Their group found that Spirulina pl

Their group found that Spirulina platensis and phycocyanin signifi- cantly reduced lipopolysaccharide-induced lactate dehydro- genase release and inhibited expression of inflammation- related genes iNOS, COX-2, TNF-α, and IL-6. Another disease, tinnitus, arises from an increase in excitatory neu- rotransmission and is associated with N-methyl d-aspartate receptor (NMDA receptor, NR) activity. Pro-inflammatory cytokines lead to tinnitus directly or via modulating NR gene expression (Hwang et al. 2011a, b). In the study of Hwang et al. (2013), a four-day salicylate treatment caused a significant increase in N-methyl d-aspartate receptor sub- unit (2BNR2B), TNF-α, and IL-1β mRNAs expression in the cochlea and inferior colliculus of mice. Dietary supple- mentation with phycocyanin or Spirulina platensis water extract significantly reduced the salicylate-induced tinnitus and downregulated the mRNAs expression of NR2B, TNF- α, IL-1β, and COX-2 in the cochlea and inferior colliculus of mice.Spirulina platensis and Spirulina lonar show anti-pyretic and anti-inflammatory properties. However, Spir‑ ulina platensis is more effective than Spirulina lonar as anti-inflammatory and anti-pyretic agent. The anti-inflam- matory and anti-pyretic properties of Spirulina platensis and Spirulina lonar were evaluated in rat models (Somchit et al. 2014). For anti-inflammatory activity assessment, the reduction in the volume of paw edema induced by pros- taglandin E2 was measured. Rats were dosed orally with 2 or 4 mg/kg of Spirulina platensis or Spirulina lonar. A significant dose-dependent reduction in the diameter of paw edema was observed. Spirulina platensis treatment revealed faster reduction in rectal temperature. Due to its antioxidant and anti-inflammatory activities, Spirulina slowed the development of arthritis in rats and inhibited the development of both macroscopic and microscopic histo- pathological lesions in rats with Freund’s adjuvant-induced arthritis (Ali et al. 2015). In the study conducted by Yogi- anti et al. (2014), the inhibitory effect of dietary Spirulina platensis on UVB-induced skin inflammatory response was evaluated in Ogg1-knockout (KO) mice and the wild- type counterpart. Dietary Spirulina platensis suppressed the tumor induction and development. Moreover, induc- tion of erythema and ear swelling, one of the hallmarks of UVB-induced inflammatory responses, was suppressed in the skin of Ogg1-KO mice and albino hairless mice fed with dietary Spirulina platensis. These findings suggest that Spirulina platensis exerts anti-tumor effects against1830 Arch Toxicol (2016) 90:1817–1840UVB irradiation in the skin through its anti-inflammatory and antioxidant effects. In another study (Muga and Chao 2014), high cholesterol levels enhanced inflammation in hamsters; however, Spirulina platensis diets regulated pro- inflammatory cytokines to near the control levels.In addition to these above animal model studies, some novel anti-inflammatory peptides were purified from the enzymatic hydrolysate of Spirulina maxima (Vo et al. 2013). Purification of the hydrolysate resulted in two pep- tides with amino acid sequences of LDAVNR (P1, 686 Da) and MMLDF (P2, 655 Da). Both P1 and P2 showed a sup- pressive effect on IL-8 expression in histamine-stimulated EA.hy926 endothelial cells. The production of intracellular ROS in the mast and endothelial cells was decreased by P1 or P2. The peptides P1 and P2 from Spirulina maxima could be used as functional ingredients with potent anti- inflammatory benefits.Taken together, from the various animal model experi- ments, the anti-inflammatory effects of Spirulina are an important aspect underlying its use as a treatment for many human and animal diseases. Under normal condi- tions immunomodulatory and anti-inflammatory activities go hand in hand (Wang et al. 2014a, b; Vázquez-Velasco et al. 2014). Due to the anti-inflammatory properties, Spir- ulina shows very efficient ameliorative effects on colitis and arthritis, as well as PD. However, it is worthy to note that all these conclusions are drawn from animal studies; many more studies need to be performed in human subjects if these effects are to be fully validated. Future clinical tri- als are required to establish the anti-inflammatory benefits in human. The immunomodulatory and anti-inflammatory activities of Spirulina and phycocyanin are summarized in Table 3.