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17 January 2019 : Animal Research  

Gamma-Secretase Inhibitor, DAPT, Prevents the Development of Retinopathy of Prematurity in a Rat Model by Regulating the Delta-Like Ligand 4/Notch Homolog-1 (DLL4/Notch-1) Pathway

Wei Sun1ABCE, Jing Li1BE, Yinan Li2AD, Jiao Zheng1CF, Xiaoming Zhang1BD, Xuelin Huang1BCF*, Shujun Li3ADFG

DOI: 10.12659/MSM.913828

Med Sci Monit 2019; 25:492-499

Abstract

BACKGROUND: Retinopathy of prematurity (ROP), or retrolental fibroplasia, affects premature infants who have undergone intensive care with oxygen therapy. This study aimed to investigate the inhibitory effect of the gamma-secretase inhibitor, DAPT, on neovascularization and its mechanism in a rat model of ROP.

MATERIAL AND METHODS: Sixty neonatal Sprague-Dawley (SD) rats included the control group (n=20), the model group (n=20), and the DAPT-treated group (n=20). The rat model of ROP was established using repeat cycles of oxygen inhalation. Enzyme-linked immunosorbent assay (ELISA) measured serum levels of vascular endothelial growth factor (VEGF), VEGF receptor-1 (VEGFR-1), and VEGFR-2. Histology of the retinal tissue included immunohistochemistry for the expression of Notch homolog-1 (Notch-1) and delta-like ligand 4 (DLL4). Retinal mRNA levels of DLL4, Notch-1, VEGF, VEGFR-1, and VEGFR-2 were evaluated with quantitative real-time polymerase chain reaction (qRT-PCR).

RESULTS: The rat model of ROP showed increased serum levels of VEGF, VEGFR-1, and VEGFR-2 compared with the control group, which were decreased in the DAPT group. Histology of the retinal tissue in the model group showed degeneration of the retinal ganglion cells, and immunohistochemistry showed increased expression of Notch-1 and DLL4 compared with the control group and DAPT group. Retinal tissue in the model group had increased mRNA levels of DLL4, Notch-1, VEGF, VEGFR-1, and VEGFR-2 compared with the control group, and the DAPT group.

CONCLUSIONS: In a rat model, treatment with DAPT reduced the retinal changes associated with ROP with a mechanism that involved VEGF and its receptors through the DLL4/Notch-1 pathway.

Keywords: Receptor, Notch1, Receptors, Vascular Endothelial Growth Factor, Retinopathy of Prematurity, Amyloid Precursor Protein Secretases, Animals, Newborn, Dipeptides, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Neovascularization, Pathologic, Signal Transduction, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-1, Vascular Endothelial Growth Factor Receptor-2

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750