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JB Allen, KA Pittman, T Keng, BC Gilger, CT Privalle, SP Fricker; Nitric Oxide Scavenger AMD6221 Suppresses Endotoxin-Induced Uveitis (EIU) in Rabbits . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3976.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Nitric oxide (NO) is an important mediator in ocular inflammation. We have shown that overproduction of NO is involved in EIU in rabbits. Administration of NOS inhibitors can either suppress or exacerbate uveitis depending on the specificity of the inhibitors and timing of administration (Exp Eye Res 62:21-28). The current study evaluated a NO scavenger (ruthenium III polyaminocarboxylate; [Ru(H3dtpa)Cl], AMD6221) as an innovative treatment on development and severity of uveitis. Methods: Right eyes of New Zealand white rabbits (n=12/group) were injected intravitreally with LPS (20 ng) and AMD6221 (3.85 mM) or control vehicle (AMD3689, the stable nitrosylated derivative of AMD6221; 3.85 mM) or saline vehicle; left eyes received saline and AMD6221 or AMD3689 or saline vehicle. Six hours later, eyes that received injections of AMD6221 received a second AMD6221 injection; eyes that received AMD3689 or saline vehicle also received second injections. Uveitic responses were assessed over 24 hours by biomicroscopic examination. Aqueous flare (AF) and iridal hyperemia (IH) were scored on a scale of 0-4. After euthanasia, aqueous humors were aspirated, protein levels and total cell counts measured, and eyes processed for histologic analysis. Results: Co-administration of AMD6221 with LPS followed by administration alone 6 hours later, resulted in a decrease in both AF (2.50.58 vs 0.50.6; P<0.05) and IH (2.5 0.41 vs 0.750.5; P<0.05), compared to LPS+vehicle. In addition, AMD6221 decreased protein extravasation by ∼60% and leukocyte infiltration by ≷90%. Histological analysis confirmed decreased inflammation in LPS+AMD6221-treated eyes. Treatment with the control nitrosylated derivative did not significantly affect the uveitic response. AMD6221 administered alone caused no abnormal ocular changes. Conclusions: NO scavengers that mediate the clearance of harmful levels of NO, preserving beneficial functions of NO, may represent an alternative approach for the treatment of uveitis and other NO-based ocular diseases. Support: NIH grant #EY11364 and funds from the State of North Carolina. CR: E.
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