How does astaxanthin protect neurons?

 Neurological diseases are common diseases leading to disability and death in human beings, and the main pathogenesis is a series of oxidative stress, inflammation, apoptosis and other pathological reactions, which activate the release of chemokines and cytokines from neuroglia, accelerating neuronal cell death and neurodegenerative diseases [1-2]. Currently, drugs for the treatment of neurological diseases are not perfect, Astaxanthin (AST), as the strongest antioxidant among carotenoids, is expected to become a multi-target drug for the treatment of neurological diseases [3].

 

1 Chemical structure and function of astaxanthin

Astaxanthin belongs to the subclass of lutein, which is a natural red pigment [4]. Natural astaxanthin is mainly produced in microalgae, bacteria, and plankton, and can also be synthesized in a few plants [5]. Astaxanthin has the structural formula C40H52O4, with a polyene ring chain with a β-phycocyanone ring attached to each of the two ends. In this polar-nonpolar-polar structure, the polar end carries ketone and hydroxyl groups, and the nonpolar middle contains 11 carbon-carbon conjugated double bonds, which makes astaxanthin lipophilic and hydrophilic[6] . Astaxanthin is suitable to flow in biological membranes and can be connected to them from the inside out to maintain more active biological properties; its conjugated double bond can terminate the free radical chain reaction in the cell, thus it has a unique antioxidant ability [7].

 

Astaxanthin can easily cross the blood-brain barrier and protect the brain from acute injuries and chronic neurodegenerative diseases [8]. A large number of experiments have demonstrated that astaxanthin plays an important role in cell signaling, and can protect neurons from damage through antioxidant stress, anti-inflammation, anti-apoptosis and senescence, and down-regulation of nitric oxide (NO). The role of astaxanthin in the treatment of neurological diseases is becoming more and more prominent [9-10].

 

2 Neuroprotective effects of astaxanthin

2.1 Antioxidant effects Neurodegenerative diseases and oxidative stress lead to excessive generation of reactive oxygen species (ROS) in the body, which damages mitochondria and mediates and exacerbates neuronal damage [11]. Astaxanthin can activate a variety of antioxidant enzymes to scavenge ROS, and at the same time, it can induce various factors involved in the process of oxidative stress, which significantly reduces the oxidative stress response in vivo [12] and protects the damaged neurons. Astaxanthin can also protect neurons by down-regulating NO, e.g., after astaxanthin treatment, the activity of nitric oxide synthase will be affected and the amount of NO release will be significantly reduced [9].

 

Astaxanthin anchors or crosses the mitochondrial membrane, prevents the loss of methyl 3-methoxypropionate (MMP), prevents the opening of the mitochondrial permeability transition pore (mPTP), and maintains mitochondrial redox homeostasis by increasing mitochondrial oxygen consumption even in the presence of hydrogen peroxide (H2O2) stimulation [13-14]. Astaxanthin can resist the damage caused by oxidative stress by increasing the levels of catalase (CAT), superoxide dismutase (SOD), heme oxygenase 1 (HO-1), quinone oxidoreductase 1 (NQO-1), etc. [14-15]. Astaxanthin pretreatment can reduce ROS production and lipid peroxidation in the ipsilateral brain of rats with middle cerebral artery occlusion (MCAO), reduce the occurrence of cerebral infarction, and promote the restoration of motor function in rats [16]. The mechanism of astaxanthin pretreatment is that it can increase the concentration of cycloadenosine monophosphate (cAMP) in the brain tissue, activate cAMP, cyclophosphorylated adenosine effector-binding protein (CREB), and cAMP-dependent protein kinase (PKK). The mechanism is to activate cAMP, cyclophosphoadenosine effector binding protein (CREB), and cAMP-dependent protein kinase (PKA) signaling pathways by increasing the concentration of cAMP in brain tissue, which promotes the recovery of cortical axons[17] .

 

ZHANG et al.[18] found that astaxanthin could protect neurons by reducing neuronal damage caused by subarachnoid hemorrhage (SAH) and restoring endogenous antioxidant enzymes glutathione (GSH) and SOD. The mRNA expression levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) can affect brain function, and astaxanthin can effectively improve BDNF and NGF in rats with acute cerebral infarction [19]. Astaxanthin can inhibit mitochondrial impairment, ROS-mediated oxidative damage, and modulate mitogen-activated protein kinases (MAKPs) and protein kinase B or Akt (PKB/Akt) signaling pathways, and has the potential to reverse homocysteine (HCY)-induced neurotoxicity and neurodegenerative diseases [20]. Scopolamine interrupts striatal-hippocampal cholinergic activity, and astaxanthin prevents oxidative damage by altering the levels of antioxidant enzymes, GSH, SOD, CAT and NO in the hippocampus [21]. Astaxanthin protects against glutamate-induced HT22 cytotoxicity by attenuating mitochondrial dysfunction [22], and prenatal use of astaxanthin up-regulates cAMP-responsive element-binding protein (CREB) [23], which reduces the level of oxidative stress and minimizes neuronal damage in the hippocampus of young rats. Astaxanthin also has a role in the prevention of chronic neurodegenerative diseases by increasing HO-1 expression, activating the extracellular regulated protein kinase (ERK) signaling pathway, promoting nuclear translocation, and preserving DNA-binding protein activity [24]. Astaxanthin positively regulates the dissociation and nuclear translocation of Nrf2, an important transcription factor in the cellular oxygenation stress response, and enhances the expression of a variety of enzymes related to antioxidants, and also negatively regulates the Sp1/NR1 signaling pathway [24], which attenuates intracellular ROS production and oxidative stress damage.

 

2.2 Anti-inflammatory effects   

Excessive inflammatory response is one of the pathologic features of neurodegenerative diseases. In the central nervous system, inflammatory transcriptional regulators are the main inflammatory mediators produced by cells. Astaxanthin has anti-inflammatory effects, inhibiting nuclear factor-κB (NF-κB) activity after subarachnoid hemorrhage, down-regulating mRNA expression levels, and reducing inflammatory mediator production[25] . Astaxanthin inhibits NF-κB and reduces LPS-induced inflammatory cytokine production by inhibiting NF-κB in lipopolysaccharide-induced neuroinflammation[26] . Inflammatory mediators such as cox-2, cox-2IL-1β, TNF-α and p50-p65 were attenuated by astaxanthin in rats with persistent epilepsy induced by Hirsutine [21]. Astaxanthin has been shown to protect cognitive function by inhibiting brain inflammation and reducing interleukin 1β (IL-1β) and IL-6 in chronic type II diabetic rats [27]. Astaxanthin can also inhibit endoplasmic reticulum stress by targeting the miR-7/SNCA axis to protect against neuronal damage caused by Parkinson's disease [28]. Astaxanthin not only reduces neuronal damage caused by cerebral ischemia/reperfusion injury (IR) [29], but also activates the cAMP/PKA/CREB signaling pathway by increasing the concentration of cAMP in the brain tissue and promotes the regeneration of cortical axons, and its anti-inflammatory and antioxidant effects are related to those of astaxanthin [17].

 

2.3 Anti-apoptotic effects   

One of the pathogenic mechanisms of neurological diseases is uncontrolled programmed cell death, i.e. apoptosis. In mouse neural precursor cell culture, KIM et al [30] found that astaxanthin inhibited H2O2-mediated apoptosis. Astaxanthin maintains the structure and function of mitochondria by regulating the p38 and mitogen-activated protein kinase (MEK) signaling pathways [31], and DONG et al. [32] reported that astaxanthin protects retinal ganglion cells, inhibits abnormal neuronal apoptosis, increases the expression of Akt, down-regulates downstream pro-apoptotic proteins, activates Caspase-3/9, and ameliorates apoptosis in mitochondria. Astaxanthin mediates the survival pathway of PI3K/Akt, promotes phosphorylation-dependent inactivation of Bad, and reduces neuronal apoptosis after subarachnoid hemorrhage [10]. Astaxanthin also reduces neuronal apoptosis induced by the neurotoxin 1-methyl-4-phenylpyridinium ion (MPP+) and attenuates symptoms in rats with cerebral ischemia [15]. Intracerebroventricular administration of astaxanthin antagonized ischemia/reperfusion-induced neuronal apoptosis and prevented apoptosis in a transient middle cerebral artery occlusion model of ischemic stroke [16].

 

Astaxanthin can significantly inhibit ROS generation, activate p38/MAPK, regulate MEK signaling pathway, inhibit caspase, attenuate the degree of cellular damage by 6-hydroxydopamine (6-OHDA), and reduce the level of apoptosis in human neuroblastoma cells (SH-SY5Y) [33]. LEE et al. [34] found that astaxanthin treatment prevented MPP+-induced Bax up-regulation and Bcl-2 down-regulation, attenuated mitochondrial membrane potential, and protected neurons from MPP+-induced mitochondrial damage and apoptosis. Astaxanthin can activate Nrf2 through the PI3K/Akt/GSK3β/Nrf2 signaling pathway, up-regulate the synthesis of heat-stimulated proteins (HSPs), inhibit oxidative damage, and reduce neuronal apoptosis caused by oxygen-glucose deprivation (OGD) [35]. Astaxanthin can resist neuronal apoptosis by affecting the Sp1/NR1 signaling pathway [24]. Non-esterified astaxanthin is neuroprotective in Parkinson's disease, with DHA-AST being the most potent inhibitor of apoptosis in dopaminergic neurons [36].

 

3 Clinical applications

Numerous studies have demonstrated that astaxanthin can delay or ameliorate the cognitive deficits associated with normal aging and attenuate the pathology of various neurodegenerative diseases. Astaxanthin at 12 mg/d has been shown to improve amnesia to some extent in middle-aged and older individuals, whereas astaxanthin at 6 mg/d has been shown to improve spatial and temporal working memory; a combination supplement containing astaxanthin and sesquiterpenes has been shown to have beneficial effects on cognitive functioning in patients with mild cognitive impairment [37]. Increased bioavailability of astaxanthin in astaxanthin nutritional formulations has been shown to be effective in correcting oxidative status in aging individuals [38].

 

4 Outlook

Cell and animal experiments have proved that astaxanthin has a protective effect on many kinds of damaged neurons in vivo and in vitro, and to a certain extent, it can protect the animal nervous system. Clinical trials have shown that astaxanthin can reduce nerve damage in humans and enable the body to repair certain neurological dysfunctions, and scientists expect astaxanthin to become a new type of drug for neurological diseases in the future. However, in order to accurately and effectively evaluate the effects of astaxanthin on specific neurodegenerative diseases, it is necessary to further investigate the protective properties and potential mechanisms of astaxanthin, and further clinical trials are needed to evaluate the clinical trials of astaxanthin for the treatment of neurological diseases, and to expand the technical methodology of the clinical trials to be more complete. Lipid carrier systems, mitochondrial targeting systems, polymeric systems, and cyclodextrin encapsulation systems are considered to be novel delivery systems to enhance the action of astaxanthin, which can improve the hydrophilicity, stability, safety, and antioxidant capacity of astaxanthin, and may be used as a novel approach for the treatment of neurodegenerative diseases in the future [39].

 

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