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M. S. Cortina, J. He, N. Li, J. Fannie, V. L. Marcheselli, N. G. Bazan, H. P. Bazan; "PEDF Plus DHA Enhances Corneal Nerve Regeneration After Experimental Surgery". Invest. Ophthalmol. Vis. Sci. 2008;49(13):2946.
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Sensory nerves exert trophic influences on the corneal epithelium. Damage to these nerves after LASIK or PRK lead to hypoesthesia and impaired wound healing. It also causes a decreased blink reflex and reduction of tear flow, which in turn produces dry eye and consequent damage to the epithelium. Docosahexanoic acid (DHA) is the precursor of neuroprotectin D1 (NPD1), a new lipid mediator that protects retinal pigment epithelial cells and neural cells from oxidative stress. Pigment epithelial-derived growth factor (PEDF) stimulates NPD1 synthesis. We hypothesize that PEDF plus DHA enhances the regeneration of corneal nerves damaged after experimental surgery.
An 8 mm corneal stromal dissection was performed in the left eye of adult New Zealand rabbits. A group of rabbits was treated with DHA + PEDF, and another group with vehicle. In vivo confocal images of the rabbit corneas were obtained at 2, 4 and 8 weeks, and the nerve surface areas were quantified. Rabbits were sacrificed at 8 weeks, and flat mount corneas as well as sections were stained with tubulin βII antibody and analyzed by immunohistochemistry. Images of the nerve surface area of the sub-basal, epithelial and stromal corneal plexus were quantified for each group. A third group of rabbits were sacrificed at 1 and 2 weeks, lipids were extracted from cornea, and LC-PDA-ESI-MS-MS-based lipidomic analysis was performed.
Confocal images at 2 and 4 weeks after surgery showed a 2.5 fold increase in corneal nerve surface area in the group treated with PEDF+DHA compared with the control group. Quantification of the sub-basal corneal nerve plexus area by immunofluorescence at 8 weeks showed a significant increase in the nerve surface area in rabbits treated with PEDF+ DHA versus controls ( 31.1 ± 0.03 % vs 8.7% ± 0.01 % respectively; p=0.0031). NPD1 accumulation measured by LC-tandem mass spectrometry peaked at 1 week and was four times higher in the PEDF+DHA treated group when compared with controls.
Our experiments show that PEDF plus DHA promotes regeneration of damaged corneal nerves. This signaling may be targeted in neurotrophic keratitis, dry eye after refractive surgery, and other corneal diseases. The neurotrophin-mediated synthesis of NPD1 is suggested by the demonstration of its accumulation upon the addition of its precursor (DHA) and of PEDF. Thus we conclude that this signaling mechanism upregulates cornea nerve regeneration.
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