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(Investigative Ophthalmology and Visual Science. 2006;47:3286-3292.)
© 2006 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.05-1205
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Promotion of Corneal Epithelial Wound Healing by a Tetrapeptide (SSSR) Derived from IGF-1

Naoyuki Yamada,1,2 Ryoji Yanai,1,2 Koji Kawamoto,1 Takashi Nagano,1,3 Masatsugu Nakamura,1,3 Makoto Inui,2 and Teruo Nishida1

1From the Departments of Biomolecular Recognition and Ophthalmology and 2Pharmacology, Yamaguchi University School of Medicine, Yamaguchi, Japan; and 3Nara Research and Development Center, Santen Pharmaceutical Co. Ltd., Nara, Japan.

PURPOSE. A prior study showed that a tetrapeptide (FGLM-amide) derived from the carboxyl terminus of substance P (SP) and a 12-residue peptide corresponding to the C domain of insulin-like growth factor (IGF)-1 mimic the synergistic effect of the full-length molecules on corneal epithelial wound healing. To develop an effective treatment for persistent corneal epithelial defects, the current study was conducted to investigate the minimal sequence within the C domain of IGF-1 that is required for such synergism with SP or FGLM-amide.

METHODS. The effects of IGF-1–derived peptides on corneal epithelial migration were evaluated with a rabbit corneal organ-culture system.

RESULTS. A tetrapeptide (SSSR; Ser33-Ser-Ser-Arg) derived from the C domain of IGF-1 was sufficient for the synergistic promotion with FGLM-amide both of corneal epithelial migration in vitro and of wound closure in vivo. The activity of the SSSR peptide was sequence specific and its potency was similar to that of IGF-1. The SSSR peptide by itself also promoted corneal epithelial migration in vitro at higher concentrations. It was devoid, however, of both the mitogenic action of IGF-1 and the ability of the full-length molecule to induce neovascularization.

CONCLUSIONS. The SSSR sequence mediates the synergistic effect of IGF-1 with SP on corneal epithelial wound healing. Clinical application of the SSSR peptide would be expected to be free of potentially deleterious side effects associated with treatment with full-length IGF-1. Local administration of the SSSR tetrapeptide, alone or in combination with FGLM-amide, is thus a potential new strategy for the treatment of nonhealing epithelial wounds.




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N Yamada, R Matsuda, N Morishige, R Yanai, T-i Chikama, T Nishida, T Ishimitsu, and A Kamiya
Open clinical study of eye-drops containing tetrapeptides derived from substance P and insulin-like growth factor-1 for treatment of persistent corneal epithelial defects associated with neurotrophic keratopathy
Br. J. Ophthalmol., July 1, 2008; 92(7): 896 - 900.
[Abstract] [Full Text] [PDF]


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