There have been numerous studies concerning the beneficial effects of astaxanthin. Astaxanthin-mediated neuroprotection in experimental models of neurological disorders involves anti-oxidation, anti-inflammation, and anti-apoptotic mechanisms. The following sections will delve into these molecular mechanisms and their potential as treatments for neurological diseases.

  1. Anti-Oxidant Effects

Oxidative stress is a key mediator in the pathology of neurological diseases. Disturbance of the equilibrium status of pro-oxidant/anti-oxidant reactions in cells can lead to oxidative stress, which causes the generation of reactive oxygen species (ROS) and free radicals. ROS, like the superoxide anion radical (O2−) and its dismutation product, hydrogen peroxide (H2O2), is detrimental to metabolic functions when produced in excessive amounts. The O2− radicals can oxidize the [4Fe-4S] clusters of dehydratases, such as aconitase, causing inactivation and release of Fe2+. After that, 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. It is worth mentioning that astaxanthin can act as a safeguard against oxidative damage through various mechanisms: quenching of singlet oxygen, scavenging of radicals, inhibiting lipid peroxidation, and regulating gene expression related to oxidative stress. For example, astaxanthin exerts beneficial effects against HgCl2-induced acute renal failure by preventing lipid and protein oxidation.

In an in vivo murine model, astaxanthin administration prevented N-Methyl-d-aspartate (NMDA)-triggered retinal damage associated with decreasing lipid peroxidation and oxidative DNA damage. Astaxanthin treatment ameliorates cyclophosphamide-induced oxidative stress and the subsequent DNA damage in rat hepatocytes. The protective effect of this molecule is attributed to the activation of the 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).

In the human retinal pigment epithelial (RPE) cell line ARPE-19, astaxanthin inhibited the intracellular production of ROS and prevented an H2O2-induced decrease in retinal pigment epithelial cell viability. Astaxanthin also increased the nuclear translocation of Nrf2. It enhanced the expression of phase II anti-oxidant enzymes by activating the phosphoinositide 3-kinase (PI3K)/Akt pathway, which eventually protected against H2O2-induced oxidative stress in ARPE-19 cells.

The anti-oxidative effects of astaxanthin have also been investigated in experimental models of acute neurological conditions. Astaxanthin provides neuroprotective effects against oxidative stress induced by oxygen-glucose deprivation in SH-SY5Y cells and 10-min global cerebral ischemia in rats. 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). Simultaneously, astaxanthin reduced cerebral infarction and promoted locomotor function recovery following MCAO.

Administration of astaxanthin had the potential to alleviate early brain injury (EBI) after subarachnoid hemorrhage (SAH) through its anti-oxidative properties. Treatment with astaxanthin is believed to confer protective effects by restoring endogenous anti-oxidant enzymes of glutathione (GSH) and superoxide dismutase (SOD) following SAH. Post-SAH astaxanthin treatment facilitated the Nrf2-ARE pathway and ameliorated EBI in a prechiasmatic cistern model of SAH. 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.

Astaxanthin also plays a role in preventing the development of chronic neurodegeneration. It boosted the expression of HO-1 and protected neurons against Aβ-induced cytotoxicity. 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 Aβ-induced neurotoxicity. In a cellular PD model, astaxanthin reduced the generation of intracellular ROS and provided cytoprotective effects against 1-methyl-4-phenylpyridinium (MPP+)-induced cytotoxicity.

In addition, astaxanthin enhanced HO-1 expression and limited NADPH oxidase 2 (NOX2)-mediated oxidative damage in MPP+-treated PC12 cells. Astaxanthin antagonized MPP+-induced oxidative stress through the regulation of specificity protein 1 (Sp1) and NMDA receptor subunit 1 (NR1) signaling pathway. Pre-treatment with astaxanthin markedly inhibited the up-regulation and nuclear transfer of Sp1, thereby alleviating MPP+-induced production of intracellular ROS and cytotoxicity in PC12 cells. Thus, astaxanthin protects against oxidative attacks in experimental neurological diseases.

  1. Anti-Inflammatory Effects

Inflammation is a series of complex immune responses that react to bodily injuries biologically. It is a host defense mechanism to remove damaged tissue from the original insult and initiate tissue repair. However, excessive or uncontrolled inflammation is detrimental to the host and can cause damage to the host’s cells and tissues. 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). Interestingly, astaxanthin exhibits anti-inflammatory effects in lipopolysaccharide-induced uveitis by directly blocking the activity of inducible nitric oxide synthase (NOS).

In addition, astaxanthin suppressed gene expression of inflammatory mediators (i.e., TNF-α and IL-1β) and alleviated endotoxin-induced uveitis by blocking the NF-κB-dependent signaling pathway. Under normal conditions, NF-κB, a heterodimer composed of p50 and p65 subunits, interacts with inhibitors of NF-κB (IκB) and remains inactive in the cytosol. Upon stimulation, IκB undergoes phosphorylation by IκB kinase β (IKKβ) and is degraded via the ubiquitin-proteasome pathway. 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. Astaxanthin treatment effectively alleviated NF-κB-related inflammation in the liver of mice subjected to high fructose and high-fat diet by suppressing IKKβ phosphorylation and nuclear translocation of the NF-κB (p65) subunit.

Astaxanthin also suppressed ROS-induced nuclear expression of NF-κB (p65). It 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). In a mouse model of experimental choroidal neovascularization, astaxanthin treatment inhibited macrophage infiltration into choroidal neovascularization.

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). 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.

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. Dietary administration of astaxanthin significantly suppressed aberrant NF-κB activation in the colonic mucosa, lowering gene expressions of IL-1β, IL-6, and COX-2, which contributes to attenuation of dextran sulfate sodium (DSS)-induced colitis.

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. In human keratinocytes, astaxanthin interrupts the auto-phosphorylation and self-activation of mitogen- and stress-activated protein kinase-1 (MSK1), decreasing phosphorylation of NF-κB (p65) and deficiency of NF-κB DNA binding activity. Consequently, these human keratinocytes were down-regulated UVB-induced expression and secretion of PGE2 and IL-8.

In a prechiasmatic cistern SAH model, astaxanthin provides neuroprotection against EBI by suppressing cerebral inflammation. 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. As a result, secondary brain injury cascades, neuronal degeneration, BBB disruption, cerebral edema, and neurological dysfunction were all alleviated after astaxanthin administration. However, there is still a lack of research documenting astaxanthin’s anti-inflammatory effects on treating neurological disorders. Several studies have reported that astaxanthin can enhance humoral and cell-mediated immune responses. Dietary supplements of astaxanthin can stimulate T cell and B cell mitogen-induced lymphocyte proliferation, increase the cytotoxic activity of the natural killer cell, and enhance IFN-γ and IL-6 production in young, healthy adult female human subjects.

Additionally, there are gender-related differences in the anti-inflammatory effects of astaxanthin on the aging rat brain. 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 to elucidate the inflammatory regulation mechanisms of astaxanthin.

  1. Anti-Apoptotic Effects

Apoptosis is a highly sophisticated energy-dependent process of programmed cell death. Morphologically, it is characterized by shrinkage of the cell, membrane blebbing, nuclear fragmentation, and chromatin condensation. Under normal physiological conditions, apoptosis is vital for embryonic development and tissue homeostasis. Under pathological conditions, uncontrolled apoptosis is harmful and contributes to the pathogenesis of various human diseases, including neurological disorders. Astaxanthin protected against H2O2-mediated apoptosis in a mouse neural progenitor cell culture model. Astaxanthin is believed 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. Astaxanthin significantly reduced apoptotic death of retinal ganglion cells and alleviated diabetic retinopathy by oxidative stress inhibition. 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.

Astaxanthin also exerts a protective effect against neuronal apoptosis in the setting of neurological diseases. 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. As a result, secondary brain injury in the early period of SAH, BBB disruption, cerebral edema, and neurological deficits were all alleviated after treatment with astaxanthin. 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. In addition, astaxanthin exhibits noticeable neuroprotection against cerebral ischemia-reperfusion insults through its anti-apoptotic actions. 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.

In an in vitro model of PD, astaxanthin attenuates 6-hydroxydopamine (6-OHDA)-induced apoptosis in human neuroblastoma SH-SY5Y cells. 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. Astaxanthin treatment prevents MPP+-induced up-regulation of Bax and down-regulation of Bcl-2, alleviating ΔΨm collapse in SH-SY5Y cells and protecting the neuron against MPP+-induced mitochondrial damage and apoptosis. 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, and the release of mitochondrial cytochrome c.

Interestingly, it has been shown that astaxanthin induces cancer cell apoptosis through a mitochondrial-dependent pathway. 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.

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. 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 cascades which leads to the inhibition of NF-κB and Wnt/β-catenin. Thus, astaxanthin may exert either anti-apoptotic or pro-apoptotic effects depending on the pathological condition.