Research Article: Silibinin treatment prevents endotoxin-induced uveitis in rats in vivo and in vitro

Date Published: April 4, 2017

Publisher: Public Library of Science

Author(s): Ching-Long Chen, Jiann-Torng Chen, Chang-Min Liang, Ming-Cheng Tai, Da-Wen Lu, Yi-Hao Chen, Partha Mukhopadhyay.


Uveitis, an intraocular inflammatory disease, occurs mostly in young people and can result in the loss of socioeconomic capabilities. Silibinin has been shown to exert anti-inflammatory effects in human retinal pigment epithelial (RPE) cells. The present study investigated the anti-inflammatory effect of silibinin pretreatment on endotoxin-induced uveitis (EIU) in rats and the mechanisms by which it exerts these effects. Uveitis was induced via injection of lipopolysaccharides (LPS) into Lewis rats. Twenty-four hours after the LPS injection, histological examination showed that silibinin decreased inflammatory cell infiltration in the anterior segment of the eyes of LPS-treated rats. Analyses of the aqueous humor showed that silibinin decreased cell infiltration, protein concentration, nitric oxide (NO), and prostaglandin (PG)-E2 production. Western blot analysis indicated that silibinin decreased the expression of inducible NO synthase (iNOS), cyclooxygenase (COX-2), and phosphorylated IkB in the iris-ciliary body (ICB). Immunohistochemistry showed that silibinin decreased intercellular adhesion molecule (ICAM-1) expression in the ICB. In addition, western blot analysis showed that silibinin attenuated the expression of iNOS, COX-2, ICAM-1, and nuclear p65 in LPS-treated RAW cells. In conclusion, silibinin pretreatment prevents EIU and the subsequent production of proinflammatory mediators and ICAM-1, at least in part, by blocking the NF-κB–dependent signaling pathway both in vivo and in vitro. These effects may contribute to the silibinin-mediated preventive effects on intraocular inflammatory diseases such as acute uveitis.

Partial Text

Uveitis is an intraocular inflammatory disease that can affect any part of the eye and cause serious complications. It accounts for 10–15% of the number of cases of total blindness and up to 20% of the cases of legal blindness in developed countries.[1, 2] It occurs mostly in young people and can result in loss of the patient’s independence and socioeconomic capabilities.[3] Currently, the therapeutic strategy to combat uveitis is to suppress inflammation and therefore corticosteroids are the mainstay of therapy;[4] however, corticosteroids can cause many unwanted ocular side effects, including accelerated cataract formation, increased intraocular pressure,[5, 6] and systemic side effects such as hypertension, diabetes, Cushing’s syndrome, and osteoporosis.[7] Therefore, investigating the mechanisms of intraocular inflammation and developing effective preventive agents for uveitis remain important issues.

Previously, we have reported that silibinin effectively suppresses TNF-α and IFN-γ-induced ICAM-1 expression and synthesis by inhibiting NF-κB activity in human RPE cells[23]; however, to the best of our knowledge, the effects of silibinin on EIU and its mechanism of action have not been clearly elucidated. In the present study, we have initiated an investigation into the anti-inflammatory effects and the possible mechanism employed by silibinin in a protective role against EIU in vivo and in vitro. The results of this study show that silibinin significantly attenuated the ocular inflammatory response in rats with EIU, with significant decreases in inflammatory cell infiltration, as well as protein, NO, and PG-E2 concentrations in the AqH. The expression of iNOS, COX-2, and ICAM-1 were also reduced by silibinin administration in the ICBs of LPS-treated rats. In addition, silibinin decreased the expression of phosphorylated IkB in the ICB of LPS-treated rats and consequently suppressed NF-kB activation. Furthermore, we also found that silibinin decreased the expression of iNOS, COX-2, ICAM-1, and nuclear p65 protein in LPS-treated RAW cells. Overall, these results suggest that silibinin attenuates the inflammatory responses of EIU in rats and RAW cells. Therefore, silibinin might be a potent preventative agent to treat acute ocular inflammation.




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