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Chadi Mehanna, Norbert Minet, Marie-Chritine Naud, Celine Olmiere, Jean-Louis Bourges, Francine Behar-Cohen; Anti-Inflammatory Effects of NOV C-ter in the Endotoxin-Induced Uveitis model: Down-regulation of Pro-inflammatory Cytokines. Invest. Ophthalmol. Vis. Sci. 2013;54(15):109. doi: https://doi.org/.
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To study the possible mechanisms of action involved in the anti-inflammatory effects observed with NOV C-ter (Sisene, France) in the endotoxin-induced uveitis (EIU) model.
Lewis male rats (6-8 weeks old) were anesthetized and uveitis was induced by footpad injection of 100 µl (2mg/ml) of LPS (Sigma-Aldrich, France). Intra-vitreous injections (5µl) of the products were performed at the same time and inflammation was assessed at 16h by a blind observer. Rats were randomly assigned to the following groups (3 rats each): LPS (6 eyes), NOV C-ter 1.25 µg (6 eyes), NOV C-ter 2.5 µg (5 eyes) and NOV C-ter 5µg (4 eyes). After the clinical grading of uveitis, animals were euthanized and irises and ciliary bodies were extracted and snap frozen. Real-time PCR analysis was performed to evaluate the expression of several genes: VEGF, VEGF-R1, VEGF-R2, IL-1β, IL-6, TNF-α, MCP-1, Cox-2, Hey-1, Notch-1 and Jagged-1. A second experiment was performed to compare the clinical effects of sub-conjunctival injections of NOV C-ter 15 µg (6 eyes) to intra-vitreous injections of NOV C-ter 2.5 µg (5 eyes), dexamethasone 20 µg (6 eyes) and PBS (6 eyes). Inflammation was assessed at 16h by a blind observer.
NOV C-ter exerted a significant anti-inflammatory effect with a U-shaped dose-response, as inflammation was lower than in the PBS group for the doses 1.25 µg (P < 0.01) and 2.5 µg (P < 0.05). NOV C-ter 2.5 µg was as effective as dexamethasone 20 µg. Real-time PCR analysis of the irises and ciliary bodies showed no significant effects on the expression of VEGF, VEGF-R1, VEGF-R2, COX-2, Hey-1, Notch-1 and Jagged-1. IL-6 was significantly downregulated by NOV 2.5 µg (P = 0.009). IL-1β, TNF-α, and MCP-1 were significantly downregulated but to a lesser extent.
Anti-inflammatory effects observed for NOV C-ter, in the endotoxin-induced uveitis model, seem to be mediated by a downregulation of pro-inflammatory cytokines, mainly IL-6, IL-1β, TNF-α and MCP-1.
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