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Spiralan®

Phycocyanin

100 or 400

Once daily for 8 days (days 11-18 after injection of Freund's adjuvant) Once daily for 9 days (Days 4-12 after zymosan injection) Once daily for 8 days (Days 4-12 after zymosan injection)

Acetic acid-induced colitis

Phycocyanin

30 min before acetic acid enema a TPA= 12-0-tetradecanoyl-phorbol-13-acetate.

Swiss Decreased paw volume; lower lysosomal enzyme albino activities (as a marker of inflammation) in plasma, mice liver, and spleen; reduced protein-bound carbohydrates (as a measure of tissue damage)

Prevention of joint destruction or pannus formation and reduction in bone erosion; attenuated joint inflammation (infiltration); decreased /¡-glucuronidase activity in the synovial fluid Prevention of joint destruction or pannus formation and pronounced reduction in bone erosion; attenuated joint inflammation (infiltration); dose-dependent inhibition of /¡-glucuronidase activity in the synovial fluid

Inhibition of inflammatory cell infiltration of colonic tissue; decreased myeloperoxidase activity, indicating reduction of neutrophil infiltration; reduced damage score

Although nitric oxide produced during inflammatory responses by the inducible form of nitric oxide synthase (iNOS) plays a vital role in the killing of intracellular pathogens, excessive levels can have harmful effects, particularly in the systemic circulation. The effects of Spirulina and phycocyanin on systemic production of nitric oxide, measured as serum nitrite concentrations, contrast with those described above in macrophages.7 Spirulina given orally to mice did not affect serum nitrite levels by itself, but inhibited the gentamycin-induced increase in serum nitrite concentrations in a dose-dependent manner.22 Similar results were obtained in animals treated with cisplatin.23 Oral administration of phycocyanin 1 h before intraperitoneal injection of LPS dose dependently and significantly reduced the LPS-induced rise in serum nitrite levels.16 Similarly, intraperitoneal administration of phycocyanin significantly reversed the increase in serum nitrite concentrations resulting from the administration of thyroid hormone.9 In addition, it inhibited the concomitant increase in liver iNOS activity to the levels seen in control animals.

Animal Models of Inflammatory Diseases

Rheumatoid arthritis is an autoimmune disease characterized by chronic inflammation of various joints, resulting in joint erosion. In an animal model of rheumatoid arthritis, oral administration of S.fusiformis (800 mg/kg per day) from Day 11 to Day 18 after arthritis induction resulted in significant suppression of inflammation24 (see also Table 8.1). In a different model Spirulina given orally for 8 days, starting 4 days after induction of arthritis, also significantly reduced inflammation and joint destruction.25 The higher dose (400 mg/kg) provided markedly better protection than the lower dose (100 mg/kg), but both were significantly less effective than the reference compound, triamcinolone. Orally administered phycocyanin at doses of 25, 50, or 100 mg/kg significantly inhibited inflammation and structural joint damage in the same model.26 Note that four-fold higher doses of Spirulina were required to obtain similar anti-inflammatory effects as seen after treatment with phycocyanin. Since phycocyanin constitutes ~20% of Spirulina dry weight, these observations are consistent with the hypothesis that phycocyanin is mainly responsible for the anti-inflammatory activity of this alga in experimental arthritis. However, that still leaves the question of why the anti-inflammatory effects of phycocyanin in Spirulina predominate in this model whereas the proinflammatory activity of other constituents prevails in others.

Orally administered phycocyanin also showed anti-inflammatory activity in acetic acid-induced colitis, an animal model of inflammatory bowel disease.27 Pretreatment with various doses of phycocyanin 30 min before the induction of colitis dose depend-ently inhibited both inflammation and histological damage. It also markedly reduced myeloperoxidase activity, a marker of neutrophil infiltration, which has been shown to correlate with the severity of the damage to the intestinal mucosa.

Allergic Inflammation

Allergic inflammation involves the same types of mediators as other inflammatory responses, but they are induced by IgE antibodies binding to mast cells and thereby triggering the release of preformed and newly synthesized inflammatory agents from these cells. Among these agents, the histamine plays a central role. Anaphylaxis is a severe and potentially life-threatening systemic allergic reaction caused by IgE-mediated release of mediators from mast cells and basophils. Like other allergic reactions, anaphylaxis requires previous sensitization to the triggering antigen.

Spirulina or phycocyanin supplementation does not enhance sensitization to allergens, as demonstrated by the findings that antigen-specific IgE levels do not differ significantly in different unsupplemented and supplemented animals sensitized to either shrimp extract or ovalbumin (OVA).28,29 Prolonged supplementation with phycocyanin may even suppress antigen-specific IgE production.29

There is growing evidence that, once allergic sensitization has occurred, Spirulina and phycocyanin can reduce the inflammatory response to allergen exposure in vitro and in animals. In vitro, brief preincubation of rat peritoneal mast cells with S. platen-sis was shown to result in significant inhibition of histamine release and TNF-a production mediated by IgE or compound 48/80, a histamine-releasing agent.30 At a concentration of 1 ^g/mL, Spirulina yielded 80% and 60% inhibition of IgE-mediated and 48/80-induced histamine release, respectively. Methanolic extracts of the same Spirulina species also inhibited compound 48/80-induced histamine release in another study.31 Interestingly, after size fractionation, most fractions exhibited significant inhibitory activity. This suggests that Spirulina contains diverse agents capable of suppressing mast cell histamine release. Other researchers showed that one of these constituents is phycocyanin, which dose dependently inhibited compound 48/80-induced histamine release from rat peritoneal mast cells.32 Note that the concentration required to obtain ~60% inhibition was three orders of magnitude higher than the effective dose of whole Spirulina in the previously discussed study (3 mg/mL vs. 1 ^g/mL).30 This lends further support to the suggestion that Spirulina contains several constituents capable of inhibiting the release of histamine from mast cells, at least in vitro.

When S. platensis powder suspended in saline was injected intraperitoneally 1 h before the induction of systemic anaphylaxis with compound 48/80, it dose depend-ently reduced mortality in rats.30,33 Spirulina products from two providers were used in these studies and exhibited different effectiveness, one providing complete protection at doses >500 mg/kg,30 and the other preventing mortality at doses >100 mg/kg.33 In one of these studies, prevention of anaphylaxis was associated with a significant and dose-dependent decrease in serum histamine concentrations,33 suggesting that the inhibition of histamine release constituted a major antianaphylactic mechanism. In the same study, Spirulina inhibited passive cutaneous anaphylaxis induced by local injection of anti-DNP IgE and intravenous antigen challenge.

Oral pretreatment with phycocyanin significantly reduced the IgE-mediated inflammatory response (ear swelling) to intracutaneous challenge with OVA following intraperitoneal sensitization.32 It also inhibited myeloperoxidase activity, a marker of neutrophil infiltration. This may have been due to the ability of phycocyanin to reduce the production of leukotriene B4,18 a substance that attracts neutrophils to the site of inflammation. Note, however, that phycocyanin at doses of 100-300 mg/kg was a much weaker inhibitor than the reference compound triamcinolone at 10 mg/kg. In another experiment reported in the same paper, oral phycocyanin dampened the skin reactions resulting from injection of histamine or of the histamine-releasing compound 48/80. This suggests that prevention of histamine release is not the only mechanism by which phycocyanin, and possibly also Spirulina, protect from allergic inflammation.

The cytokine IL-4 is known to play a central role in the production of IgE antibodies by B cells and the activation of several other cell types involved in the processes thatlead to allergic symptoms. When peripheral blood mononuclear cells from healthy volunteers were incubated with the soluble fraction of a Spirulina supplement, their IL-4 production was significantly increased compared to cells incubated in medium alone.13 The mitogen PHA induced markedly higher levels of this cytokine, and these were further enhanced (by up to fourfold) in the presence of Spirulina. This suggested the possibility that this alga could enhance allergic reactions. However, incubation with Spirulina alone also resulted in a 13-fold increase in IFN-y synthesis and in combination with PHA induced significantly greater production of this cytokine than seen with PHA alone. IFN-y can antagonize many of the functions of IL-4, and it is the ratio between these two cytokines, rather than their absolute levels, that determines the nature of the immune response. Nevertheless, the increase in IFN-y production, though pronounced, was not statistically significant owing to high variability in the responses of individual subjects. This suggests that, in some individuals, the ability of Spirulina to induce IFN-y production might not be strong enough to counterbalance the rise in IL-4.

In a recent placebo-controlled trial, 36 patients with allergic rhinitis were assigned to one of three groups receiving 1000 mg/d or 2000 mg/d of a Spirulina-based dietary supplement or placebo, respectively.34 Before and after 12 weeks of supplementation, the ability of peripheral blood mononuclear cells, to produce certain cytokines in response to stimulation (with PHA) was examined. The higher, but not the lower, dose of Spirulina was associated with a significant reduction in the secretion of IL-4 compared to the baseline values of this group. Two other cytokines that could oppose the production of IL-4, IL-2, and IFN-y, were not significantly affected by consumption of Spirulina. It remains to be established whether the discrepancies between the in vitro and in vivo cytokine responses are due to differential effects of Spirulina in healthy and allergic subjects or to differences between in vitro and in vivo conditions.

NK Cells

Natural killer (NK) cells represent another arm of the innate immune system. One of their main functions is to kill virus-infected cells, and they also play an important role in the destruction of certain types of tumor cells. Newly hatched chicks whose diet was supplemented with Spirulina for 7 weeks exhibited significantly enhanced NK cell cytotoxic activity compared to unsupplemented controls.6 Oral administration of a hot water extract of Spirulina to four human volunteers for 4 weeks markedly increased the cytolytic activity of NK cells in two of them, but did not further augment it in the two other subjects, who exhibited high NK activity at baseline.35 NK cells are an important source of interferon (IFN)-y, a cytokine that activates macrophages and induces other immune responses vital for the elimination of intracellular pathogens. Spirulina supplementation was associated with significant production of IFN-y by NK

cells after stimulation with IL-12 and with even higher responses to the combination of IL-12 andIL-18. Both are well known inducers of IFN-y, but were unable to elicit detectable levels of this cytokine in NK cells obtained before supplementation with Spirulina.

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