Synergistic effect with Phe‐Gly‐Leu‐Met‐NH₂ of the C‐terminal of substance P and insulin‐like growth factor‐1 on epithelial wound healing of rabbit cornea

Abstract

1 We previously reported that substance P and insulin-like growth factor-1 (IGF-1) synergistically stimulate corneal epithelial wound healing in vitro and in vivo. We wished to identify which portion of the amino acid sequence of substance P might be responsible for this synergism. 2 Corneal epithelial migration was not a ected by the addition of any one of the following factors: substance P; Phe-Gly-Leu-Met-NH 2 (C-terminal of substance P); Val-Gly-Leu-Met-NH 2 (C-terminal of neurokinin A, neurokinin B, and kassinin); Tyr-Gly-Leu-Met-NH 2 (C-terminal of physalaemin); Ile-Gly-Leu-Met-NH 2 (C-terminal of eledoisin); or Gly-Leu-Met-NH 2 (common C-terminal of tachykinins). 3 In the presence of IGF-1, only substance P and Phe-Gly-Leu-Met-NH 2 were synergistic in stimulating corneal epithelial migration in a dose-dependent fashion. 4 The combination of Phe-Gly-Leu-Met-NH 2 and IGF-1 did not a ect the incorporation of [ 3 H]-thymidine into corneal epithelial cells. 5 Treatment with Phe-Gly-Leu-Met-NH 2 and IGF-1, but not with Phe-Gly-Leu-Met-NH 2 or IGF-1 alone, increased attachment of corneal epithelial cells to a ®bronectin matrix. 6 The levels of a5 and b1 integrin were not a ected by Phe-Gly-Leu-Met-NH 2 or IGF-1 alone, but they were signi®cantly increased by the combination of Phe-Gly-Leu-Met-NH 2 and IGF-1. 7 Topical application of the same combination facilitated corneal epithelial wound closure in vivo. 8 These results demonstrated that Phe-Gly-Leu-Met-NH 2 , a sequence of 4 amino-acids of the Cterminal of substance P, is the minimum sequence necessary to produce the synergistic e ects of substance P and IGF-1 on corneal epithelial wound healing.

Substance P Promotes Diabetic Corneal Epithelial Wound Healing Through Molecular Mechanisms Mediated via the Neurokinin-1 Receptor

“…Although previous studies have confirmed that SP enhances corneal epithelial migration when combined with IGF-1 or EGF (41,44,45), the exact mechanism remains unclear. Here we show that SP reactivates Akt, EGFR, and Sirt1 and promotes ROS scavenging capacity that are impaired by hyperglycemia.…”

Epidermal Growth Factor Receptor Transactivation Mediates Substance P-induced Mitogenic Responses in U-373 MG Cells

“…Although SP is a potent positive regulator of cell proliferation, SP activity has also been correlated with cell attachment and migration, and, more loosely, with cellular differentiation. SP, in synergy with insulin-like growth factor-1, has been shown to induce rabbit corneal epithelial cell attachment to fibronectin matrix, promote subsequent migration, and increase levels of the integrins ␣ 5 and ␤ 1 mRNA (50,51). Furthermore, SP has been implicated in angiogenesis by inducing the formation of capillary-like structures from endothelial cells placed on a Matrigel matrix (52).…”

Persistent Epithelial Defects Due to Neurotrophic Keratopathy Treated with a Substance P-Derived Peptide and Insulin-Like Growth Factor 1

“…10 The four-amino-acid sequence at the carboxyl terminus of substance P (phenylalanineglycine-leucine-methionine amide, or FGLM-amide) mimics the synergistic effects of the full-length molecule with IGF-1 on the corneal epithelium. 11 Moreover, we applied eye drops containing FGLM-amide and IGF-1 to treat successfully a case of neurotrophic keratopathy. 12 We have now evaluated in an open trial the clinical effi cacy of eye drops containing this combination of agents in the treatment of persistent epithelial defects in individuals with neurotrophic keratopathy.…”