Effects of fucoxanthin on lipopolysaccharide-induced inflammation in vitro and in vivo
Introduction
Endotoxin-induced uveitis (EIU) is an acute anterior segment intraocular inflammation that can be induced by injection of lipopolysaccharide (LPS) (Bhattacherjee et al., 1983, Hikita et al., 1995, Suzuma et al., 1998). It has been suggested that this phenomenon could serve as a model for certain types of human uveitis such as those associated with seronegative arthritis, where a gram-negative bacteria may play a role in the pathogenesis (Rosenbaum et al., 1980). The inflammatory response in EIU is characterized by a breakdown of the blood-aqueous barrier and is cell-mediated with leakage of proteins into the anterior chamber of the eye and infiltration with a large number of inflammatory cells. Exposure to LPS stimulates cellular inflammatory responses, and releases factors such as cytokines (Hoekzema et al., 1991, Tracey and Cerami, 1994) and chemokines (Tuaillon et al., 2001).
Prostaglandin (PG)-E2 is a major cyclooxygenase (COX) product at inflammatory sites where it contributes to local blood flow increases, edema formation, and pain sensitization. We have previously reported that the PGE2 levels in the aqueous humour significantly increase in EIU, and therefore these data suggest that COX plays an important role in EIU (Shiratori et al., 2004). Also, one of the responses in the eye to LPS injection is the generation of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) (Goureau et al., 1995, McMenamin and Crewe, 1997). In addition, LPS and pro-inflammation cytokines induce iNOS in macrophages, neutrophils and endothelial cells, which can further contribute to the levels of nitric oxide in the eye during EIU (Mandai et al., 1994).
Carotenoids have been demonstrated to have beneficial effects on health. Fucoxanthin is a carotenoid that is found in common edible seaweed, such as Hijikia fusiformis, Undaria pinnatifida and Sargassum fulvellum. The chemical structures of fucoxanthin are shown in Fig. 1. Many biological functions of this compound have been studied, including cancer-preventing (Kotake-Nara et al., 2001), antimutagenic effects (Nishino, 1998). Recently, Ohgami et al. (2003) reported that carotenoid astaxanthin prevents the inflammation of EIU.
In the present study, we investigated the influence of fucoxanthin on EIU in rats. The anti-inflammatory potency of fucoxanthin in vivo was compared with that of prednisolone. In addition, we also investigated the in vitro concentrations of NO, PGE2, and tumour necrosis factor (TNF)-alpha and the expression of iNOS and COX-2 in RAW 264.7 cells after treatment with fucoxanthin in order to clarify the anti-inflammatory effect. To the best of our knowledge, there have been no reports on the effect of fucoxanthin on ocular inflammation.
Section snippets
Animals groups and EIU
Eight-week-old male Lewis rats were used. The rats weighed about 250 g. EIU was induced by injection into one footpad of 200 μg of LPS from Salmonella typhimurium (Sigma, St. Louis, MO) that had been diluted in 0.2 ml of saline.
The rats were injected intravenously with 0.1, 1 or 10 mg kg−1 fucoxanthin or 10 mg kg−1 prednisolone (Sigma, St. Louis, MO) in a 0.1% dimethyl sulfoxide solution (Sigma, St. Louis, MO) mixed with 0.1 ml phosphate-buffered saline (PBS). Fucoxanthin was isolated from brown algae
Effects on LPS-induced cellular infiltration in the aqueous humour
Cells were not detected in the aqueous humour of the control group. In the LPS group, the number of cells in the aqueous humour was 62.1±11.7×105 cells ml−1. Treatment with 0.1, 1 or 10 mg kg−1 of fucoxanthin showed reduced numbers of cells (0.1 mg kg−1; 27.2±5.5×105 cells ml−1, 1 mg kg−1; 18.3±6.5×105 cells ml−1, 10 mg kg−1; 12.8±3.5×105 cells ml−1). Statistically significant differences were observed (P<0.01) between the LPS and fucoxanthin groups. The effect of 10 mg kg−1 fucoxanthin on the number of cells in
Discussion
In the present study, we investigated the effect of fucoxanthin on EIU in rats. The results of the study indicate that fucoxanthin suppressed the development of EIU in a dose-dependent fashion. The anti-inflammatory activity of 10 mg kg−1 of fucoxanthin was comparable to that of 10 mg kg−1 of prednisolone. Clinical side effects of steroids were often reported, but no side effects of prednisolone were observed in this study.
Three types of NOS isoforms have been identified in cells. Endothelium NOS
Acknowledgements
This work was supported in part by a grant for Research on Sensory and Communicative Disorders, Ministry of Health, Labour and Welfare, Japan, and Uehara memorial foundation.
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