Effects of substance P and IGF-1 in corneal epithelial barrier function and wound healing in a rat model of neurotrophic keratopathy.
OBJECTIVE
To establish a rat model of neurotrophic keratopathy and to examine the effects of the combination of substance P (SP) and insulin-like growth factor (IGF)-1 on corneal epithelial barrier function and wound healing in this model.


METHODS
Corneal denervation was achieved by thermocoagulation of the ophthalmic branch of the trigeminal nerve. A modified Schirmer test was performed without topical anesthesia. Corneal epithelial barrier function was assessed by measurement of fluorescein permeability with an anterior fluorophotometer. Epithelial wound healing was evaluated by measurement of the area of the defect at various times after removal of the entire epithelium. Eye drops containing both 1 mM SP and IGF-1 (1 micro g/mL) were administered six times daily.


RESULTS
The Schirmer test result in eyes subjected to trigeminal denervation was lower than that in control eyes. The fluorescein permeability of the corneal epithelium of denervated eyes was increased relative to that of control eyes. Furthermore, trigeminal denervation induced a delay in corneal epithelial wound healing. Application of eye drops containing SP and IGF-1 to denervated corneas restored the fluorescein permeability of the corneal epithelium to control levels and abolished the delay in epithelial wound healing.


CONCLUSIONS
A rat model of neurotrophic keratopathy, characterized by reduced tear secretion, loss of corneal sensation, impaired epithelial barrier function, and delayed epithelial wound healing, was established by trigeminal denervation. Treatment with both SP and IGF-1 improved corneal epithelial barrier function and stimulated corneal epithelial wound healing in this model.
Nagano
Takashi
T
Research and Development Center, Santen Pharmaceutical Co., Ltd., Nara, Japan. takashi.nagano@santen.co.jp
Nakamura
Masatsugu
M
Nakata
Katsuhiko
K
Yamaguchi
Takeshi
T
Takase
Kenji
K
Okahara
Akihiko
A
Ikuse
Toshimi
T
Nishida
Teruo
T
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002463:Cell Membrane Permeability; D003316:Corneal Diseases / Q000188:drug therapy* / Q000378:metabolism; D003389:Cranial Nerve Diseases / Q000188:drug therapy* / Q000378:metabolism; D003714:Denervation; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D019573:Epithelium, Corneal / Q000502:physiology*; D019793:Fluorescein / Q000378:metabolism; D015590:Fluorophotometry; D007334:Insulin-Like Growth Factor I / Q000627:therapeutic use*; D008297:Male; D009882:Ophthalmic Nerve / Q000502:physiology; D009883:Ophthalmic Solutions; D051381:Rats; D011914:Rats, Inbred BN; D013373:Substance P / Q000627:therapeutic use*; D013666:Tears / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects*
D009883:Ophthalmic Solutions; D013373:Substance P; D007334:Insulin-Like Growth Factor I; D019793:Fluorescein