|Year : 2014 | Volume
| Issue : 3 | Page : 147-153
Oxidative stress and astaxanthin: The novel supernutrient carotenoid
Department of Pharmacology, V.S.S Medical College and Hospital, Burla, Odisha, India
|Date of Web Publication||13-Aug-2014|
Department of Pharmacology, V.S.S Medical College and Hospital, Burla, Odisha
Source of Support: None, Conflict of Interest: None
Background: Oxidative stress and inflammation leads to, generation and overproduction of the reactive oxygen species and reactive nitrogen species and hence are responsible for many diseases such as Alzheimer's disease, Parkinson's disease, diabetes mellitus, rheumatoid arthritis, and neurodegenerative motor neuron diseases. Antioxidants are found in varying amounts in vegetables, fruits, grain cereals, eggs, meat, legumes and nuts. However, there is always a search for antioxidants that can quench and breakup the chain of generation of free-radicals. Aims: Astaxanthin, a ketocarotenoid, has exceptional antioxidant activity and hence can be used for prevention of cardiovascular diseases, inflammatory and neurodegenerative diseases, boosting of the immune system, anti-Helicobacter pylori activity, and cataract prevention. Hence, an attempt has performed in this review to compile data on astaxanthin and its several diverse applications over the last decade with an aim to escalate the intense interest in undertaking new research on this natural fascinating molecule. Materials and Methods: A literature search using astaxanthin and antioxidants as keywords using Google as the search engine was done and the data obtained were compiled and presented. Results and Conclusions: Astaxanthin can be a great supplement for everyone in enhancing immunity, preventing a myriad of diseases in our hectic lifestyle by providing more energy, reducing oxidative damage, producing clarity of vision as well as protection from the harmful ultraviolet rays of the sun! Further the immunomodulatory, antioxidative, and antiinflammatory activity of astaxanthin a bioactive natural supernutrient carotenoid may be very important to human health in treating many such untreatable diseases.
Keywords: Antioxidant, astaxanthin, carotenoids, oxidative stress, supernutrient
|How to cite this article:|
Biswal S. Oxidative stress and astaxanthin: The novel supernutrient carotenoid. Int J Health Allied Sci 2014;3:147-53
| Introduction|| |
Oxidative stress leading to mitochondrial dysfunction, represents an imbalance between the overproduction of singlet or free-radical oxygen and the ability of the human body to detoxify these reactive intermediates.  Oxygen atoms usually remain in pairs, singlet oxygen atoms are hence highly unstable thereby leading to the generation of reactive oxygen species (ROS), which include free-radicals, peroxides and superoxides, which in turn damages the cellular lipids and proteins, causing disruption in the cellular homeostasis, resulting in inflammation and ultimately in damage to the DNA.  It is also thought to contribute to the accelerated process of aging. Moreover, oxidative stress is thought to be both the cause as well as the consequence of many life threatening and debilitating diseases such as diabetes, atherosclerosis cardiovascular diseases, certain neurodegenerative diseases, stroke, and so on. 
To counteract this oxidative stress, the body produces several antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione S-transferase, etc.  Which neutralize the harmful free-radicals, reduce the inflammatory action of such singlet or free-radical oxygen and are thus essential in lengthening and improving the quality of our lives. Such endogenous antioxidants are usually of two broad categories. 
- Water soluble antioxidants: These are present in the blood, intracellular and extracellular fluid and are Vitamin C, glutathione, and catechins, which neutralize the oxidants generated inside the cytoplasm and in the blood
- Lipid soluble antioxidants: These are localized to the cellular membranes and the lipoproteins hence protect the cell membranes from lipid peroxidation. These are Vitamin E, Vitamin A, and beta-carotene.
| Materials and methods|| |
The articles discussed in this review were located by conducting Internet searches using Google as the search engine. A literature search using astaxanthin and antioxidants as key words was done and the data obtained from the available literature was compiled and produced here. The related data obtained was over 50. Then some specific search terms like pharmacological actions of astaxanthin were used to specify our search areas. A literature review was done, which included the obtained literature search materials, subsequent finally understanding and analysis of the collected literature which done and put into the context of this review project. A focus on selected evidenced based studies on astaxanthin was done and analyzed. The articles which were based on justified animal or human studies were taken into account and cited in this study.
Finally, overall summary of the literature review was done particular highlighting any gaps in research and conflicts. An attempt has been done in this review to link together many studies on astaxanthin different topics, for the purposes of reinterpretation and interconnection.
| Antioxidants in food|| |
Apart from their endogenous nature, antioxidants are also found in varying amounts in certain foods such as vegetables, fruits, grain cereals, eggs, meat, legumes, and nuts. These are present either in the form of vitamins, phytonutrients and carotenoids, which are usually destroyed by long-term storage or prolonged cooking due to the complex process involved in cooking and food processing  or in the form of polyphenolic antioxidants, which are relatively more stable and are present in whole-wheat cereals and in tea.  Hence in general, processed foods contain lesser amounts of antioxidants in comparison to fresh and uncooked foods. 
Such nutritional antioxidants have the ability to decrease the oxidation of lipids and proteins (during oxidative stress), thereby have the potential to protect against certain debilitating and degenerative diseases. 
Carotenoids, a nutritional pigmented antioxidant are tetraterpenoid substances (containing 40 carbon atoms, built from 4 terpene units each containing 10 carbon atoms) that are naturally found in plants, microorganisms such as algae, some bacteria, and in some fungus. They are also a common feature in animals, for they impart a distinct color to them, the pink color of flamingos and salmon, and the red color of cooked lobsters are due to such carotenoids. They are usually of two types: 
- Carotenes: Which contains no oxygen atoms are called lycopene (the red pigment in tomatoes) and beta-carotene (the orange pigment in carrots) are carotenes
- Xanthophylls: Which contain oxygen atoms: lutein, canthaxanthin (the gold pigment in chanterelle mushrooms), zeaxanthin, and astaxanthin.
Studies report that people consuming diets rich in carotenoids from natural foods, such as fruits and vegetables, are healthier with a lower incidence of morbidity and mortality arising from chronic illnesses for carotenoids are efficient free-radical scavengers and hence minimize the oxidative stress and associated cellular damage. 
Astaxanthin is one particular oxycarotenoid, chemically similar to beta-carotene, but more powerful than beta-carotene, lycopene, lutein, and other members of its chemical family in terms of singlet oxygen quenching activities and hence in its antioxidant activity. Singlet oxygen is an active oxygen species that is generated in the human skin by exposure to ultraviolet (UV) radiation which has the potential to cause DNA damage and disease. Certain studies have shown that at doses as low as 2 mg/day given orally to human subjects for 4 weeks, there was a significant reduction in the measurable endogenous oxidative DNA damage by about 40%.  Thus, astaxanthin is the strongest natural carotenoid antioxidant as it is 65 times more powerful than Vitamin C, 54 times more powerful than beta-carotene, and 14 times more powerful than Vitamin E, for which it has jumped to the forefront in terms of its antioxidant status as a "supernutrient" due to some remarkable properties rarely found in other antioxidants. 
| Astaxanthin|| |
The United States Food and Drug Administration have approved astaxanthin as a nutaceutical.  It is a fat soluble reddish colored pigment of the carotenoid family, found in certain plants and animals that give them their distinctive colorful appearance (salmon, shrimp, and lobster), the depth of their color depends on the concentration of astaxanthin in them. Compared to other carotenoids it has a unique structure in containing a keto and a hydroxyl group on each end of its molecule, which is thought to contribute to its enhanced antioxidant properties as evident from [Figure 1]. The cis isomer of astaxanthin, especially the 9-cis astaxanthin, has much higher antioxidant potency when compared to its trans isomer. 
|Figure 1: Beta carotene is made up of 8 isoprene units which are cyclized at each end this is 3, 31 -dihydroxy-beta carotene-4,41 -dione|
Click here to view
However, it differs from other carotenoids in the following features 
- It is lipid soluble so it can cross the blood-brain barrier and the blood-retinal barrier whereas beta-carotene and lycopene cannot cross and can thus prevent the damage caused by free-radicals. Gray matter in the brain is composed of 60% fatty acids by composition which is extremely vulnerable to damage by free-radicals, which can ultimately result in degeneration of the neuronal cells
- It is a potent absorber of the UVB rays as evident from the algae, Haematococcus pluvialis behavior which protects itself from intense UV radiation by creating increased amounts of astaxanthin pigment which serves as a natural sunscreen
- It is also a very powerful natural anti-inflammatory agent.
| Sources of astaxanthin|| |
It is most prevalent in some microalgae and phytoplankton, but it also can be found in some fungi, bacteria, yeast, salmon, trout, krill, shrimp, crayfish and crustaceans as evident from [Table 1].  Currently, the primary natural source for astaxanthin is the microalgae, H. pluvialis which has the highest levels.  This microalgae is usually grown in two phases. In the first phase, the cells are given an abundance of nutrients to promote proliferation of cells. In the subsequent phase, the cells are deprived of nutrients and subjected to intense sunlight, during which the algae produce high levels of astaxanthin as a protective mechanism against the environmental stress. This represents the algae's survival mechanism from lack of nutrition and/or intense sunlight where production of astaxanthin serves as a shield to protect the algae. Commercially around 40 g of astaxanthin can be obtained from 1 kg of the dry algae biomass. 
Other marine animals that consume this algae (such as salmon, shellfish, and krill) also have a high concentration of astaxanthin, the highest concentration of which is found in the salmon, where it is concentrated in their muscles and assists them to swim up rivers and waterfalls without getting fatigued, thereby making them the endurance heroes of the animal kingdom.  Salmon are usually born white, but turn to a pinkish orange color because of the H. pluvialis that they eat. However, wild salmon have higher astaxanthin concentration as compared to farmed salmon. Commercial astaxanthin is collected from the discarded shell waste obtained during processing of shrimps. 12,000 pounds of wet shrimp shells can yield 6-8 gallons of a mixture of astaxanthin and some triglycerides, from which the former is finally extracted and purified. 
However, because of very low yields in the above-mentioned processes, bioengineering methods using a plasmid-free Escherichia coli strain is now being recently tried for improved and increased biosynthesis of astaxanthin.  Nearly all commercial astaxanthin is being produced synthetically, however, synthetic production of astaxanthin is not preferred in some cases because synthetic astaxanthin is manufactured from petrochemical products and hence contains a mixture of both cis and trans stereoisomers, whereas as stated earlier it is only the cis isomer, which has much higher beneficial antioxidant properties.
| Discussion on the pharmacological roles of astaxanthin|| |
Though carotenoids exhibit antioxidant properties due to their strong total singlet oxygen quenching rate constants as compared to other antioxidants, astaxanthin shows the strongest activity amongst them. Studies comparing the effects of beta-carotene and astaxanthin on the peroxidation of liposomes induced by adenine dinucleotide phosphate and Fe 2+ have revealed that though both the compounds inhibited production of lipid peroxides, astaxanthin was more effective by two-fold in protecting the mitochondria from the damage induced by Fe 2+ catalyzed lipid peroxidation in comparison with beta-carotene. This inhibitory effect on mitochondrial lipid peroxidation was also stronger than that of alphatocopherol. 
There are studies that suggests that astaxanthin supplementation has significant anti-inflammatory activities on carrageenan induced models of acute inflammation,  cardioprotective effect in ischemic reperfusion animal models,  with a reduction in lipid peroxidation products,  thereby hinting at their beneficial role as potential antithrombotic agents in reducing the incidence of thrombosis.  They also have proven benefits in various animal models of ischemic heart diseases. 
Pretreatment with astaxanthin also attenuated the cyclophosphamide induced oxidative stress in mice suggesting its use as a chemoprotective agent. 
Immune cells in particular are more sensitive to the effect of oxidative stress for they produce more amounts of oxidative byproducts.  Treatment of Helicobacter pylori infected mice with astaxanthin has shown to reduce the associated gastric inflammation, the total bacterial load and decreased levels of inflammatory cytokines.  Observations from a double blind study has revealed that astaxanthin causes enhanced cell mediated and humoral mediated immune responses as evident by an increase in the number of circulating total T- and B-cells, proliferation of the circulating lymphocyte, amplification of the cytotoxic activity of natural killer cells and can significantly increases the delayed-type hypersensitivity response and also reduces inflammation underlying arthritis and bronchial asthma. 
Since astaxanthin modulates the immune system, it is effective in reducing the colonization of this bacteria by increasing the activity of t-helper cells.  Thereby there is reduction in gastric inflammation and hence a decreased incidence of reduction in incidence of ulcers.
Disorders of the eye
Of all the carotenoids, the retina concentrates zeaxanthin and lutein, which in turn absorb the damaging UV rays of the sun thereby protecting the macula lutea from UV light induced free-radical damage by a process called photo oxidation.  Epidemiological studies have shown that diets high in lutein and zeaxanthin, in addition to increasing the retinal blood flow, can prevent damages as a result of many an occular inflammatory change and thus are associated with a reduced risk of cataracts and age-related macular degeneration (ARMD), photoreceptor cell damage, ganglion cell damage and neuronal damage. 
Astaxanthin being highly lipid soluble, accumulate in the eyes in considerable amounts which also protects the UV light-induced damages and hence their supplementation has been proved to be effective in preventing or treating a whole array of opthalmic diseases, like ARMD, diabetic retinopathy, cystoid macular edema, central retinal arterial and venous occlusion, glaucoma. Besides it has beneficial role in certain inflammatory conditions of the eye such as retinitis, iritis, keratitis, and scleritis. 
Astaxanthin suppresses the synthesis of inflammatory mediators such as tumor necrosis factor alpha, prostaglandins, leukotriens and interleukins, nitric oxide, cyclooxygenase-1 and -2 (COX-1 and COX-2) enzymes. Experimental studies have shown that it also decreases the serum levels of these mediators in lipopolysaccharide (LPS) administrated mice, and inhibits NF-kappa B-cell activation as well as nitric oxide synthetase promoter activity in RAW264.7 cells stimulated with LPS.  It also suppressed the synthesis of various inflammatory mediators such as tumor necrosis factor alpha, prostaglandin E2, interleukin-1B and nitric oxide by its inhibitory effects on the cyclooxygenase enzymes (COX-1 and COX-2). Comparing this inhibitory effect with celecoxib, a selective COX-2 inhibitor, it was evident that celecoxib was 300 times stronger in its COX-2 inhibitory property as compared to astaxanthin. However, the COX-1 inhibitory action of the both of them was almost similar.  So by attenuating inflammation, it can help prevent as well as a treat, a number of inflammatory conditions such as rheumatoid arthritis, tennis elbow, carpal tunnel syndrome and other repetitive stress injuries.
In yet another questionnaire based study on 247 patients it was observed that around 90% of them with symptoms of either chronic back pain, bronchial asthma, osteoarthritis or rheumatoid arthritis reported a symptomatic relief with astaxanthin supplementation in their diet.  Astaxanthin's anti-inflammatory properties are due to its antioxidant activity. Antioxidants usually exhibit an anti-inflammatory activity as well.
C-reactive protein (CRP) is one of the markers of inflammation that is produced in the liver and coronary arteries and is raised in various inflammatory conditions as well as in cardiac disorders. Studies have reported that there was a reduction in the raised serum CRP levels of patients by 20% with 8 weeks of therapy with astaxanthin, whereas in another study, the existing high CRP levels of 43% of patients in chronic inflammation dropped to the normal range with astaxanthin  suggesting their potential anti-inflammatory actions. Hence, it might be suggested that astaxanthin therapy would stabilize an atheromatous plaque by virtue of their anti-inflammatory action. Their antiinflammatory property could possibly, significantly inhibit LDL oxidation, decrease macrophage infiltration into an atherosclerotic plaque, diminish apoptosis in macrophages and decrease expressions of matrix metalloproteinase that otherwise could have resulted in rupture of an existing plaque.
There is increased production of certain ROS in the body, due to insulin lack and resultant hyperglycemia associated in patients of diabetic mellitus. Nonenzymatic glycosylation of proteins and mitochondria is a major source of ROS; this can result in reduction of insulin expression by pancreatic β-cells and induction of cell death (apoptosis). Studies have demonstrated that certain antioxidants when given to animal models of diabetes (N-acetyl-L-cysteine, Vitamins C and E) exerted beneficial effects of improving and preserving β-cell function.  Hence, it is likely that a more potent antioxidant as astaxanthin can also preserve the pancreatic function and would thereby improve the insulin secretion and release by protecting the β-cells from glucotoxicity. Furthermore, its potential anti-inflammatory properties are also likely to protect such diabetic persons from associated complications arising out of oxidative stress.
Neuroprotective effects of astaxanthin have been seen at relatively high doses where it prevented the ischemic-induced brain damage in experimental animals. Rats were given oral astaxanthin 24 h and 1 h prior to induction of cerebral ischemia by occluding the rats' middle arteries for 1 h. The rats were given another dose of astaxanthin after the blood flow was resumed after removing the occlusion. These rats were then sacrificed, their brains removed and compared with control rats, where it was observed that the rats fed astaxanthin had 40% less brain damage suggesting a neuroprotective action of the drug.  It may also improve the memory in subjects of vascular dementia.  However, further research in humans is essential to fully understand its potential benefit, but observations from these preclinical studies suggests that astaxanthin may help improve the outcome in many a central nervous system disorders.
Radioprotective and antiaging properties
Researchers have shown that topical astaxanthin alone or in combination with retinol can be remarkably effective in protecting the skin against the photodamages such as lipid peroxidation, sunburn reaction, phototoxicity and photoallergy induced by UVA light-induced singlet oxygen.  Topically applied astaxanthin, can scavenge singlet oxygen moiety as a result of its antioxidant property, as a result can prevent UV induced collagen degradation, formation of wrinkles, reduce melanin production in the skin and can help ward off age spots and freckles.
A double blind study conducted in Japan evaluated the effect of a combination of 2 mg/day of astaxanthin with Vitamin E on women around 40 years of age. Measurements of several skin parameters were noted after 2 weeks and after 4 weeks of therapy. At the end of 4 weeks, the study subjects had significantly increased moisture levels, a reduction of fine wrinkles and pimples. On a self-assessment survey, treated subjects reported less puffiness of the eyes, improved elasticity with a better subjective skin texture. The placebo group however showed no improvements even after 4 weeks and on the contrary their skin conditions actually worsened on exposure to the sun. 
The comparative anticancer activities of beta-carotene, astaxanthin and canthaxanthin against the growth of mammary tumors were studied in female 8-week-old BALB/c mice, where tumor inhibition by astaxanthin was dose-dependent and higher than that of canthaxanthin and beta-carotene. Lipid peroxidation activity in such tumors was lower (P < 0.05) in mice which were fed with 40 μg/kg body weight/day of astaxanthin, but not in those fed with beta-carotene or canthaxanthin. As evident from such studies astaxanthin can reduce the risk for many types of malignancies (including cancers of the breast, colon, bladder, and mouth) by stimulating apoptosis while inhibiting lipid peroxidation. 
In a double-blind, placebo-controlled clinical trial in infertile men with abnormal sperm quality, 16 mg of natural astaxanthin per day for 3 months resulted in an improvement in the conception rate in the treated group by 78% over the placebo group. 
Astaxanthin supplementation in obese mice fed a high fat diet inhibited the increases in body weight and weight of adipose tissue, reduced the liver weight, serum triglycerides and total cholesterol levels. Hence, it might be of value in reducing the likelihood of obesity and metabolic syndrome in affluent societies. 
| Pharmakokinetics|| |
Astaxanthin is though less absorbed orally, bioavailability can be enhanced in the presence of fat. Since it is virtually impossible to get the optimal amount of antioxidants from food alone the recommended dose of astaxanthin is however 1 mg twice a day along with oily or fatty food. The elimination half-life is 16 h.  But, unlike other carotenoids it is not converted into Vitamin A in the body.
Though even in very high doses, no known toxic side-effects have been reported in humans or animals, some people notice a slight orange tint coloration of their fecal matter which might be due to the small amounts of the unabsorbed pigment.
Acute and sub-acute toxicity studies in Wistar rats has shown no untoward effects on body weight or on other viscera when compared to the control group.  Sometimes there might be an increased deposition of the pigment in the straight part of the proximal convoluted tubule of the kidney which was seen in 5 out of 10 female rats when treated with an extremely high dose (20% of the biomass [w/w] for 90 days.). However, these changes were not considered as toxicologically significant.  However, unlike other antioxidants, there are no stated reports on the pro-oxidant activity of the supernutrient astaxanthin, irrespective of the quantity one takes in the diet. 
On the other hand, individuals with a history of allergy or hypersensitivity to sea foods or related carotenoids may develop hypersensitivity reactions with astaxanthin. A minority of such subjects can have hypotension, pigmentation of skin, excessive growth of hair, hypokalcemia and decreased libido during intake.  Hence, it is to be used with caution in such patients as well as in patients with hypertension, bronchial asthma, disorders of the parathyroid and osteoporosis. 
However, this wonder drug is exceptionally unstable when subjected to oxidation. Since it is a strong antioxidant on exposure to the atmosphere it will form oxidized products with oxygen in the air and itself would get degraded that has no therapeutic benefit. So, considerable care must be taken during handling and storage of astaxanthin, to be sure that it does not oxidize.
| Conclusion|| |
Astaxanthin is nature's most powerful antioxidant which has caused a surge in the nutraceutical market. For the encapsulated product provides an impressive array of health benefits, for what astaxanthin does for the salmon, can do the same for humans. These results support the assumption that protecting body tissues from oxidative damage with daily ingestion of natural astaxanthin may be a natural, practical and beneficial strategy in health care management. However, further research in establishing its potential therapeutic benefit in cardiovascular disease, neurodegenerative disease, cancer, immune function status and visual health are highly necessary.
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