Topical Combination of NGF and DHA Increases Rabbit Corneal Nerve Regeneration after Photorefractive Keratectomy

Esquenazi, Salomon; Bazán, Haydee E. P.; Bui, Viet Trang; He, Jiucheng; Kim, Dooho B.; Bazán, Nicolás G.

doi:10.1167/iovs.05-0241

Cited by 89 publications

(67 citation statements)

References 26 publications

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“…Neurotrophins are survival signals, in addition to being modulators of neurite branching, synaptogenesis, and synaptic plasticity (33,34). In this regard, nerve growth factor and DHA activate nerve regeneration after experimental cornea injury (35). Thus, the ability of neurotrophins to promote cell survival through NPD1 in the RPE cell, as described here, is also highly relevant to the response of the nervous system to injury and neurodegeneration.…”

Section: Discussionmentioning

confidence: 76%

Neurotrophins enhance retinal pigment epithelial cell survival through neuroprotectin D1 signaling

Mukherjee

Marcheselli

Barreiro

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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152

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Integrity of retinal pigment epithelial cells is necessary for photoreceptor survival and vision. The essential omega-3 fatty acid, docosahexaenoic acid, attains its highest concentration in the human body in photoreceptors and is assumed to be a target for lipid peroxidation during cell damage. We have previously shown, in contrast, that docosahexaenoic acid is also the precursor of neuroprotectin D1 (NPD1), which now we demonstrate, acts against apoptosis mediated by A2E, a byproduct of phototransduction that becomes toxic when it accumulates in aging retinal pigment epithelial (RPE) cells and in some inherited retinal degenerations. Furthermore, we show that neurotrophins, particularly pigment epithelium-derived factor, induce NPD1 synthesis and its polarized apical secretion. Moreover, docosahexaenoic acid (DHA) elicits a concentration-dependent and selective potentiation of pigment epithelial-derived factor-stimulated NPD1 synthesis and release through the apical RPE cell surface. The bioactivity of signaling activated by pigment epithelium-derived factor and DHA uncovered synergistic cytoprotection with concomitant NPD1 synthesis when cells were challenged with oxidative stress. Also, DHA and pigment epithelium-derived factor synergistically modify the expression of Bcl-2 family members, activating antiapoptotic proteins and decreasing proapoptotic proteins, and by attenuating caspase 3 activation during oxidative stress. Thus, our findings demonstrate that DHA-derived NPD1 protects against RPE cell damage mediated by aging/disease-induced A2E accumulation. Also, our results identify neurotrophins as regulators of NPD1 and of its polarized apical efflux from RPE cells. Taken together, these findings imply NPD1 may elicit autocrine actions on RPE cells and paracrine bioactivity in cells located in the proximity of the interphotoreceptor matrix.docosahexaenoic acid ͉ pigment epithelial-derived factor P hotoreceptor outer segment renewal is a process whereby new membranous disks containing the phototransduction apparatus are constitutively assembled at the proximal end of this lightsensitive structure, and the oldest disks are intermittently shed from the distal outer segment (1). The process of shedding is accompanied by phagocytosis of the disk membranes by the retinal pigment epithelium (RPE), a blood barrier-forming monolayer of polarized cells whose apical surface is in close contact with the distal outer segment and whose basal surface faces the capillary bed nourishing the photoreceptor cells. The RPE provides important nutrients to the photoreceptors and all-trans retinol (vitamin A), the precursor to the visual pigment chromophore for vision (2, 3), and docosahexaenoic acid (DHA) (22:6; n Ϫ 3), both of which are continuously recycled between the RPE and the rod and cone photoreceptor cells (4). The RPE also provides neurotrophins essential for photoreceptor cell survival (5). These critical RPE functions render it essential for photoreceptor cell survival and normal vision.DHA, a member of the essent...

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Section: Discussionmentioning

confidence: 76%

Neurotrophins enhance retinal pigment epithelial cell survival through neuroprotectin D1 signaling

Mukherjee

Marcheselli

Barreiro

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

152

140

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“…6 Also, animal studies have shown that NGF increases corneal cell proliferation in rabbits and dogs. 10,11 In the present study, we used hens as a better model to reproduce in vivo human corneal wound healing. [27][28][29][30][31][32][33][34][35][36] In addition, we tested the in vitro effects of NGF using Telomerase-immortalized HCLEs in contrast to previous works concentrated on the effect of NGF on corneal fibroblasts and conjunctiva epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…1 Clinical experience has shown that topical administration of NGF improves epithelial healing in patients with neurotrophic corneal ulceration [2][3][4][5] or after cataract surgery 6 and is also used to treat inflammation. 7,8 Animal models have also shown NGF benefits in corneal wound healing and nerve regeneration [9][10][11] ; however, detailed mechanisms by which NGF elicits its effect on the corneal surface remains unknown.…”

mentioning

confidence: 99%

Nerve Growth Factor Promotes Corneal Epithelial Migration by Enhancing Expression of Matrix Metalloprotease-9

Blanco–Mezquita

Martínez‐García

Proença

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Nerve growth factor (NGF) is a neuropeptide essential for the development, survival, growth, and differentiation of corneal cells. Its effects are mediated by both TrkA and p75 receptors. Clinically relevant use of NGF was introduced to treat neurotrophic ulcerations in patients. Herein, we examine the mechanisms by which NGF enhances epithelial wound healing both in vivo and in vitro.METHODS. An animal model using adult hens was implemented for the in vivo experiments. Laser ablation keratectomy was performed and animals were observed for up to 7 days. Epithelial healing was measured with fluorescein. In addition, proliferation was measured using BrdU incorporation and both TrkA and matrix metalloprotease-9 (MMP-9) expression were measured by immunohistochemistry (IHC) and Western blot (WB). In vitro experiments were carried out with telomerase-immortalized human corneal epithelial cells (HCLE). The rate of proliferation was measured using a colorimetric assay and BrdU incorporation. Realtime migration was evaluated with an inverted microscope. MMP-9 expression was evaluated by immunocytochemistry (ICC), WB, zymography, and RT-PCR. Finally, beta-4 integrin (b4) expression was assessed by ICC and WB.RESULTS. Faster epithelial healing was observed in NGF-treated corneas compared with controls (P < 0.01). These corneas showed increased proliferation, TrkA upregulation, and enhanced MMP-9 presence (P < 0.01). In vitro, faster spreading and migration were observed in response to NGF (P < 0.01). Enhanced proliferation, as well as enhanced TrkA and MMP-9 expression, and decreased b4 levels were observed after adding NGF (P < 0.01).CONCLUSIONS. NGF plays a major role during the epithelial healing process by promoting migration, a process that is accelerated by cell spreading. This effect is mediated by both the upregulation of MMP-9 and cleavage of b4 integrin.

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“…Topical administration of these dietary compounds and their derivatives has also been investigated in animal models but this is not the subject of this review (Cortina et al, 2010;Esquenazi et al, 2005;Li et al, 2010;Rashid et al, 2008).…”

Section: Micronutrient Supplementation/dietary Nutraceuticalsmentioning

confidence: 99%

Diet, nutraceuticals and the tear film

Jalbert

2013

Experimental Eye Research

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Topical Combination of NGF and DHA Increases Rabbit Corneal Nerve Regeneration after Photorefractive Keratectomy

Cited by 89 publications

References 26 publications

Neurotrophins enhance retinal pigment epithelial cell survival through neuroprotectin D1 signaling

Neurotrophins enhance retinal pigment epithelial cell survival through neuroprotectin D1 signaling

Nerve Growth Factor Promotes Corneal Epithelial Migration by Enhancing Expression of Matrix Metalloprotease-9

Diet, nutraceuticals and the tear film

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