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Jasmine Elison, Yongdong Zhou, Jennifer J. Lentz, William C. Gordon, Nicolas G. Bazan; Lau-0901 Modulation Of Inflammatory Cytokine Signaling In A Rat Model Of Lps-induced Uveitis. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2747.
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Platelet activating factor (PAF), a lipid mediator, is a component of the inflammatory response, activating release of arachidonic acid and production of prostaglandins in the eye. Inflammation and increased vascular permeability result. The purpose of this study is to investigate the modulatory action of LAU-0901 (a novel small molecule PAF receptor antagonist) on inflammatory cytokines in response to treatment of uveitis.
Uveitis was induced in Lewis rats by injecting 100 ul (200 ug) of lipopolysaccharide (LPS) into their right hind paw. 1 ul/g of LAU-0901 [60 ug/ul] was injected intraperitoneally 4 h after LPS injection and was repeated 16 h after the first injection. Groups of 5 animals were used for each treatment. Treatments included: uveitis-induced, uveitis-induced plus LAU-0901, no uveitis plus LAU-0901, and no uveitis plus no LAU-0901 (naïve control). The LAU-0901 vehicle was 45% cyclodextran in saline. This same experiment was repeated with the same number of animals (for each treatment, n = 8-10 animals). Fundus imaging (Topcon slitlamp) and Spectral Domain Ocular Coherence Tomography (SD OCT) (Heidelberg Engineering) were used for anterior segment photography and posterior pole OCT. Rats were euthanized 4 h after the second LAU-0901 injection in this 24 h model, and aqueous humor was collected. Aqueous protein was quantified (BioRad Protein Assay) and cytokines were quantified from aqueous humor according to directions on the Quantikine Immunoassay kits.
SD-OCT revealed many punctuate spots within the vitreous along the inner surface of the retina in the uveitis treatments but almost no spots in the uveitis plus LAU-0901 treatments; no spots were observed in non-uveitis treatments. Histology showed these spots to be individual cells within the vitreous. Aqueous analysis of total protein levels, compared with controls, revealed an increase in total protein in uveitis animals, but LAU-0901 treatment resulted in a reduction in inflammation. ELISA analysis of aqueous humor for TNF-alpha showed 1.6 ±2.9 pg/ml in naïve control animals, and 83.9 ±18.1, 8.2 ±8.9, and 2.8 ±2.7 in uveitis, uveitis + LAU-0901, and LAU-0901 alone, respectively.
Based on ocular analysis by SD-OCT, histology, and ELISA analysis for cytokine expression in aqueous humor, the PAF antagonist LAU-0901 greatly reduces inflammation in a rat model of anterior uveitis. Thus, LAU-0901 may be an alternative or adjunctive treatment for ocular inflammation.
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