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Enrique J De La Rosa, A. M. Hernandez-Pinto, M. Marchena, J. L. M. San-Martin, P. Fernandez, F. de Pablo, M. Morales; Retinal ganglion cell death is attenuated by a PI3K activating synthetic peptide. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1750.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal ganglion cell (RGC) damage and loss is a common trait of several retinal diseases, including glaucoma. RGC loss, leading to visual impairment, seems to be mediated by programed cell death. Therefore, activation of survival pathways, such as that of PI3K/Akt, is a potential therapeutical target to delay retinal degeneration. The aim of this study is to test in retinal explants the effect of PTD4-PI3KAc, a synthetic peptide combining a PI3K activator and a membrane transductor, on NMDA-induced RGC excitotoxicity and death.
Activation of PI3K was by the PTD4-PI3KAc peptide, which consists in a transduction domain, PTD4 (Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg), fused to a phosphopeptide containing the intracellular phosphorylated domain of the PDGF receptor C-terminus (Gly-Ser-Asp-Gly-Gly-pTyr-Met-Asp-Met-Ser). PTD4-PI3KAc effect was monitored by measuring Akt phosphorylation in the SH-SY5Y human cell line as well as by determining survival of NMDA-treated rat hippocampal neurons in culture. C57BL/6 mouse retinal explants were cultured 48 h in the presence of 50 µM NMDA alone or together with IGF-I (10 nM) or PTD4-PI3KAc (25 µM). RGC death was determined by TUNEL.
PTD4-PI3KAc treatment of SH-SY5Y cells induced an 162%-increase of phospho-AKT(S473) levels in comparison with the control peptide. Further, PTD4-PI3KAc reduced by 34% the death of NMDA-treated rat hippocampal neurons. NMDA treatment of retinal explants induced a consistent RGC death that was reduced by 80% in the presence of PTD4-PI3KAc and by 88% in the presence of IGF-I.
PTD4-PI3KAc attenuates excitotoxic RGC death and may provide a useful drug candidate for the treatment of retinal degenerative diseases.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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