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Y Saishin, Y Saishin, K Takahashi, S Vinores, PA Campochiaro; PKC412 Inhibits Vascular Endothelial Growth Factor(VEGF)-and Prostaglandin E2(PGE2)-Induced Breakdown of the Blood-Retinal Barrier(BRB) . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1272.
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Purpose:There is evidence suggesting that PGs and tumor necrosis factor-a (TNFa) may exert some of their effect on the BRB indirectly through VEGF. To test this hypothesis, we used VEGF receptor kinase inhibitors to determine if blocking VEGF signaling decreased PG- or TNFa-induced BRB breakdown. Methods:Adult C57BL/6 mice were given 50 mg/kg of PKC412 (VEGF receptor, PDGF receptor, and PKC inhibitor), SU1498 (VEGF receptor kinase inhibitor), Glivec (inhibitor of PDGF receptors, c-met, and v-abl), or vehicle by gavage for 3 days and then received an intraocular injection of 1 ml of 10-6 M of VEGF or TNFa, 10-5 M PGE2, or vehicle. After 24 hours, the mice were given an intraperitoneal injection of 1 mCi per gram body weight of [3H]mannitol and 1 hour later, the ratio of CPM per mg retina / CPM per mg lung (retina to lung leakage ratio, RLLR) or kidney (retina to renal leakage ratio, RRLR) were calculated. Results:PKC412 and SU1498 each caused a significant reduction in VEGF-induced BRB breakdown (48% and 30% reduction in the RLLR, respectively) compared to vehicle alone, while treatment with Glivec was no different from treatment with vehicle. PKC412 also caused a significant decrease in PGE2-induced breakdown of the BRB (63% reduction in the RLLR), while treatment with SU1498, or Glivec showed no difference from treatment with vehicle. None of the drugs reduced TNFa-induced breakdown of the BRB. Conclusion:These data do not support the hypothesis that PGE2-induced breakdown of the BRB occurs indirectly through VEGF, however, they suggest that PKC may be involved in the effect of PGE2, which has been implicated in postsurgical and inflammatory macular edema. PKC412 may be useful for treatment of macular edema in multiple disease processes.
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