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T. Caillaud, T. Amar, A. Ottlecz, M. Wong, G.N. Lambrou, P.–P. Elena; PKC412 Reduces Retinal Neovascularization Induced by Hypoxic Stimuli in Pup Mice . Invest. Ophthalmol. Vis. Sci. 2004;45(13):4062.
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Purpose: The aim of this study was to evaluate the efficacy of CGP41251 (PKC412), a selective inhibitor of protein kinase C (PKC), using a well–known mouse model of retinopathy of prematurity (ROP) in pup mice following topical applications of PKC412 ointments. Methods: Oxygen–induced retinopathy was induced by exposing C57BL/6J 7–day old mice to a 75% oxygen atmosphere for 5 consecutive days. Then, in a normal oxygen atmosphere, pup mice were treated in both eyes with 2–µl ocular applications of 0%, 0.25%, 0.5% or 1% PKC412 ointment twice a day for 6 consecutive days. Since the eyes were still closed at that age, the lids were gently mechanically opened before each administration. A positive control group (75% oxygen, untreated) was also added. Each group consisted of 3 different litters totalizing 15 pups. After treatment, animals were sacrified, eyes removed, fixed in 4% paraformaldehyde / PBS solution, embedded in paraffin wax, cut (8 sections per eye, 2x4 sections apart from the optic nerve), stained with periodic acid Schiff (PAS), hematoxylin and picroindigocarmin. The number of nuclei in neovessels were then counted and statistically compared using a MANOVA LSD test using all sections. Results: Animals weighed 5 to 6 g at sacrifice whatever the treatment. The number of nuclei in retinal neovessels were (mean ± SD; n = 184 to 208 sections): 34.4 ± 19.4 for untreated animals, 31.8 ± 19.9 for placebo ointment, 34.8 ± 19.7 for 0.25% PKC412 ointment, 32.0 ± 14.9 of 0.5% PKC412 ointment and 24.6 ± 15.4 for 1% PKC412 ointment. No difference (p > 0.05) was observed between untreated animals and pups treated with placebo, 0.25% and 0.5% ointments. However, treatment with 1% PKC412 ointment significantly reduced the number of neovessel nuclei compared to untreated animals (28.3% reduction; p < 0.001), or animals treated with placebo ointment (22.5% reduction; p < 0.001), 0.25% PKC412 ointment (29.2% reduction; p < 0.001), and 0.5% PKC412 ointment (23.1% reduction; p < 0.001). Conclusions: In this study, we demonstrated that 1% CGP41251 (PKC412) ointment, administered topically twice a day for 6 consecutive days after hyperoxia, was able to reduce the number of neovessel nuclei (by 28%) when compared to untreated animals or with animals treated with placebo ointment. These results could be related to the kinetics of PKC412 in retina and choroid of pup mice. (see abstract: Elena P.P. et al. "PKC content in retina, choroid and plasma of pup mice with retinal neovascularization induced by hypoxic stimuli.").
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