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J.A. Matsubara, X.F. Wang, J. Cui; Inhibitory Effect of Copper Chelators on Ocular Inflammation . Invest. Ophthalmol. Vis. Sci. 2003;44(13):1291.
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Purpose: We investigated the effects of copper chelators on ocular inflammation induced by photocoagulation and photodynamic laser treatment in an animal model. Methods: Sixteen normal Long-Evans rats (400-450g) were pretreated with one of three types of copper chelators adminstered by intraperitoneal injection: DPA (sulfhydryl-containing), TRIEN (polyamine) or TETREN (polyamine) at dosage of 0.5 mmol/kg/day for 7 days prior to photocoagulation laser treatment. Each animal underwent unilateral photocoagulation using a Coherent argon dye laser (545nm). 5 laser burns were made in each eye. In a second study, pigmented rabbits (2-3 kg) were pretreated with TRIEN at a dosage of 0.2 mmol/kg/day for 7 days prior to PDT. The rabbits were given an iv infusion of verteporfin 2 mg/kg via the marginal ear vein. Animals were irradiated with a 689 nm diode laser at 50 J/cm2, 600 mW/cm2, two spots at 5mm. Animals were sacrificed at 24 hours post PDT. Both eyes were enucleated, with the untreated eye serving as control. The enucleated eyes were fixed and processed for histology. Five micra frozen sections were placed on glass slides. Sections were stained with hematoxylin and eosin and retinal thickness measured under 100X magnification. Alternate sections were immunoreacted for ED-1 and HO-1. Results: Results from photocoagulation treatment in rats show that retinal thickness in TRIEN- or TETREN-treated animals was significantly less than that of the control (saline treated) group. The retinal thickness of DPA-treated animals was significantly greater than the control group. Immunohistochemical analysis revealed fewer macrophages, as identified by an antibody against ED-1, were present in the laser sites following laser treatment in TRIEN- and TETREN-treated groups compared to control groups. Results from the rabbits undergoing PDT show that the inducible enzyme, hemeoxidase HO-1, immunoreactivity was significantly upregulated in choroid. Retinal edema, measured by retinal thickness was dramatically reduced in TRIEN-treated rabbits compared to the control group after PDT. Conclusions: Copper chelators inhibit ocular inflammation secondary to laser treatment in the eye. The mechanism of action appears to involve an inhibition of free radical formation by chelating copper, a potent catalyst for the generation of free radicals in tissues. Administration of copper chelators before laser treatment may reduce the unwanted side effects, such as ocular inflammation. Less tissue inflammation after laser treatment can potentially minimize the growth and angiogenic factors produced by retinal cells, and thus limit the recurrence of neovascularization.
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