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H. Bazan, S. Esquenazi, V. Bui, J. He, D.B. Kim, N.G. Bazan; Topical Combination of NGF and DHA Increases Corneal Nerve Regeneration After PRK in Rabbits . Invest. Ophthalmol. Vis. Sci. 2005;46(13):2148.
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Purpose: The polyunsaturated fatty acid docosahexaenoic acid (DHA) is enriched in neurons including nerve fibers and nerve endings (J Lipid Res,44:2221, 2003). A DHA–derived messenger, neuroprotectin (NPD1), promotes cell survival by inhibiting proinflammatory gene expression and modulating Bcl–2 pro– and anti–apoptotic protein expression (PNAS,101:8491, 2004). Here, we tested in a rabbit PRK model the hypothesis that DHA in combination with NGF promotes corneal nerve regeneration. Methods: Unilateral PRK was performed in 21 New Zealand albino rabbits. Three groups, each consisting of six rabbits, were randomized to receive twice–per–week treatments with DHA, NGF, or NGF plus DHA, delivered by collagen shields. A fourth control group received treatment with albumin. Rabbits were monitored for 8 weeks and tear–secretion tests were conducted every 15 days. The eyes were prepared for immunostaining with monoclonal antibodies for class III ß tubulin, calcitonin gene–related peptide (CGRP), substance P, and Ki–67. The nerve areas were calculated with an Image Pro Plus 4.5 program. Results: There were no significant differences in the tear–secretion tests among the four groups. However, no eyes treated with DHA + NGF developed rose Bengal–positive staining at 1 month after PRK, compared with 50% in the control group and 33% in the DHA–treated group. A higher percentage of Ki–67–positive cells was observed in the DHA+NGF– and NGF–treated groups, compared with DHA alone or controls. The tubulin–positive sub–basal nerve bundle area was 3.1 mm/mm² in the DHA+NGF group, 2.15 mm/mm2 in the NGF group, 1.4 mm/mm2 in the DHA group, and 0.85 mm/mm2 in the control group. The CGRP–positive sub–basal nerve bundle areas were 1.9 mm/mm2, 1.45 mm/mm2, 0.85 mm/mm2, and 0.62 mm/mm2 for the DHA+NGF, NGF, DHA, and control groups, respectively. No differences were noted in the SP–positive nerve bundles with the treatments. Conclusions: Topical NGF plus DHA treatment after PRK in rabbits is associated with increased corneal nerve surface area and less rose bengal staining compared with NGF, DHA, or vehicle control alone. A growth factor–mediated DHA utilization, as a component of corneal nerve cell membrane phospholipids and/or as a precursor of pro–survival NPD1, may modulate corneal nerve regeneration after PRK. NGF plus DHA yielded faster functional nerve recovery after PRK, and may be used to treat post–PRK dry eye or other neurotrophic keratopathies
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