissue is highly sensitive to oxidative stress and this is a prominent factor in both chronic and acute neurodegeneration. Based on this, therapeutic strategies using antioxidant molecules towards redox equilibrium have been widely used for the treatment of several brain pathologies. Globally, polyphenols, carotenes and vitamins are among the most typical exogenous antioxidant agents that have been tested in neurodegeneration as adjunctive therapies. However, other types of antioxidants, including hormones, such as the widely used melatonin, are also considered neuroprotective agents and have been used in different neurodegenerative contexts. This review highlights the most relevant mitochondrial antioxidant targets in the main neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease and also in the less represented amyotrophic lateral sclerosis, as well as traumatic brain injury, while summarizing the latest randomized placebo-controlled trials.
... Animals, including humans, consume phototrophic organisms and utilize carotenoids or apocarotenoids for important physiological functions, including body coloration, sexual attractiveness, vitamin A production, antioxidant activity, transcription factor activation and photoreception. Pharmacological studies have also demonstrated the diverse biological activities of carotenoids and apocarotenoids, including antimicrobial, antifungal, antidiabetic, immunostimulant, anti-obesity, anti-inflammatory, anticarcinogenic and cancer-preventive, antimetastatic, antiangiogenic, radioprotective, anti-atherosclerotic, neuroprotective and chemosensitizing properties of multidrug-resistant cancer cells [37,39,41,43,44,[47][48][49][50][51][52][53][54] Due to their color and health-promoting properties, carotenoids find a wide range of applications in the food, pharmaceutical, nutraceutical and cosmeceutical industries [55]. ...
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For more than 40 years, marine microorganisms have raised great interest because of their major ecological function and their numerous applications for biotechnology and pharmacology. Particularly, Archaea represent a resource of great potential for the identification of new metabolites because of their adaptation to extreme environmental conditions and their original metabolic pathways, allowing the synthesis of unique biomolecules. Studies on archaeal carotenoids are still relatively scarce and only a few works have focused on their industrial scale production and their biotechnological and pharmacological properties, while the societal demand for these bioactive pigments is growing. This article aims to provide a comprehensive review of the current knowledge on carotenoid metabolism in Archaea and the potential applications of these pigments in biotechnology and medicine. After reviewing the ecology and classification of these microorganisms, as well as their unique cellular and biochemical characteristics, this paper highlights the most recent data concerning carotenoid metabolism in Archaea, the biological properties of these pigments, and biotechnological considerations for their production at industrial scale.
... Due to its outstanding anti-oxidant activity, ASX has an extraordinary potential to protect the organism against ailments such as oxidative cell damage, different types of cancer, and some diseases of the immunological system (27). Due to this feature, its effectiveness has been shown in the literature in important diseases such as aging (28), neurological diseases (29), cancer (30), and alcoholic liver damage (31). However, its efficacy against ovarian ischemia and reperfusion injury has not yet been demonstrated. ...
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Objectives: We thought that astaxanthin (ASX) might be a protective agent in oxidative stress damage that develops against ischemia and reperfusion injury in the rat ovary. Materials and methods: The experimental groups consisted of healthy, I (Ischemia), I+ASX50, I+ASX100, I/R (Ischemia/Reperfusion), I/R+ ASX50, and I/R+ ASX100. Vascular clamps were applied to the ovaries for 3 hr to induce ischemia. For the reperfusion groups, the clamps were opened and blood flow was restored to the ovaries for 3 hr. At the end of the experiment, biochemical, histopathological, and immunohistochemical analyses were made from the tissue samples taken. Results: While MDA levels increased significantly in I and I/R groups, SOD levels decreased. It was found that ASX significantly decreased MDA levels and increased SOD activity in treatment groups depending on the dose. Caspase 3, IL-1 β, and IL-6 expressions were severely increased in ischemia and I/R groups, while the severity of I+ASX50 and I/R+ASX100 immunoreactivity was decreased. While severe hemorrhage areas were observed in I and IR groups, minimal hemorrhage areas were observed in the treatment groups, especially in I/R+ASX100 groups. In addition, inflammatory cells and necrotic cells in the I/R group were not observed in I/R+ASX50 and I/R+ASX100 groups. Conclusion: As a result, it was determined that ASX has a strong protective role against oxidative damage in the treatment of ovarian ischemia-reperfusion injury.
... They activate the PI3K/Akt survival pathway, promote the phosphorylationdependent inactivation of Bad, which leads to a decrease in caspasedependent neuronal apoptosis. Also, they maintain mitochondria integrity through modulation of p38 and mitogen-activated protein kinase (MEK) signalling pathways, which reduces the cytochrome c release and inhibits caspasedependent apoptosis (Wu et al., 2015). mechanisms by which Astragalus active chemicals modulate common molecular signalling pathways and exert their unique therapeutic effects on neurological illnesses is still ongoing. ...
Neurodegenerative and neuropsychiatric illnesses are prevalent and life-threatening disorders characterized by a wide range of clinical syndromes and comorbidities, all of which have complex origins and share common molecular pathomechanisms. Although the pathophysiology of neurological illnesses is not completely understood, researchers have discovered that several ion channels and signalling pathways may have played a role in disease pathogenesis. Active substances from Astragalus sp. are being employed for nutrition, and their usefulness in the treatment of neurological illnesses is receiving more attention. Because their extracts and active components exert different pharmacological effects on a variety of ailments, they have a long history of usage as a cure for various diseases. This review summarizes the research work on Astragalus and their biologically active constituents as potential candidates for the protection against and treatment of neurodegenerative and neuropsychiatric disorders to show the potential efficacy of Astragalus sp. and its active ingredients in treating some neurological diseases. Simultaneously, the chemical structures of these active compounds, their sources, biological properties, and mechanisms are also listed. In ethnopharmacological applications, Astragalus membranaceus and spinosus have been studied as traditional medicines worldwide. The chemical constituents of Astragalus species mainly comprise terpenoids, flavonoids, and polysaccharides. The extracts and phytochemical compounds of Astragalus species exhibit various pharmacological activities, including antioxidant, anti-inflammatory, anticancer, antitumor, anticonvulsive, immunomodulatory, and other activities. Based on the current literature, we conclude that Astragalus is a promising dietary herb with multiple potential signal modulating applications that mainly include the modulation of neurotransmitters and receptors, anti-inflammatory activities, inhibition of amyloid aggregation, induction of myelin sheath repair and neurogenesis, as well as activation of the signalling pathways relevant to neurological diseases.
... e structure of AST determines its strong antioxidant ability. e polyene chain can capture free radicals in the cell membrane, and the terminal ring can scavenge free radicals inside and outside the cell membrane [20]. erefore, AST protects the membrane structure by neutralizing singlet oxygen, preventing chain reactions, and inhibiting lipid peroxidation (LPO), hence, increasing the function of the antioxidant enzymes [21,22]. ...
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Astaxanthin (AST) is a naturally occurring carotenoid that has strong antioxidant, anti-inflammatory, and antiapoptosis effects and is used for the prevention of cancer. There is growing evidence that AST has multiple protective effects against various eye diseases. This article reviews the function and the potential mechanism of AST in dry eye syndrome, keratitis, cataract, diabetic retinopathy, age-related macular degeneration, high intraocular pressure, and other ocular diseases. It provides a theoretical basis for the clinical application of AST as a potential nutraceutical.
... In addition, ATX can cross the blood-brain barrier (BBB) and accumulate in the brain, where it can potentially provide a beneficial effect [17]. Due to these advantages, ATX has been regarded as a promising therapeutic agent for neurological diseases [18]. ...
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Astaxanthin is a powerful biological antioxidant and is naturally generated in a great variety of living organisms. Some studies have demonstrated the neuroprotective effects of ATX against ischemic brain injury in experimental animals. However, it is still unknown whether astaxanthin displays neuroprotective effects against severe ischemic brain injury induced by longer (severe) transient ischemia in the forebrain. The purpose of this study was to evaluate the neuroprotective effects of astaxanthin and its antioxidant activity in the hippocampus of gerbils subjected to 15-min transient forebrain ischemia, which led to the massive loss (death) of pyramidal cells located in hippocampal cornu Ammonis 1-3 (CA1-3) subfields. Astaxanthin (100 mg/kg) was administered once daily for three days before the induction of transient ischemia. Treatment with astaxanthin significantly attenuated the ischemia-induced loss of pyramidal cells in CA1-3. In addition, treatment with astaxanthin significantly reduced ischemia-induced oxidative DNA damage and lipid peroxidation in CA1-3 pyramidal cells. Moreover, the expression of the antioxidant enzymes superoxide dismutase (SOD1 and SOD2) in CA1-3 pyramidal cells were gradually and significantly reduced after ischemia. However, in astaxanthin-treated gerbils, the expression of SOD1 and SOD2 was significantly high compared to in-vehicle-treated gerbils before and after ischemia induction. Collectively, these findings indicate that pretreatment with astaxanthin could attenuate severe ischemic brain injury induced by 15-min transient forebrain ischemia, which may be closely associated with the decrease in oxidative stress due to astaxanthin pretreatment.
Astaxanthin, a high value carotenoid used in pharmaceutical and nutritional applications, is high in shrimp relative to other crustaceans. This study investigates waste fish oil as an alternative to vegetable oil/organic solvents for astaxanthin recovery and presents the first comprehensive analysis of yield and composition of lipid/fatty acid and astaxanthin using fish oil from shrimp processing by-products as a function of time, temperature and oil:waste ratio and pre-treatment. Box–Behnken design was used to determine the conditions that maximized astaxanthin yield (65 °C, 9:1 oil/by-product and 1.5 h). The extracts were high in triacylglycerols/omega-6 fatty acids relative to other solvents. Overall, pre-treatment to remove water increased astaxanthin yield. Long extraction times at lower temperature or high temperatures at lower extraction times reduce astaxanthin degradation/isomerisation.
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Neuroinflammation is a protective mechanism against insults from exogenous pathogens and endogenous cellular debris and is essential for reestablishing homeostasis in the brain. However, excessive prolonged neuroinflammation inevitably leads to lesions and disease. The use of natural compounds targeting pathways involved in neuroinflammation remains a promising strategy for treating different neurological and neurodegenerative diseases. Astaxanthin, a natural xanthophyll carotenoid, is a well known antioxidant. Mounting evidence has revealed that astaxanthin is neuroprotective and has therapeutic potential by inhibiting neuroinflammation, however, its functional roles and underlying mechanisms in modulating neuroinflammation have not been systematically summarized. Hence, this review summarizes recent progress in this field and provides an update on the medical value of astaxanthin. Astaxanthin modulates neuroinflammation by alleviating oxidative stress, reducing the production of neuroinflammatory factors, inhibiting peripheral inflammation and maintaining the integrity of the blood-brain barrier. Mechanistically, astaxanthin scavenges radicals, triggers the Nrf2-induced activation of the antioxidant system, and suppresses the activation of the NF-κB and mitogen-activated protein kinase pathways. With its good biosafety and high bioavailability, astaxanthin has strong potential for modulating neuroinflammation, although some outstanding issues still require further investigation.
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Astaxanthin is a xanthophyll carotenoid commonly found in marine organisms. Due to its super antioxidative ability, astaxanthin has been widely applied as a human nutraceutical supplement for health benefits. In order to enhance the bioavailability of astaxanthin, we used soybean phosphatidylcholine to encapsulate astaxanthin for liposomal formation. The physical properties of astaxanthin (asta)-loaded liposomes were determined by particle size, encapsulation efficiency and polydispersity index. The results revealed that the particle sizes of asta-loaded liposomes with various concentrations exhibited mean diameters in the range of 109 to 134 nm and had a narrow PDI value. As expected, the entrapment efficiency of liposomes loaded with a low concentration of astaxanthin (0.05 μg/mL) was 89%, and that was reduced to 29% for 1.02 μg/mL asta loading. Alizarin red staining and calcium content measurement showed that there was a significant reduction in calcium deposition for 7F2 osteoblasts treated with asta-loaded liposomes (0.25–1.02 μg/mL) in comparison with the cells treated with drug-free liposomes and mineralization medium (MM). Although liposomal formulation can reduce the cytotoxicity of astaxanthin and possess antioxidant, anti-inflammatory and anti-osteoclastogenic activities in RAW264.7 macrophages, asta-loaded liposomes with high concentrations may suppress ALP activity and mineralization level in 7F2 osteoblasts. Therefore, astaxanthin extract may be able to protect bones against oxidative stress and inflammation through liposomal formulation.
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Early acute kidney injury (AKI) is a devastating complication in critical burn patients, and it is associated with severe morbidity and mortality. The mechanism of AKI is multifactorial. Astaxanthin (ATX) is a natural compound that is widely distributed in marine organisms; it is a strong antioxidant and exhibits other biological effects that have been well studied in various traumatic injuries and diseases. Hence, we attempted to explore the potential protection of ATX against early post burn AKI and its possible mechanisms of action. The classic severe burn rat model was utilized for the histological and biochemical assessments of the therapeutic value and mechanisms of action of ATX. Upon ATX treatment, renal tubular injury and the levels of serum creatinine and neutrophil gelatinase-associated lipocalin were improved. Furthermore, relief of oxidative stress and tubular apoptosis in rat kidneys post burn was also observed. Additionally, ATX administration increased Akt and Bad phosphorylation and further down-regulated the expression of other downstream pro-apoptotic proteins (cytochrome c and caspase-3/9); these effects were reversed by the PI3K inhibitor LY294002. Moreover, the protective effect of ATX presents a dose-dependent enhancement. The data above suggested that ATX protects against early AKI following severe burns in rats, which was attributed to its ability to ameliorate oxidative stress and inhibit apoptosis by modulating the mitochondrial-apoptotic pathway, regarded as the Akt/Bad/Caspases signalling cascade.
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Purpose: Astaxanthin is a type of carotenoid known to have strong antioxidant effects. The purpose of this study was to investigate whether astaxanthin confers a neuroprotective effect against glutamate stress, oxidative stress, and hypoxia-induced apoptotic or necrotic cell death in primary cultures of rat retinal ganglion cells (RGCs). Methods: Purified rat RGCs were exposed to three kinds of stressors induced by 25 μM glutamate for 72 h, B27 medium without an antioxidant for 4 h, and a reduced oxygen level of 5% for 12 h. Each assay was repeated 12 times, with or without 1 nM, 10 nM, and 100 nM astaxanthin. The number of live RGCs was then counted using a cell viability assay. RGC viability in each condition was evaluated and compared with controls. In addition, we measured apoptosis and DNA damage. Results: We found that under glutamate stress, RGC viability was reduced to 58%. Cultures with 1 nM, 10 nM, and 100 nM astaxanthin showed an increase in RGC viability of 63%, 74%, and 84%, respectively. Under oxidative stress, RGC viability was reduced to 40%, and astaxanthin administration resulted in increased viability of 43%, 50%, and 67%, respectively. Under hypoxia, RGC viability was reduced to 66%, and astaxanthin administration resulted in a significant increase in viability to 67%, 77%, and 93%, respectively. These results indicate that 100 nM astaxanthin leads to a statistically significant increase in RGC viability under the three kinds of stressors tested, compared to controls (Dunnett's test, p<0.05). The apoptotic activity of RGCs under glutamate stress increased to 32%, but was reduced to 15% with 100 nM astaxanthin administration. Glutamate stress led to a 58% increase in DNA damage, which was reduced to 43% when cultured with 100 nM astaxanthin. Thus, 100 nM astaxanthin showed a statistically significant reduction in apoptosis and DNA damage in RGCs (Wilcoxon rank-sum test, p<0.05). Conclusions: Our results suggest that astaxanthin has a neuroprotective effect against RGC death induced by glutamate stress, oxidative stress, and hypoxia, which induce apoptotic and necrotic cell death.
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Astaxanthin (ATX) has been proven to ameliorate early brain injury (EBI) after experimental subarachnoid hemorrhage (SAH) by modulating cerebral oxidative stress. This study was performed to assess the effect of ATX on the Nrf2-ARE pathway and to explore the underlying molecular mechanisms of antioxidant properties of ATX in EBI after SAH. A total of 96 male SD rats were randomly divided into four groups. Autologous blood was injected into the prechiasmatic cistern of the rat to induce an experimental SAH model. Rats in each group were sacrificed at 24 h after SAH. Expressions of Nrf2 and heme oxygenase-1 (HO-1) were measured by Western blot and immunohistochemistry analysis. The mRNA levels of HO-1, NAD (P) H: quinone oxidoreductase 1 (NQO-1), and glutathione S-transferase-α1 (GST-α1) were determined by real-time polymerase chain reaction (PCR). It was observed that administration of ATX post-SAH could up-regulate the cortical expression of these agents, mediated in the Nrf2-ARE pathway at both pretranscriptional and posttranscriptional levels. Meanwhile, oxidative damage was reduced. Furthermore, ATX treatment significantly attenuated brain edema, blood-brain barrier (BBB) disruption, cellular apoptosis, and neurological dysfunction in SAH models. This study demonstrated that ATX treatment alleviated EBI in SAH model, possibly through activating the Nrf2-ARE pathway by inducing antioxidant and detoxifying enzymes.
Cell death via apoptosis is a prominent feature in mammalian neural development. Recent studies into the basic mechanism of apoptosis have revealed biochemical pathways that control and execute apoptosis in mammalian cells. Protein factors in these pathways play important roles during development in regulating the balance between neuronal life and death. Additionally, mounting evidence indicates such pathways may also be activated during several neurodegenerative diseases, resulting in improper loss of neurons.
Astaxanthin, a powerful antioxidant, is a good candidate for the prevention of intracellular oxidative stress. The aim of the study was to compare the antioxidant activity of astaxanthin present in two natural extracts from Haematococcus pluvialis, a microalgae strain, with that of synthetic astaxanthin. Natural extracts were obtained either by solvent or supercritical extraction methods. UV, HPLC-DAD and (HPLC-(atmospheric pressure chemical ionization (APCI)+)/ion trap-MS) characterizations of both natural extracts showed similar compositions of carotenoids, but different percentages in free astaxanthin and its ester derivatives. The Trolox equivalent antioxidant capacity (TEAC) assay showed that natural extracts containing esters displayed stronger antioxidant activities than free astaxanthin. Their antioxidant capacities to inhibit intracellular oxidative stress were then evaluated on HUVEC cells. The intracellular antioxidant activity in natural extracts was approximately 90-times higher than synthetic astaxanthin (5 μM). No modification, neither in the morphology nor in the viability, of vascular human cells was observed by in vitro biocompatibility study up to 10 μM astaxanthin concentrations. Therefore, these results revealed the therapeutic potential of the natural extracts in vascular human cell protection against oxidative stress without toxicity, which could be exploited in prevention and/or treatment of cardiovascular diseases.
Chronic inflammation appears to play a critical role in sickness behavior caused by diabetes mellitus. Astaxanthin has been used in treating diabetes mellitus and diabetic complications because of its neuroprotective and anti-inflammatory actions. However, whether astaxanthin can improve sickness behavior induced by diabetes and its potential mechanisms are still unknown. The aim of this study was to investigate the effects of astaxanthin on diabetes-elicited abnormal behavior in mice and its corresponding mechanisms. An experimental diabetic model was induced by streptozotocin (150 mg/kg) and astaxanthin (25 mg/kg/day) was provided orally for 10 weeks. Body weight and water consumption were measured, and the sickness behavior was evaluated by the open field test (OFT) and closed field test (CFT). The expression of glial fibrillary acidic protein (GFAP) was measured, and the frontal cortical cleaved caspase-3 positive cells, interleukin-6 (IL-6), and interleukin-1β (IL-1β) expression levels were also investigated. Furthermore, cystathionine β-synthase (CBS) in the frontal cortex was detected to determine whether the protective effect of astaxanthin on sickness behavior in diabetic mice is closely related to CBS. As expected, we observed that astaxanthin improved general symptoms and significantly increase horizontal distance and the number of crossings in the OFT and CFT. Furthermore, data showed that astaxanthin could decrease GFAP-positive cells in the brain and down-regulate the cleaved caspase-3, IL-6, and IL-1β, and up-regulate CBS in the frontal cortex. These results suggest that astaxanthin provides neuroprotection against diabetes-induced sickness behavior through inhibiting inflammation, and the protective effects may involve CBS expression in the brain.
Astaxanthin (Ax) is a ketocarotenoid belonging to the xanthophylls family with activity in antioxidation, integrity of cell membranes preservation and redox state and functional mitochondria integrity preservation. The aim was to investigate potential gender-related differences in astaxanthin (Ax) effects aged rats brain. In females, IL1 beta was significantly lower in treated rats in both cerebral areas, and in cerebellum, treated animals had also a significantly higher concentration of IL10; in males, no differences were envisaged in cerebellum, but in hippocampus, IL1 beta and IL10 were significantly higher in treated rats. These are the first results that showed gender-related differences in the Ax effect on the aging brain, strengthening the necessity to carefully analyze female and male peculiarities when the anti-aging potentialities of this ketocarotenoid are evaluated. Our observation leads to the hypothesis that Ax exerted different anti-inflammatory effects in female and in male brain. This article is protected by copyright. All rights reserved.