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 damage 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, 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-1β) 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 colonic 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 cell-mediated immune responses [
26,
80,
81,
82,
83]. 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.