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kyung sook cho, Young Hee Yoon, Jeong A Choi, Jae-Young Koh; The anti-ALS drug riluzole attenuates MCP-1 by high glucose, advanced glycation end product (AGE) or TNF-α in cultured human retinal pericytes. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3244. doi: https://doi.org/.
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The early event of DR is the blood-retinal barrier (BRB) breakdown leading to the increased permeability of blood vessel and the secretion of inflammatory cytokines, resulting in diabetic macular edema (DME). In this process, the functional abnormalities and eventual loss of pericytes changes may play a critical role. Riluzole is the only FDA-approved treatment for ALS, and was shown to inhibit PKC βΠ, playing a key role in VEGF signaling. PKC is also implicated in the diabetic-induced pericyte changes. Hence, in the present study, we examined whether riluzole has any effect on the induction of cytokines in a cultured human retinal pericyte (HRP) cell line by possible mediators of diabetic retinopathy.
HRP cell lines were obtained from cell systems and cultured in Dulbecco’s Modified Eagle Medium supplemented with 10% fetal bovine serum and penicillin-streptomycin. After exposure of HRP cells to high glucose (HG), TNF-α, or advanced glycation endproduct (AGE), concentrations of various inflammatory cytokines (MCP-1, Interlukin-6 (IL-6), I-CAM, MMP-2, and VEGF) in the media were measured using Human VersaMAP Multiplex Development System Luminex Screening Assay and Human CCL2/MCP-1 ELISA.
HRP cells were exposed to HG (25 mM) for 72 hrs, or to TNF-α (10 ng/ml) or AGE (500 µg/ml) for 24 hrs. At these concentrations, no cell death was observed in any condition. However, when the levels of cytokines were measured by Luminex and ELISA assay, all these exposure increased levels of MCP-1 in HRP cells; on the other hand, levels of other cytokines such as IL-6 and I-CAM did not change. Indicating that PKC activation mediated increases in the MCP-1 level in these condition, addition of GF109203X (5 µM), a pan-PKC inhibitor, attenuated them. Riluzole (15 µM), a PKC βΠ inhibitor, also reduced the increase in MCP-1 levels induced by all three.
These results indicated that 1) HG, AGE, and TNF-α may activate PKC in retinal pericytes, 2) thus activated PKC may induced MCP-1, and 3) riluzole inhibits the MCP-1 induction, likely by acting as a PKC inhibitor. These results suggest the possibility that riluzole may prove useful in ameliorating diabetic retinopathy.
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