Hypolipidemic, antioxidant, and antiinflammatory activities of microalgae spirulina

Hypolipidemic, Antioxidant, and Antiinflammatory Activities
of Microalgae Spirulina
Ruitang Deng1 & Te-Jin Chow2
1 Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, USA2 Department of Biotechnology, Fooyin University, Kaohsiung, Taiwan Keywords
Antioxidant; Antiinflammatory; Hypolipidemic;Lipids disorder/atherosclerosis; Spirulina.
Spirulina is free-floating filamentous microalgae growing in alkaline water bodies. With itshigh nutritional value, Spirulina has been consumed as food for centuries in Central Africa.
Correspondence
It is now widely used as nutraceutical food supplement worldwide. Recently, great attention Dr. Ruitang Deng, Department of Biomedical and extensive studies have been devoted to evaluate its therapeutic benefits on an array of diseased conditions including hypercholesterolemia, hyperglycerolemia, cardiovascular dis- eases, inflammatory diseases, cancer, and viral infections. The cardiovascular benefits of Spirulina are primarily resulted from its hypolipidemic, antioxidant, and antiinflammatory activities. Data from preclinical studies with various animal models consistently demonstrate the hypolipidemic activity of Spirulina. Although differences in study design, sample size, and patient conditions resulting in minor inconsistency in response to Spirulina supplemen- tation, the findings from human clinical trials are largely consistent with the hypolipidemiceffects of Spirulina observed in the preclinical studies. However, most of the human clinicaltrials are suffered with limited sample size and some with poor experimental design. Theantioxidant and/or antiinflammatory activities of Spirulina were demonstrated in a large number of preclinical studies. However, a limited number of clinical trials have been car-ried out so far to confirm such activities in human. Currently, our understanding on theunderlying mechanisms for Spirulina's activities, especially the hypolipidemic effect, is lim-ited. Spirulina is generally considered safe for human consumption supported by its longhistory of use as food source and its favorable safety profile in animal studies. However,rare cases of side-effects in human have been reported. Quality control in the growth andprocess of Spirulina to avoid contamination is mandatory to guarantee the safety of Spirulinaproducts.
Introduction
Early studies were mainly focused on the nutritional value of Spirulina as a food source. As early as over 400 years ago, Spirulina is referred to free-floating filamentous microalgae Spirulina was eaten as food by the Mayas, Toltecs, and Kanembu with spiral characteristics of its filaments. It is formally called in Mexico during the Aztec civilization [7]. Spirulina growing Arthrospira, belonging to the class of cyanobacteria with charac- in the Lake Texcoco were harvested, dried and used to make teristic photosynthetic capability [1,2]. Spirulina was initially clas- Spirulina cake as food. It has also been over centuries for the sified in the plant kingdom because of its richness in plant pig- Chadian to consume Spirulina in Central Africa. Spirulina har- ments as well as its ability of photosynthesis. It was later placed vested from the Lake Kossorom (Chat) is used to make cake or in the bacteria kingdom based on new understanding on its ge- broths as meals and also sold on the market [8]. The nutritional netics, physiology, and biochemical properties [3]. Spirulina nat- value of Spirulina is well recognized with its unusual high pro- urally grows in high-salt alkaline water reservoirs in subtrop- tein content (60-70% by dry weight) and its richness in vitamins, ical and tropical areas including America, Mexico, Asian, and minerals, essential fatty acids, and other nutrients [3,4]. Because Central Africa [3,4]. Among large number of Spirulina species, of its unusual high nutritional values, the Intergovernmental In- three species of Spirulina, including Spirulina platensis (Arthrospira stitution for the use of Micro-algae Spirulina Against Malnutrition platensis), Spirulina maxima (Arthrospira maxima), and Spirulina (IIMSAM) was launched in the middle 1970s to promote Spirulina fusiformis (Arthrospira fusiformis) are most intensively investigated as high nutritional food to fight against starvation and malnutri- as those Spirulina species are edible with high nutritional as well tion in the world [9]. In addition, due to its concentrated nutrition, as potential therapeutic values [3-6].
Spirulina was recommended by both National Aeronautics and Space Cardiovascular Therapeutics 28 (2010) e33-e45 c 2010 Blackwell Publishing Ltd
Hypolipidemic, Antioxidant, and Antiinflammatory Activities of Microalgae Spirulina Administration (NASA) and the European Space Agency (ESA) as by Spirulina was suggested as a mechanism for improving the hy- one of the primary foods during long-term space missions.
perlipidemia induced by high fructose diet. In another study with Starting at middle 1980s, great efforts and extensive investi- rats [17], fatty liver was induced by intraperitoneal injection of gations have been turned to the development of nutraceuticals carbon tetrachloride (CCl4), resulting in an increase in liver total or functional food for preventing or managing various diseases.
cholesterol and triacylglycerols. However, such increases were sig- Spirulina has become one of such nutraceutical food with diverse nificantly reduced by feeding oil extracts of Spirulina or defatted beneficial effects on an array of disease conditions. It has been fraction of Spirulina. In addition, CCl4-induced increase in total reported that consumption of Spirulina as diet supplement has cholesterol level was completely prevented by feeding a diet con- health benefits in preventing or managing hypercholesterolemia, taining whole Spirulina. A similar study was performed in CD-1 hyperglycerolemia, certain inflammatory diseases, allergies, can- mice [18]. Fatty liver was induced by a daily dose of simmvastatin cer, environmental toxicant- and drug-induced toxicities, viral in- (75 mg/kg body weight) for 5 days with a high cholesterol diet and fections, cardiovascular diseases, diabetes, and other metabolic dis- 20% ethanol in the drinking water. Serum and hepatic triacylglyc- ease among others [5,6,10]. In this review, emphasis is given to erols, total lipids and cholesterol were all significantly increased.
the potential beneficial effects of Spirulina on cardiovascular dis- However, Spirulina feeding for 2 weeks prior to the onset of fatty eases with highlights on Spirulina's hypolipidemic, antioxidant, liver induction decreased hepatic total lipids by 40%, triacylglyc- and antiinflamatory activities in preclinical and clinical studies.
erols by 50%, and serum triacylglycerols by 45%, accompanied by In addition, our current understanding on the mechanisms of ac- a 45% increase in serum HDL cholesterol. The hypolipidemic ac- tion and the potential side-effects of Spirulina consumption are tivity of Spirulina was also confirmed in a diabetic mouse model [19]. Diabetic condition was induced by administration of alloxan(250 mg/kg body weight), resulting in evident fatty liver accompa-nied by altered serum and hepatic triacylglycerols and cholesterol Hypolipidemic Effects
levels. However, mice receiving a diet containing 5% Spirulina 1week after the administration of alloxan for 4 weeks totally pre- Cholesterol is the building block for cell membrane and a pre- vented fatty liver production, decreased serum and hepatic triacyl- cursor of steroid hormones. It forms several distinct particles with glycerols, and fully or partially normalized HDL, LDL, and VLDL lipoproteins, mainly high-density lipoproteins (HDL), low-density cholesterol levels. The study also showed that female mice were lipoproteins (LDL), and very low-density lipoproteins (VLDL). It is more resistant to diabetes induction by alloxan whereas more re- well established that LDL and VLDL cholesterol levels are athero- sponsive to Spirulina treatment than male mice.
genic whereas HDL-cholesterol has protective effects on the devel- The hypolipidemic effects of Spirulina observed in mice and rats opment of atherosclerosis [11,12]. Increased LDL and VLDL levels were verified in two recent studies with hamsters [20] and rabbits are the major independent risk factor for cardiovascular events [21]. A group of hamsters fed an atherogenic diet supplemented whereas low level of HDL and elevated triglycerides (TG) are also with Spirulina or its ingredient phycocyanin exhibited lower total recognized as residual risk for cardiovascular diseases [13]. Agents cholesterol, LDL, and VLDL cholesterol whereas HDL cholesterol with the ability to decrease LDL/VLDL or total cholesterol levels, was not affected. Furthermore, aortic fatty streak area was signif- increase HDL cholesterol or lower TG have beneficial effects on icantly reduced in hamsters receiving Spirulina supplement, indi- cating the antiatherogenic activity of Spirulina [20]. In the studywith rabbits, hypercholesterolemia was induced by a high choles- Preclinical Studies
terol diet and the effects of feeding Spirulina (0.5 g daily) for 30 and60 days on the induced hypercholesterolemia was evaluated [21].
The hypolipidemic effect of Spirulina or its extracts have been At the end of the study, serum total cholesterol was decreased by demonstrated in various animal models including mouse, rat, 49% while HDL cholesterol was increased by 25%. No significant hamster, and rabbit. The cholesterol lowering activity of Spirulina changes in serum triacylglycerols were observed.
was first reported in albino rats [14], followed by in mice [15].
Taken together, the results from studies with various animal In the mouse study, supplementation of 16% Spirulina in a high models consistently demonstrate the hypolipidemic activity of fat and cholesterol diet resulted in a significant reduction in to- Spirulina, lowering serum total cholesterol, LDL, and VLDL frac- tal serum cholesterol, LDL, VLDL cholesterol, and phospholipids tions. In addition, other improvements in lipid profile were also whereas serum HDL cholesterol was concurrently increased. In observed in certain studies, including an increase in HDL choles- addition, high hepatic lipids induced by the high fat and choles- terol levels, decrease in atherogenic indices and triacylglycerol terol diet were markedly reduced by Spirulina consumption [15].
Since the initial report of hypolipidemic effects of Spirulina, sev- eral in vivo studies were carried out in rats and mice under variousexperimentally induced conditions. In one study [16], hyperlipi- Clinical Studies
demia was induced in Wistar rats by a high fructose (68%) diet.
Inclusion of increasing percentages of Spirulina (5%, 10%, and A number of human clinical trials have been performed to eval- 15%) in the diet significantly improved the hyperlipidemic pro- uate the hypolipidemic activity of Spirulina (Table 1). The target files. Correlating with such improvement in lipid profiles, Spirulina populations include healthy volunteers, patients with ischaemic feeding resulted in a significant increase in lipoprotein lipase and heart disease, type 2 diabetes and nephrotic syndrome, and elderly hepatic triglyceride lipase activity. Such increased lipase activity subjects with or without hypercholesterolemic condition.
Cardiovascular Therapeutics 28 (2010) e33-e45 c 2010 Blackwell Publishing Ltd
Hypolipidemic, Antioxidant, and Antiinflammatory Activities of Microalgae Spirulina Table 1 Hypolipidemic effects of Spirulina in human clinical studies
Total serum cholesterol and LDL were reduced significantly. Triglyceride levels decreased slightlywhereas HDL-cholesterol showed no significantchanges. The reduction of serum cholesterol was evengreater in those men with the highest cholesterol levels.
Total plasma cholesterol, LDL, VLDL and triglycerides were significantly reduced by 22.4% (2 g group)/33.5%(4 g group), 31%/45%, 22%/23%, and 22%/23%,respectively. HDL was significantly increased by11.5%/12.8%. In addition, a significant reduction in bodyweight was achieved in both treatment groups.
A significant reduction was detected in triglycerides, total cholesterol and free fatty acid levels. LDL and VLDLwere also decreased. In addition, blood sugar andglycated serum protein levels were significantlydecreased.
Total serum cholesterol and LDL fraction were reduced whereas HDL was slightly increased. As a result, asignificant decrease in atherogenic indices and theratios of total cholesterol/HDL and LDL/HDL wasobserved. Furthermore, triglycerides and fasting andpostprandial blood glucose levels were significantlyreduced. Finally, the level of apolipoprotein B showed asignificant fall with a concurrent significant increase inthe level of apolipoprotein A1.
Total serum cholesterol, LDL cholesterol and triglycerides were all significantly decreased by46 mg/dL, 33 mg/dL, and 45 mg/dL, respectively. Theratios of LDL/HDL and total cholesterol/HDL were alsodecreased significantly.
Total plasma cholesterol and triacylglycerols were significantly reduced by 10% and 28%, respectively. HDLwas significantly increased by 15% whereas LDLcholesterol was significantly decreased. In addition,both systolic and diastolic blood pressures weresignificantly reduced in both men and women.
The plasma concentrations of triglycerides, total cholesterol and LDL cholesterol were decreased after4 weeks of the supplementation. No differences inhypolipidemic effects of Spirulina were observedbetween mild hypercholesterolemic (cholesterol at orabove 200 mg/dL and normocholesterolemic subjects.
Serum levels of total cholesterol, LDL cholesterol and oxidized LDL were significantly reduced. In addition,apolipoprotein B, IL-6, and IL-6 production by peripheralblood lymphocyte were also decreased.
Total serum cholesterol, LDL fraction and triglycerides were reduced with the subjects with higher initial totalcholesterol, LDL-cholesterol and triglycerides showinghigher reduction. In addition, blood pressure and IL-6levels were also decreased. Finally, a significantreduction in plasma malondialdehyde level wasobserved.
Cardiovascular Therapeutics 28 (2010) e33-e45 c 2010 Blackwell Publishing Ltd
Hypolipidemic, Antioxidant, and Antiinflammatory Activities of Microalgae Spirulina Table 1 Continued
A significant decrease was observed in serum total cholesterol, triglycerides, LDL, and VLDL cholesterol inSpirulina treatment groups. In addition, both fasting andpostprandial blood glucose levels were also significantlydecreased accompanied with decreased meancarbohydrate and protein intake.
Total plasma cholesterol and LDL fraction were significantly reduced in female subjects whereas asignificant lowering effect on plasma total cholesterolby repeated test for treatment was observed in malesubjects. However, no significant effect was detected inLDL fraction in male subjects. The levels of HDL fractionand triglycerides did not change after the interventionin both men and women The first human study was carried out in 1988 with 30 healthy cluded that supplementation of Spirulina at a daily dose of 2 or 4 g male volunteers with mild hyperlipidemia or hypertention [22].
for 3 months significantly improved the lipid profile of the patients The 30 subjects were divided into two groups; one group received 4.2 g of Spirulina daily for 8 weeks whereas the other group was Noninsulin-dependent diabetes mellitus (NIDDM) or type 2 dia- given Spirulina for 4 weeks, followed by on regular food for an- betes mellitus is a recognized independent risk factor for cardiovas- other 4 weeks. Intake of Spirulina for 4 or 8 weeks significantly de- cular diseases, such as coronary artery disease. The distinction be- creased total serum cholesterol and the decrease was more marked tween type 2 diabetes mellitus and cardiovascular disease has been in mild hypercholesterolemic than in normocholesterolemic sub- blurred and prevention of cardiovascular diseases is becoming an jects. Discontinuation of Spirulina supplement for 4 weeks resulted integrated part of diabetes management. Patients with type 2 di- in returning of the cholesterol level to the baseline (prior to Spir- abetes are frequently affected by atherosclerotic vascular disease.
ulina supplementation) and HDL levels were slightly increased The abnormalities of both quantity and quality of lipoproteins in but not statistically significant. There were no changes in serum type 2 diabetes patients contribute to an increase in atherosclerotic triglycerides and body weight. In addition, no subjects reported ad- vascular disease. So far, four human clinical studies have been per- verse effects during the study. In a recent before-and-after clinical formed to investigate the hypolipidemic and hyperglycerolemic ef- trial with 36 healthy volunteers (16 male and 20 female) between fects of Spirulina in type 2 diabetic patients [25-28]. The two early ages 18 to 65 [23], ingestion of Spirulina at a dose of 4.5 g daily studies were carried out by Dr. Iyer's group in India [25,26]. In a for 6 weeks decreased total plasma cholesterol and triacylglycerols before-and-after study with 15 type 2 diabetes patients [25], sup- by 10% and 28%, respectively. Lipoprotein analysis showed that plementation of Spirulina at a dose of 2 g daily for 2 months re- HDL cholesterol was increased by 15% whereas LDL cholesterol sulted in a significant decrease in total serum cholesterol, triglyc- was significantly decreased. In addition, both systolic and dias- erides, and free fatty acid levels. Analysis of lipoprotein fractions tolic blood pressures were significantly reduced in both men and revealed that LDL and VLDL cholesterol levels were appreciably reduced. Blood sugar and glycated serum protein levels were also The hypolipidemic effect of Spirulina was also demonstrated in significantly decreased. In a second randomized and controlled ischaemic heart disease patients with hypercholesterolemic con- study [26], 25 patients with type 2 diabetes mellitus were ran- dition (serum total cholesterol levels above 250 mg/dL) [24], a domly assigned to a study or control group. Subjects in the study total of 30 patients were divided into three groups. Two treatment group received Spirulina at a dose of 2 g/day for 2 months. At the groups received 2 or 4 g of Spirulina daily for 3 months whereas end of the study, total serum cholesterol and LDL fraction were re- control group was not supplemented with Spirulina. At the end duced whereas HDL was slightly increased in the study group. As of the supplementation, plasma total cholesterol was significantly a result, a significant decrease in atherogenic indices and the ra- decreased by 22.4% and 33.5% in groups receiving 2 and 4 g Spir- tios of total cholesterol/HDL and LDL/HDL was achieved. Triglyc- ulina, respectively, whereas no significant change was detected in erides and fasting and postprandial blood glucose levels were sig- the control group. Lipoprotein fraction analysis showed that LDL nificantly reduced. Finally, the level of apolipoprotein B showed a and VLDL cholesterol levels were significantly reduced by 31% significant fall with a concurrent significant increase in the level of and 45%, and 22% and 23% in the two treatment groups, re- apolipoprotein A1. Thus, the hypolipidemic and hypoglycerolemic spectively. On the other hand, HDL was significantly increased by effects of Spirulina were consistently detected in both clinical stud- 11.5% and 12.8%. Furthermore, the concentration of triglycerides was significantly reduced by 22% and 23%. Finally, a significant The findings from the early studies were confirmed in the two loss in body weight was observed in both treated groups whereas recent human clinical trials with type 2 diabetic patients [27,28].
no change was detected in the control group. Thus, it was con- Both trials were randomized, controlled studies with a relatively Cardiovascular Therapeutics 28 (2010) e33-e45 c 2010 Blackwell Publishing Ltd
Hypolipidemic, Antioxidant, and Antiinflammatory Activities of Microalgae Spirulina large sample size. One study enrolled 37 patients being randomly were significantly reduced in female subjects whereas the lower- divided into a treatment or control group [27]. Intake of Spirulina ing effect on plasma total cholesterol and LDL fraction was not at a dose of 8 g daily for 12 weeks significantly reduced total statistically significant in male subjects. The levels of HDL fraction serum cholesterol, LDL fraction, and triglyceride levels. Subjects and triglycerides did not change after the intervention in both men with higher initial total cholesterol, LDL-cholesterol, and triglyc- and women. The data from those clinical trials largely support the eride levels showed higher reduction. In addition, blood pressures notion that Spirulina supplement is beneficial for managing aging- were also decreased. The second trial included 60 male patients ag- induced alterations in lipid profile in the elderly population.
ing from 40 to 60 years [28]. The subjects were randomly assigned Taken together, although differences in study design, sample into two treatment groups or a control group. The two treatment size and patient conditions resulting in minor inconsistency in re- groups received 1 or 2 g Spirulina daily for 2 months. A significant sponse to Spirulina supplementation, the cumulative data from decrease was observed in serum total cholesterol, triglycerides, those studies clearly demonstrate the hypolipidemic activity of LDL and VLDL cholesterol in the two treatment groups. Both fast- Spirulina in human. However, the majority of those human clin- ing and postprandial blood glucose levels were also decreased by ical trials are suffered with limited sample size and poor experi- 16.3% and 12.5% in 1 g-treated group and by 21.8% and 18.9% mental design. Additional clinical trials with large sample size and in 2 g-treated group whereas no significant changes were detected high quality experimental design are warranted to confirm the hy- in the control group. It was also found that mean carbohydrate polipidemic and hypoglycerolemic benefits of Spirulina in various and protein intake was significantly decreased in both treatment groups. Taken together, the data are consistent with the notionthat Spirulina is a promising agent as a functional food supplementfor controlling hyperglycerolemia and hypercholesterolemia and Antioxidant and Antiinflammatory Effects
thus reducing cardiovascular risk in the management of type 2diabetes.
Oxidative stress and inflammation both contribute to the patho- The hypolipidemic benefit of Spirulina was also reported in pa- genesis of cardiovascular diseases, including atherosclerosis, car- tients with nephrotic syndrome and hyperlipidemia [29]. One diac hypertrophy, heart failure and hypertension. Overproduction group of patients received medication alone whereas the other of reactive oxygen species (ROS) indicating the oxidative stress group received medication and Spirulina capsules. Supplementa- have been observed in those cardiovascular disease conditions tion of Spirulina at a dose of 1 g daily for 2 months resulted in a [36]. ROS also contributes to vascular dysfunction and remodeling reduction in total serum cholesterol, LDL fraction and triglycerides through oxidative damages in endothelial cells [37]. In addition, by 46, 33, and 45 mg/dL, respectively. The ratios of LDL/HDL evidence indicates that LDL oxidation is essential for atherogenesis and total cholesterol/HDL were also decreased significantly. It was [38,39]. On the other hand, the microenvironment present within thus concluded that Spirulina supplementation was an effective the atherosclerotic lesion is proinflammatory. In addition to being approach to reduce the increased levels of lipids in patients with a disorder of lipid metabolism, atherosclerosis is now recognized as a chronic inflammatory disease [40,41]. Accumulating evidence Total and LDL cholesterol levels increase with aging [30,31] as demonstrates that excessive inflammation within the arterial wall does the incidence of cardiovascular disease [32]. Three human is a risk factor for cardiovascular diseases and can promote athero- clinical studies have been carried out to investigate the therapeu- genesis. Agents with antioxidant and/or antiinflammatory activity tic effects of Spirulina in elderly population [33-35]. In one study may prove to be beneficial in combating cardiovascular diseases.
with 12 subjects (6 male and 6 female) between the ages 60 and75 [33], subjects received a supplement of Spirulina at a dose of7.5 g/day for 24 weeks. Plasma concentrations of triglycerides, Preclinical Studies
total cholesterol and LDL fraction were decreased after 4 weeks In Vitro Studies
of the supplementation while no changes were observed in di-etary intake and anthropometric parameters. It was also noticed A number of studies have reported the antioxidant and/or an- that no differences in the hypolipidemic effects of Spirulina were tiinflammatory activities of Spirulina or its extracts in vitro and observed between mild hypercholesterolemic (cholesterol at or in vivo, suggesting that Spirulina may provide a beneficial effect above 200 mg/dL) and normocholesterolemic subjects (cholesterol in managing cardiovascular conditions. In a study with neuroblas- below 200 mg/dL). The second before-and-after trial included 26 toma SH-SY5Y cells [42], the effects of Spirulina protean extract elderly women aged over 60 with hypercholesterolaemic condi- on iron-induced oxidative stress were investigated. Spirulina treat- tion (serum total cholesterol above 200 mg/dL) [34]. Intake of ment protected the activity of the cellular antioxidant enzymes Spirulina at a dose of 7.5 mg/day for 8 weeks resulted in a sig- including glutathione peroxidase (GPX), selenium-dependent glu- nificant reduction in serum levels of total cholesterol, LDL choles- tathione peroxidase (GPX-Se), and oxidized glutathione reductase terol and oxidized LDL. In addition, apolipoprotein B levels were (GR), and increased glutathione levels reduced in response to iron also decreased. The most recent clinical trial was a randomized, insult. The results clearly demonstrated the antioxidant activity of double-blinded, and placebo-controlled study [35]. Seventy-eight Spirulina extract. In a recent in vitro study [43], the antioxidant subjects between the ages 60 and 87 were randomly assigned into and antiinflammatory properties of four different Spirulina prepa- a study or placebo group. After consumption of Spirulina at a dose rations were evaluated with a cell-free as well as a cell-based as- of 8 g/day for 16 weeks, total plasma cholesterol and LDL fraction say. It was found that Spirulina dose-dependently inactivated free Cardiovascular Therapeutics 28 (2010) e33-e45 c 2010 Blackwell Publishing Ltd
Hypolipidemic, Antioxidant, and Antiinflammatory Activities of Microalgae Spirulina superoxide radicals generated during an oxidative burst. Equally as tumor necrosis factor-alpha (TNFα) and TNFβ. Spirulina supple- significant, Spirulina dose-dependently reduced the metabolic ac- mentation also significantly decreased the oxidative marker MDA tivity of functional neutrophils, indicating the antiinflammatory whereas increased the cerebellar beta-adrenergic receptor func- tion which was reduced by aging. The data thus demonstrated the Tissue homogenates were used in several in vitro studies to as- antioxidant and antiinflammatory activities of Spirulina in aged sess the antioxidant activity of Spirulina. In an early study [44], the antioxidant effect of methanolic extract of Spirulina on spon- Doxorubicin (DOX) is an anthracyclin antibiotic primarily used taneous lipid peroxidation of rat brain homogenate was investi- in the treatment of cancers. However, its application is limited gated. It was showed that Spirulina extract dramatically inhibited due to its cardiac toxicity. The generation of ROS, lipid peroxida- the production of thiobarbituric acid reactive substances (TBARS), tion, iron-dependent oxidative damage leading to mitochondrial such as malondialdehyde (MDA), by almost 95%, indicating the dysfunction have been implicated in DOX-induced cardiotoxicity potent antioxidant activity of Spirulina. Fluorouracil (5-FU) is an [54,55]. To determine whether Spirulina has cardioprotective ac- anticancer drug with cardiac toxicity and such cardiotoxicity is tivity in DOX-induced cardiotoxicity, mice were treated with DOX resulted from 5-FU-induced impairment in the myocardial an- alone or DOX with Spirulina [56]. As expected, mice administrated tioxidant defense system, leading to cardiac peroxidation [45]. To with DOX exhibited severe cardiac pathologies. However, feeding evaluate the protective effects of Spirulina on 5-FU-induced lipid of Spirulina at a dose of 250 mg/kg significantly decreased the mor- peroxidation, liver homogenate from goat was exposed to 5-FU or tality, ascites and lipid peroxidation; normalized the antioxidant 5-FU and Spirulina water extract [46]. As expected, 5-FU caused enzymes levels; and minimized the microscopic damages to the an increase in biomarkers of lipid peroxidation, MDA and 4- heart. The data indicated that Spirulina had a protective effect on hydroxy-2-nonenal (4-HNE), and a decrease in glutathione and cardiotoxicity induced by DOX, most likely through its antioxidant nitric oxide content. However, Spirulina water extract significantly reduced the levels of MDA and 4-HNE, and increased the reduced As described previously, Spirulina extracts increased the basal content of glutathione. It was thus concluded that water extract of synthesis and release of nitric oxide and cyclooxygenase- Spirulina significantly suppressed 5-FU-induced lipid peroxidation.
dependent vasoconstricting agent prostanoid by the endothelium Cardiovascular diseases, such as hypertention, atherosclosis, in vitro [51,52]. Such findings were confirmed in two animal stud- and ischemic injury, are associated with altered endothelium func- ies in vivo. In one early study with rats [57], feeding of a con- tion [47]. Vascular tone modification is an important function trolled diet containing 5% Spirulina significantly decreased the of the endothelium achieved by the synthesis and release of ei- maximal tension of the aorta rings developed in response to vaso- ther vasodilating or vasoconstricting agents. Studies have demon- constrictor PE. On the other hand, supplementation with Spirulina strated a dysfunction in nitric oxide synthesis and release, and an significantly increased the maximal relaxation in response to va- increased secretion of endothelium derived contracting factors in sodilating agent carbachol. The data thus indicated that Spirulina those disease conditions [48,49]. On the other hand, both LDL increased the synthesis and release of endogenous vasodilating and oxidized-LDL are inhibitors of the endothelium dependent agents, such as nitro oxide, whereas decreased the synthesis and vasodilator responses [50]. Two studies with rat aorta rings were release of vasoconstricting agents, such as eicosanoid, leading to carried out to evaluate the effects of Spirulina on vascular tone.
decreased vascular tone. Consistent results were obtained from an- In one study [51], ethanol extract of Spirulina dose-dependently other study with rats [58], in which feeding a diet containing 5% decreased the contractile response of the aortic ring to vasocon- Spirulina prevented the decrease of the endothelium-dependent stricting agent phenylephrine (PE) whereas enhanced the relax- vasodilator responses of the aorta rings induced by a high fructose ation response to vasodilating agent carbachol, consistent with the notion that Spirulina extract increased the basal synthesis and/or In addition, a large number of animal studies were carried out release of nitric oxide by the endothelium and cyclooxygenase- to investigating the preventive or protective effects of Spirulina in- dependent vasoconstricting prostanoid by vascular smooth muscle take on environmental toxicant, chemical, heavy metal or drug- cells. Similar findings were obtained in a recent study with aortic induced oxidative stress and inflammation. Those studies were rings from fructose-induced obese rats [52]. Ethanolic extract of summarized in Table 2 [59-73]. Accumulative data from those Spirulina significantly decreased PE-induced vasocontriction in a studies concluded that Spirulina ingestion significantly relieved dose-dependent manner whereas no effects on carbachol-induced or totally prevented the oxidative stress or inflammation, and vasodilation were observed. The results suggested that ethanolic their associated pathological damages induced by insulting com- Spirulina extract increased the synthesis and release of nitric ox- pounds. Although those studies were not directly investigating ide but inhibited the synthesis and release of a cyclooxygenase- Spirulina's effects on cardiovascular conditions, the findings clearly dependent vasoconstrictor metabolite of arachidonic acid.
demonstrated the antioxidant and antiinflammatory activities ofSpirulina.
In Vivo Studies
Clinical Studies
A number of animal studies have been carried out to evaluatethe antioxidant and/or antiinflammatory activities of Spirulina.
In contrast to numerous preclinical studies, a limited number In one study with aged male rats [53], Spirulina reversed age- of clinical trials have been carried to evaluate the antioxidant related increase in proinflammatory cytokines in cerebellum, such and/or antiinflammatory activities of Spirulina in human. In one Cardiovascular Therapeutics 28 (2010) e33-e45 c 2010 Blackwell Publishing Ltd
Hypolipidemic, Antioxidant, and Antiinflammatory Activities of Microalgae Spirulina Table 2 Antioxidant and antiinflammatory activities of Spirulina in preclinical studies
Effects of Spirulina or its extracts Enzymatic and nonenzymatic antioxidants were significantly improved, and the tardive dyskinesiainduced by haloperidol was decreased Significantly and dose-dependently restored renal functions damaged by cisplatin. A decreasein lipid peroxidation with an increase inglutathione levels, superoxide dismutase, andcatalase activities The β-glucuronidase that had been increased by zymosan was significantly reduced.
Histopathological and ultrastructural evaluationshowed inhibition of the inflammatory reactionwith no destruction of cartilage, well-preservedchondrocytes, normal rough endoplasmicreticulum and mitochondria All the three doses resulted in a significant reduction in chromosomal damage and lipidperoxidation with concomitant changes inantioxidants and detoxification systems.
malondialdehyde, conjugated diene andhydroperoxide.
collagen-induced arthritis and decreased lipidperoxidation. Serum albumin was significantlyelevated accompanied with a decrease in theserum cholesterol, alkaline phosphatase and acidphosphatase activities accompanied with an increase in endogenousantioxidants levels. In addition, thecadmium-induced histopathological changeswere minimized Significant nephroprotection was achieved by decreasing lipid peroxidation and elevating thelevels of glutathione, superoxide dismutase, GPX,NO. Histological examination confirmed thenephroprotective effects of Spirulina tetrachloride-induced elevation of serumaspartate aminotransferase and livertriacylglycerols values. In addition, a significantdecrease in free fatty acids and thiobarbituricacid reactive substances was observed oxaloacetate and serum glutamate pyruvatetransaminase activity along with increase in liverGSH level. The activities of antioxidants enzymessuperoxide dismutase, catalase, andglutathione-S-transferase were alsoconcomitantly restored to near normal level bySpirulina supplementation to mercuric chlorideintoxicated mice.
Cardiovascular Therapeutics 28 (2010) e33-e45 c 2010 Blackwell Publishing Ltd
Hypolipidemic, Antioxidant, and Antiinflammatory Activities of Microalgae Spirulina Table 2 Continued
Effects of Spirulina or its extracts characterized by a significant increase in tissuemarker lysosomal enzymes, glycoproteins andthe paw volume. All those arthritic alterationswere almost completely normalized by Spirulinaingestion Genotoxicity induced by cisplatin and urethane was protected by Spirulina, accompanied with asignificant reduction in the extent of lipidperoxidation and a concomitant increase in theliver enzymatic (GPx, GST, SOD, CAT) andnonenzymatic (reduced glutathione) antioxidants Spirulina dose-dependently inhibited compound 48/80 or anti-DNP IgE induced allergic reactions.
Serum histamine levels and histamine releasefrom peritoneal mast cells (RPMC) weredose-dependently decreased by Spirulina. Inaddition, the level of cyclic AMP in RPMC wassignificantly increased by 70-fold and theanti-DNP IgE-induced tumor necrosis factor-αproduction was inhibited Spirulina protected cyclosporine induced- nephrotoxicity, evidenced by a decrease inplasma urea and creatinine. A significantdecrease in plasma and local tissue MDA wasobserved. In addition, histopathological analysisrevealed that the severe isometric vacuolizationand widening of the interstitium induced bycyclosporine were completely prevented bySpirulina.
At a dose of 0.15 g/kg, Spirulina partially reversed the dopamine-depleting effect of MPTP and completely blocked the oxidative stress induced study with 26 elderly women, intake of Spirulina 7.5 mg/day for ducted to investigate the effects of Spirulina on preventing excise- 8 weeks significantly decreased serum IL-6 levels and IL-6 pro- induced skeletal muscle fatigue and damage through its antioxi- duction from peripheral blood lymphocytes [34], demonstrating dant property. In one study with 16 student volunteers, intake of the antiinflammatory activity of Spirulina. In a recent randomized, a diet containing 5% Spirulina for 3 weeks resulted in a significant double-blind and placebo-controlled study with 78 healthy elderly reduction of plasma oxidative marker MDA with a concurrent in- subjects [35], supplementation of Spirulina at a dose of 8 g/day for crease in the blood superoxide dismutase activity [75]. In a recent 16 weeks resulted in a significant rise in plasma interleukin (IL)-2 study with nine male subjects [76], supplementation of Spirulina concentrations in both male and female subjects with a concurrent with a daily dose of 8 g for 4 weeks significantly prolonged the reduction in IL-6 concentration in male subjects, and an increase time to fatigue, reduced TBARS induced by excise, and increased in superoxide dismutase activity in female subjects. Finally, a re- the plasma glutathione, protein carbonyls, catalase, and total an- cent clinical trial with 37 type 2 diabetes patients revealed that tioxidant capacity levels. In addition, ingestion of Spirulina also Spirulina ingestion at a dose of 8 g daily for 12 weeks significantly significantly decreased carbohydrate oxidation rate by 10.3% and reduced serum interleukin 6 (IL-6) and oxidative marker MAD increased fat oxidation rate by 10.9%. Taken together, the data levels [27]. The data from those studies demonstrated the antiox- indicated that supplementation of Spirulina had preventive effects idant and antiinflammatory activities of Spirulina in vivo.
on skeletal muscle fatigue and damage mainly through its antiox- It is well established that exercise promotes the production of reactive oxygen and nitrogen species, which contribute to skele- Allergic rhinitis is characterized by allergic airway inflammation tal muscle fatigue and damage [74]. Two clinical trials were con- and hyperresponsiveness to nonspecific stimuli, often involving Cardiovascular Therapeutics 28 (2010) e33-e45 c 2010 Blackwell Publishing Ltd
Hypolipidemic, Antioxidant, and Antiinflammatory Activities of Microalgae Spirulina activation of mast cells by IgE. To investigate whether Spirulina has prostaglandin E(2) production [83,85,88-90]. In addition, phy- therapeutic effects on alleviating allergic rhinitis through its anti- cocyanin has been reported to suppress the activation of nuclear inflammatory and antioxidant activities, two human clinical stud- factor-κB (NF-κB) through preventing degradation of cytosolic ies were carried out with allergic rhinitis patients. In a randomized, IκB-α [89] and modulate the mitogen-activated protein kinase double-blinded crossover study [77], intake of Spirulina at a dose (MAPK) activation pathways, including the p38, c-Jun N-terminal of 2 g/day for 12 weeks reduced IL-4 levels by 32% released from kinase (JNK), and extracellular-signal-regulated kinase (ERK1/2) phytohemagglutinin (PHA)-stimulated peripheral blood mononu- clear cells whereas no significant changes were observed for inter- Another ingredient of Spirulina, β-carotene, has been reported feron gamma (IFNγ ) and IL-2. In another recent trial [78], Spir- to have antioxidant and antiinflammatory activities [97-99]. In ulina consumption significantly improved the allergic symptoms a study to compare β-carotene, vitamin E, and nitric oxide as compared with placebo, including nasal discharge, sneezing, nasal membrane antioxidants, it was found that β-carotene protected congestion and itching. Thus it was concluded that Spirulina was against singlet oxygen-mediated lipid peroxidation [97]. Studies clinically effective on managing allergic rhinitis through its antiin- also showed that β-carotene inhibited the production of nitric flammatory and/or antioxidant properties.
oxide and prostaglandin E(2), and suppressed the expression ofiNOS, COX-2, TNF-α, and IL-1β. Such suppression of inflamma-tory mediators by β-carotene is likely resulted from its inhibition Mechanism of Action
of NF-κB activation through blocking nuclear translocation of NF-κB p65 subunit [98]. In addition, β-carotene suppressed the tran- Hypolipidemic Activity
scription of inflammatory cytokines including IL-1β, IL-6, and IL- Although the hypolipidemic effect of Spirulina has been demon- 12 in macrophage cell line stimulated by lipopolysaccharide (LPS) strated in preclinical and clinical studies, our understanding on its mechanism of action is almost totally lacking. The active ingredi-ents in Spirulina responsible for the hypolipidemic activity remainto be identified. In a study with S. platensis concentrate (SPC), it Safety Profile
was found that SPC could bind cholesterol metabolites bile acids Spirulina has been consumed as food by man for long time in and decreased cholesterol solubility. Feeding rats with SPC signifi- Mexico and Central Africa and is currently used widely as nu- cantly increased fecal excretion of cholesterol and bile acid. It was traceutic food supplement, especially in Asian. Over the history of thus proposed that decreases in intestinal cholesterol and bile acid Spirulina use by human, it has been generally considered safe to absorption following SPC feeding may represent a mechanism for ingest Spirulina. Consistent with such notion are the results from a the hypocholesterolemic action of SPC [79].
number of animal studies. However, few clinical studies have been Phycocyanin is a water soluble protein and enriched in Spir- carried out to systemically establish the safety profile of Spirulina in ulina. Ingestion of phycocyanin preparation made from SPC re- sulted in a significant decrease in serum total cholesterol and To determine whether Spirulina feeding have any side effects atherogenic index whereas serum HDL cholesterol was concur- on the growth and development of embryo and fetus, four ani- rently increased. It was thus suggested that phycocyanin might mal studies with pregnant rats have been conducted [100-103]. In be the active ingredient in Spirulina responsible for the hypolipi- one study [100], Spirulina was administrated to pregnant rats from demic activity [79]. However, addition studies with highly pu- days 1-14, 1-21, and 7-14 of gestation with increasing doses (from rified or expressed phycocyanin are required to confirm the 0 to 30 g/100 g body weight). It was found that Spirulina feed- ing did not change the maternal and fetal weight. No teratogenic-ity was detected with consumption of Spirulina even with highest Antioxidant and Antiinflammatory Effects
dose and longest duration. Consistent results were obtained witha similar study in pregnant rats [101]. Supplementation of Spir- Spirulina contains several active ingredients, notably phycocyanin ulina in the diet at the doses much higher than any anticipated and β-carotene that have potent antioxidant and antiinflamma- human consumption did not cause any signs of embryotoxic ef- tory activities. The antioxidant and antiinflammatory properties fects. In another study with rats [102], the effects of Spirulina alone of phycocyanin were first reported in 1998 [80,81] and confirmed or in combinations with other supplements on pregnancy were by numerous studies thereafter [20,82-92]. Phycocyanin has the investigated. Maximal maternal weight gain was associated with ability to scavenge free radicals, including alkoxyl, hydroxyl, and Spirulina/wheat gluten diet whereas wheat gluten diet resulted in peroxyl radicals. It also decreases nitrite production, suppresses least weight gain. Intake of diet containing Spirulina significantly inducible nitric oxide synthase (iNOS) expression, and inhibits increased litter size whereas birth weights of pups were compa- liver microsomal lipid peroxidation [20,80-92]. Using recombi- rable to those from other groups. Finally, a study with pregnant nant technology, phycocyanin protein has been expressed and the rats to assess the general reproductive performance showed that antioxidant activity is also demonstrated with the recombinant Spirulina feeding did not change body weight of male and female rats with no signs of toxicity and was not associated with any ad- verse effects on any measures of reproductive performance includ- proinflammatory cytokine formation, such as TNFα, sup- ing fertility, gestation and abnormal pups [103]. Taken together, presses cyclooxygeanase-2 (COX-2) expression and decreases it was concluded that Spirulina had no detectable adverse effects Cardiovascular Therapeutics 28 (2010) e33-e45 c 2010 Blackwell Publishing Ltd
Hypolipidemic, Antioxidant, and Antiinflammatory Activities of Microalgae Spirulina on reproductive performance, embryo and fetus development and ious diseased conditions including hypercholesterolemia, hyper- glycerolemia, cardiovascular diseases, inflammatory diseases, can- To evaluate the safety of relatively long-term feeding of Spir- cer, and viral infections. The cardiovascular benefits of Spirulina ulina, mice were fed with a diet containing increasing percentages are primarily resulted from its hypolipidemic, antioxidant, and an- (from 0% to 30% w/w) of Spirulina for 13 weeks [105]. Ingestion tiinflammatory activities. Data from preclinical studies with var- of Spirulina had no effects on behavior, food and water intake, ious animal models consistently demonstrate the hypolipidemic growth, and survival. Hematologic and clinical chemistry analy- activity of Spirulina. Although differences in study design, sam- ses revealed no abnormality. In addition, no gross or microscopic ple size and patient conditions resulting in minor inconsistency changes were detected with histological evaluation. In a recent in response to Spirulina supplementation, the findings from hu- study with short and long-term Spirulina feeding in rodents [106], man clinical trials are largely consistent with the hypolipidemic feeding mice with high dose of Spirulina (30 g and 10 g/kg body effects of Spirulina observed in the preclinical studies. However, weight of fresh and dried Spirulina, respectively) for 7 days re- most of the human clinical trials are suffered with limited sample sulted in no signs of toxicity. In the long-term feeding study, rats size and some with poor experimental design. Additional clinical were administrated with Spirulina at various doses for 12 weeks.
trials with large sample size and high quality experimental design Consumption of Spirulina did not cause any changes in behavior, are warranted to confirm the hypolipidemic benefits of Spirulina food and water intake, growth, health status, and measurements in various target human populations.
The antioxidant and/or antiinflammatory activities of Spirulina Despite of favorable safety profile in rodents, there were reports have been demonstrated in a large number of preclinical studies.
raising the concerns of the safety of Spirulina consumption. A low However, a limited number of clinical trials have been carried out level of mercury and other heavy metals were reported in Spirulina so far to confirm such activities in human. Future clinical trials are grown in open water source [107]. Consumption of such Spirulina required to establish the antioxidant and antiinflammatory bene- preparation could lead to increased deposit of mercury and other fits in human. In addition, efforts should be taken to standardize heavy metals causing toxic effects. However, with controlled wa- the dose of Spirulina in future human clinical studies. Spirulina is ter sources for growing Spirulina, commercial Spirulina products generally considered safe for human consumption supported by its tested contained mercury or lead at the levels much lower than the long history of use as food source and its favorable safety profile in guidelines for daily intake of those elements by the WHO's Food animal studies. However, rare cases of side-effects in human have and Agriculture Organization (FAO) [108]. Certain cyanobacterial been reported. Additional clinical studies are required to system- species produce cyanotoxin and contamination of those species in ically establish the safety profile of Spirulina in human. Quality the Spirulina products may be deleterious for consumers [109].
control in the growth and process of Spirulina is a key measure- In a newly reported study, anatoxin-a, a cyanotoxin with acute ment to avoid contamination and guarantee the safety of Spirulina neurotoxicity, were detected in 3 of the 39 cyanobacterial samples products. Currently, our understanding on the underlying mech- [110]. It was thus recommended that quality control of cyanobac- anisms for Spirulina's activities, especially the hypolipidemic ef- terial food supplements including Spirulina was required to avoid fect, is still limited. Future studies to identify the active ingredients potential adverse effects in animals and humans.
in Spirulina and uncover the mechanistic insights into Spirulina's Finally, a few rare incidences associated with consumption of therapeutic effects will provide the bases for developing new drugs Spirulina supplements in human have been reported. One case of for preventing or treating hypercholesterolemia and cardiovascu- hepatotoxicity was possibly associated with Spirulina intake [111], although the patient also took three other medications. A case ofrhabdomyolysis was recently reported as a result of Spirulina in- Acknowledgments
take [112]. Finally, an association of Spirulina consumption anddevelopment of a mixed immunoblistering disorder with charac- The authors' research is supported in part by the National Insti- teristic features of bullous pemphigoid and pemphigus foliaceus tutes of Health [Grant R01-DK087755] and National Center for was reported in an 82-year-old healthy woman [113].
Research Resources [Grant P20-RR016457] (the Rhode Island- Taken together, Spirulina is generally considered safe for human Institutional Development Awards Network of Biomedical Re- consumption supported by its long history of use as food source, search Excellence grant); and by the Rhode Island Foundation and its favorable safety profile in animal studies. However, rare cases of side-effects have been reported and should be taken intoconsideration. In addition, additional clinical studies are requiredto systemically establish the safety profile of Spirulina in human.
Conflict of Interest
Finally, quality control in the growth and process of Spirulina to The authors declare no conflict of interests.
avoid contamination is mandatory to guarantee the safety of Spir-ulina products.
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