Topical nerve growth factor ameliorates experimental type 1 diabetic keratopathy.
Shannon Hextrum , Bruce Gaynes, O.D., PharmD , Ping Bu, MD , Andrew Logeman
Edward Hines, Jr. VA Hospital, Hines, Illinois Loyola University Stritch School of Medicine, Department of Ophthalmology, Maywood, IL
Neuropathy is a primary cause of many of
the complications related to diabetes
neurotrophic keratopathy due to abnormal
corneal nerve conductance as well as
dysfunction in retinal electrical signaling.1
Nerve growth factor (NGF) is a signaling
neurotrophin that plays an important role
regulating inflammatory responses, and
maintaining appropriate nerve function.2
Based on the known supportive role of
NGF in maintaining physiologic nerve
activity, it is hypothesized that NGF
would be of benefit in ameliorating
keratitis associated with diabetes mellitus.
Corneal Staining: was performed
with topical application of sodium
fluorescein followed by corneal
imaging with a conventional digital
camera on a dissecting microscope at
baseline, day 7, and day 14.
Grading System: (grades 0-5) of
epithelial damage were assigned to all
photographs based on standardized
fluorescein staining criteria developed by
Olan Suwan-apichon et al.4 (5=maximal
staining, 0=no staining).
NGF- treated left eye at baseline.
NGF- treated left eye at day 14
Treatment animals showed marked
improvement of epithelial damage by day
14, with all mice showing staining of less
than or equal to grade one. While PBStreated mice showed improvement from
baseline by day 14, the results were modest
compared to NGF-treated mice. In
conclusion, NGF appears to improve
keratitis associated with experimental
models of type 1 diabetes mellitus.
Representative corneal fluorescein images at baseline and following
14 days of NGF treatment.
1) Kaji Y. Prevention of diabetic keratopathy. British Journal of Ophthalmology 2005;89:254-255.
Ten nonobese diabetic mice from the
Jackson Laboratory (NOD/LtJ) were used
for this study.3 Blood glucose was
markedly elevated at baseline in all mice.
The study protocol was as follows:
Treatment Group: 5L NGF was applied L NGF was applied
to both eyes of each mouse, 3X daily, for
Control Group: 5 L NGF was applied L PBS was applied to
both eyes of each control mouse, 3X daily,
for 14 days.
Both Groups received 5 L NGF was applied L of
benzalkonium chloride on the left eye only,
in order to exacerbate the effects of
diabetic dry eye. This was applied 2X daily
from day 3-14.
2) Flugel A, Matsumuro K, Neumann H, Klinkert WEF, Birnbacher R, Lassman H, Otten U, Wekerle H. Anti-inflammatory
activity of nerve growth factor in experimental autoimmune encephalomyelitis: inhibition of monocyte transendothelial
migration. European Journal of Immunology 2001;31:11-22.
4) Suwan-apichon O, Rizen M, Rangsin R, Herretes S, Reyes JMG, Lekhanont K, Chuck RS. Botulinum toxin B-induced
mouse model of keratoconjunctivitis sicca. Investigative Ophthalmology and Visual Science 2006;47:133-139.
5) Kaiserman I, Kaiserman N, Nakar S, Vinker S. Dry eye in diabetic patients. American Journal of Ophthalmology
6) Nepp J, Abela C, Polzer I, Derbolav A, Wedrich A. Is there a correlation between the severity of diabetic retinopathy and
keratoconjunctivitis sicca. Cornea 2000;19:487-491.
7) Joo MJ, Yuhan KR, Hyon JY, Lai H, Hose S, Sinha D, OBrien TP. The effect of nerve growth factor on corneal
sensitivity after laser in-situ keratomileusis. Archives of Ophthalmology 2004;122:1338-1341.
8) Jain S. Dry eye in diabetes. Diabetes Care 1998;21:1375-1376.
9) Fan H, Longacre A, Meng F, Patel V, Hsiao K, Koh JS, Levine JS. Cytokine dysregulation induced by apoptotic cells is a
shared characteristic of macrophages from non-obese diabetic and systemic lupus prone mice. Journal of Immunology
10) Barile GR, Pachydaki SI, Tari SR, Lee SE, Donmoyer CM, Ma W, Rong LL, Buciarelli LG, Wendt T, Horig H, Hudson
BE, Qu W, Weinberg AD, Yan SF, Schmidt AM. The RAGE axis in early diabetic retinopathy. Investigative Ophthalmology
and Visual Science 2005;46:2916-2924.
We would like to acknowledge the support of the Illinois Society for the Prevention of Blindness, the Richard A. Perritt Charitable Foundation and
the Loyola University STAR research program for the conduct of this work. In addition, Phillip Williams and Christine Staunton provided significant
help in handling and caring for the mice.
11) Lieth E, Gardner TW, Barber AJ, Antonetti DA. Retinal neurodegeneration: an early pathology in diabetes. Clinical and
Experimental Ophthalmology 2000;28:3-8.
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topical medication of a preservative benzalkonium chloride. Investigative Ophthalmology and Visual Science 2008;49:
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mice. A potential role of the angiogenic factor adrenomodulin. Experimental Biology and Medicine 2006;231:1101-1105.
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