Oxidative stress and inflammation both contribute to the pathogenesis of cardiovascular diseases, including atherosclerosis, cardiac hypertrophy, heart failure and hypertension. Overproduction of reactive oxygen species (ROS) indicating the oxidative stress have been observed in those cardiovascular disease conditions . ROS also contributes to vascular dysfunction and remodeling through oxidative damages in endothelial cells . In addition, evidence indicates that LDL oxidation is essential for atherogenesis [38,39]. On the other hand, the microenvironment present within the atherosclerotic lesion is proinflammatory. In addition to being a disorder of lipid metabolism, atherosclerosis is now recognized as a chronic inflammatory disease [40,41]. Accumulating evidence demonstrates that excessive inflammation within the arterial wall is a risk factor for cardiovascular diseases and can promote atherogenesis. Agents with antioxidant and/or antiinflammatory activity may prove to be beneficial in combating cardiovascular diseases.
In vitro studies
A number of studies have reported the antioxidant and/or antiinflammatory activities of Spirulina or its extracts in vitro and in vivo, suggesting that Spirulina may provide a beneficial effect in managing cardiovascular conditions. In a study with neuroblastoma SH-SY5Y cells , the effects of Spirulina protean extract on iron-induced oxidative stress were investigated. Spirulina treatment protected the activity of the cellular antioxidant enzymes including glutathione peroxidase (GPX), selenium-dependent glutathione peroxidase (GPX-Se) and oxidized glutathione reductase (GR), and increased glutathione levels reduced in response to iron insult. The results clearly demonstrated the antioxidant activity of Spirulina extract. In a recent in vitro study , the antioxidant and antiinflammatory properties of four different Spirulina preparations were evaluated with a cell-free as well as a cell-based assay. It was found that Spirulina dose-dependently inactivated free superoxide radicals generated during an oxidative burst. Equally significant, Spirulina dose-dependently reduced the metabolic activity of functional neutrophils, indicating the antiinflammatory activity.
Tissue homogenates were used in several in vitro studies to assess the antioxidant activity of Spirulina. In an early study , the antioxidant effect of methanolic extract of Spirulina on spontaneous lipid peroxidation of rat brain homogenate was investigated. It was showed that Spirulina extract dramatically inhibited the production of thiobarbituric acid reactive substances (TBARS), such as malondialdehyde (MDA), by almost 95%, indicating the potent antioxidant activity of Spirulina. Fluorouracil (5-FU) is an anticancer drug with cardiac toxicity and such cardiotoxicity is resulted from 5-FU-induced impairment in the myocardial antioxidant defense system, leading to cardiac peroxidation . To evaluate the protective effects of Spirulina on 5-FU-induced lipid peroxidation, liver homogenate from goat was exposed to 5-FU or 5-FU and Spirulina water extract . As expected, 5-FU caused an increase in biomarkers of lipid peroxidation, MDA and 4-hydroxy-2-nonenal (4-HNE), and a decrease in glutathione and nitric oxide content. However, Spirulina water extract significantly reduced the levels of MDA and 4-HNE, and increased the reduced content of glutathione. It was thus concluded that water extract of Spirulina significantly suppressed 5-FU-induced lipid peroxidation.
Cardiovascular diseases, such as hypertention, atherosclosis and ischemic injury, are associated with altered endothelium function . Vascular tone modification is an important function of the endothelium achieved by the synthesis and release of either vasodilating or vasoconstricting agents. Studies have demonstrated a dysfunction in nitric oxide synthesis and release, and an increased secretion of endothelium derived contracting factors in those disease conditions [48,49]. On the other hand, both LDL and oxidized-LDL are inhibitors of the endothelium dependent vasodilator responses . Two studies with rat aorta rings were carried out to evaluate the effects of Spirulina on vascular tone. In one study , ethanol extract of Spirulina dose-dependently decreased the contractile response of the aortic ring to vasoconstricting agent phenylephrine (PE) whereas enhanced the relaxation response to vasodilating agent carbachol, consistent with the notion that Spirulina extract increased the basal synthesis and/or release of nitric oxide by the endothelium and cyclooxygenase-dependent vasoconstricting prostanoid by vascular smooth muscle cells. Similar findings were obtained in a recent study with aortic rings from fructose-induced obese rats . Ethanolic extract of Spirulina significantly decreased PE-induced vasocontriction in a dose-dependent manner whereas no effects on carbachol-induced vasodilation were observed. The results suggested that ethanolic Spirulina extract increased the synthesis and release of nitric oxide but inhibited the synthesis and release of a cyclooxygenase-dependent vasoconstrictor metabolite of arachidonic acid.
In vivo studies
A number of animal studies have been carried out to evaluate the antioxidant and/or antiinflammatory activities of Spirulina. In one study with aged male rats , Spirulina reversed age-related increase in proinflammatory cytokines in cerebellum, such as tumor necrosis factor-alpha (TNFα) and TNFβ. Spirulina supplementation also significantly decreased the oxidative marker MDA whereas increased the cerebellar beta-adrenergic receptor function which was reduced by aging. The data thus demonstrated the antioxidant and antiinflammatory activities of Spirulina in aged rats.
Doxorubicin (DOX) is an anthracyclin antibiotic primarily used in the treatment of cancers. However, its application is limited due to its cardiac toxicity. The generation of ROS, lipid peroxidation, iron-dependent oxidative damage leading to mitochondrial dysfunction have been implicated in doxorubicin (DOX)-induced cardiotoxicity [54,55]. To determine whether Spirulina has cardioprotective activity in DOX-induced cardiotoxicity, mice were treated with DOX alone or DOX with Spirulina . As expected, mice administrated with DOX exhibited severe cardiac pathologies. However, feeding of Spirulina at a dose of 250 mg/kg significantly decreased the mortality, ascites and lipid peroxidation; normalized the antioxidant enzymes levels; and minimized the microscopic damages to the heart. The data indicated that Spirulina had a protective effect on cardiotoxicity induced by DOX, most likely through its antioxidant activity.
As described previously, Spirulina extracts increased the basal synthesis and release of nitric oxide and cyclooxygenase-dependent vasoconstricting agent prostanoid by the endothelium in vitro [51,52]. Such findings were confirmed in two animal studies in vivo. In one early study with rats , feeding of a controlled diet containing 5% Spirulina significantly decreased the maximal tension of the aorta rings developed in response to vasoconstrictor PE. On the other hand, supplementation with Spirulina significantly increased the maximal relaxation in response to vasodilating agent carbachol. The data thus indicated that Spirulina increased the synthesis and release of endogenous vasodilating agents, such as nitro oxide, whereas decreased the synthesis and release of vasoconstricting agents, such as eicosanoid, leading to decreased vascular tone. Consistent results were obtained from another study with rats , in which feeding a diet containing 5% Spirulina prevented the decrease of the endothelium-dependent vasodilator responses of the aorta rings induced by a high fructose intake.
In addition, a large number of animal studies were carried out to investigating the preventive or protective effects of Spirulina intake on environmental toxicant, chemical, heavy metal or drug-induced oxidative stress and inflammation. Those studies were summarized in Table 2 [59–73]. Accumulative data from those studies concluded that Spirulina ingestion significantly relieved or totally prevented the oxidative stress or inflammation, and their associated pathological damages induced by insulting compounds. Although those studies were not directly investigating Spirulina’s effects on cardiovascular conditions, the findings clearly demonstrated the antioxidant and antiinflammatory activities of Spirulina.
In contrast to numerous preclinical studies, a limited number of clinical trials have been carried to evaluate the antioxidant and/or antiinflammatory activities of Spirulina in human. In one study with 26 elderly women, intake of Spirulina 7.5mg/day for 8 weeks significantly decreased serum IL-6 levels and IL-6 production from peripheral blood lymphocytes , demonstrating the antiinflammatory activity of Spirulina. In a recent randomized, double-blind and placebo-controlled study with 78 healthy elderly subjects , supplementation of Spirulina at a dose of 8g/day for 16 weeks resulted in a significant rise in plasma interleukin (IL)-2 concentrations in both male and female subjects with a concurrent reduction in IL-6 concentration in male subjects, and an increase in superoxide dismutase activity in female subjects. Finally, a recent clinical trial with 37 type 2 diabetes patients revealed that Spirulina ingestion at a dose of 8g daily for 12 weeks significantly reduced serum interleukin 6 (IL-6) and oxidative marker MAD levels . The data from those studies demonstrated the antioxidant and anti-inflammatory activities of Spirulina in vivo.
It is well established that exercise promotes the production of reactive oxygen and nitrogen species, which contribute to skeletal muscle fatigue and damage . Two clinical trials were conducted to investigate the effects of Spirulina on preventing excise-induced skeletal muscle fatigue and damage through its antioxidant property. In one study with 16 student volunteers, intake of a diet containing 5% Spirulina for 3 weeks resulted in a significant reduction of plasma oxidative marker MDA with a concurrent increase in the blood superoxide dismutase activity . In a recent study with 9 male subjects , supplementation of Spirulina with a daily dose of 8g for 4 weeks significantly prolonged the time to fatigue, reduced TBARS induced by excise, and increased the plasma glutathione, protein carbonyls, catalase, and total antioxidant capacity levels. In addition, ingestion of Spirulina also significantly decreased carbohydrate oxidation rate by 10.3% and increased fat oxidation rate by 10.9%. Taken together, the data indicated that supplementation of Spirulina had preventive effects on skeletal muscle fatigue and damage mainly through its antioxidant activity.
Allergic rhinitis is characterized by allergic airway inflammation and hyperresponsiveness to nonspecific stimuli, often involving activation of mast cells by IgE. To investigate whether Spirulina has therapeutic effects on alleviating allergic rhinitis through its antiinflammatory and antioxidant activities, two human clinical studies were carried out with allergic rhinitis patients. In a randomized, double-blinded crossover study , intake of Spirulina at a dose of 2g/day for 12 weeks reduced IL-4 levels by 32% released from phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells whereas no significant changes were observed for interferon gamma (IFNγ) and IL-2. In another recent trial , Spirulina consumption significantly improved the allergic symptoms compared with placebo, including nasal discharge, sneezing, nasal congestion and itching. Thus it was concluded that Spirulina was clinically effective on managing allergic rhinitis through its antiinflammatory and/or antioxidant properties.