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P. K. Mukherjee, K. Meerovitch, T. Lama, H. U. Saragovi, N. G. Bazan; Neurotrophins Peptidomimetics Protect Retinal Pigment Epithelial (RPE) Cells Against Oxidative Stress-induced Apoptosis. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2163.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal degenerations trigger complex cell-signaling pathways leading to RPE and photoreceptor cell apoptosis. Neurotrophins induce RPE cell survival and are agonists of neuroprotectin D1 (NPD1) synthesis that, in turn, downregulates oxidative stress-induced apoptosis (PNAS 104:13152;2007). The aim of this study was to assess the bioactivity of peptidomimetic agonists of neurotrophin receptors during oxidative stress-induced apoptosis in RPE cells.
APRE19 cells were plated in complete media, then serum deprived for 8h and exposed to oxidative stress (TNF and H2O2), in the presence or absence of test articles or controls for 16h. Apoptosis was quantified as the percentage of dead cells over total cells by counting nuclei stained with Hoechst reagent. Test articles included Nerve Growth Factor (NGF, an agonist of TrkA and p75 receptors), Neurotrophin-3 (NT-3, an agonist of TrkC and p75 receptors), agonistic antibodies directed to TrkA or TrkC, and four peptidomimetics that are selective agonists of TrkA and/or TrkC (D3, 3Ak, 3Ae, and 3Aa).
Oxidative stress resulted in 94% apoptotic death of APRE19 cells. Neurotrophins NGF and NT-3 (4 nM) reduced the death of APRE19 cells to ~80%. Anti-receptor antibodies to TrkA and TrkC (50 nM) promoted 50% cell survival. Peptidomimetic agonists of TrkA/TrkC (25 uM) afforded a robust protection from apoptosis, in a dose dependent manner. Treatment with mimetics 3Ae, 3Ak, D3, 3Aa resulted in reduced apoptosis to 16%, 24%, 29%, and 50%, respectively.
Pharmacological agonism of TrkA and/or TrkC receptors protect RPE cells from oxidative-stress apoptosis. These receptors are therefore potential targets for therapy of retinal degenerations. Selective Trk agonists are more effective than the natural neurotrophin ligands, suggesting that agonism of p75 coreceptor may not be desirable. Future work will address the potential significance of the p75 neurotrophin receptor.
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