title: Poly(ADP-Ribose) Polymerase Inhibition Improves Corneal Epithelial Innervation and Wound Healing in Diabetic Rats.
abstract: OBJECTIVE
  We evaluated the effect of poly(ADP-ribose) polymerase (PARP) inhibition by using 1,5-isoquinolinediol (ISO) on corneal epithelial innervation in diabetic rats.
  
  
  METHODS
  ISO (3 mg/kg, intraperitoneal) or vehicle was administered to rats with diabetes induced by streptozotocin for 4 weeks. Epithelial innervation, epithelial wound healing, and corneal sensation were evaluated in diabetic rats (DM rats), diabetic rats treated with ISO (DM-ISO rats), and nondiabetic (non-DM) rats. The density of epithelial innervation was calculated separately as nerve terminals and sub-basal nerve plexus by analyzing the images of whole-mount corneas. Healed areas of epithelial defect were measured at 0, 18, and 36 hours after creating a 4-mm wound on the cornea. Corneal sensitivity test was conducted using a Cochet-Bonnet handheld esthesiometer. Additionally, PARP1 and poly(ADP-ribosyl)ated polymers (pADPr) as its products, were identified in trigeminal ganglions (TGs) by Western blot analysis and immunofluorescence staining.
  
  
  RESULTS
  In DM rats, the density of nerve terminals (5.57% ± 0.94%) and sub-basal nerve plexus (22.08 ± 1.78 mm/mm(2)) was significantly reduced in comparison with that in DM-ISO rats (8.64% ± 1.42%, 30.82 ± 2.01 mm/mm(2), respectively) and non-DM rats (9.02 ± 1.14%, 34.77 ± 4.45 mm/mm(2), respectively). The percentages of healed area of the epithelial defects at 18 and 36 hours were significantly smaller in DM rats (23.8 ± 5.2%, 53.2 ± 4.6%, respectively) than in DM-ISO rats (43.2 ± 1.4%, 75.8 ± 2.2%, respectively) and non-DM rats (48.1 ± 8.6%, 86.1 ± 3.3%, respectively). Corneal sensitivity decreased in DM rats (51.1 ± 0.3 mm) but not in DM-ISO rats (57.8 ± 0.2 mm). There were no differences between parameters in DM-ISO rats and those in non-DM rats.
  
  
  CONCLUSIONS
  Diabetic corneas showed loss of epithelial innervation, resulting in delayed epithelial healing and decreased corneal sensitivity. Inhibition of poly(ADP-ribose) polymerase (PARP) with 1,5-isoquinolinediol alleviated these diabetes-induced alterations in the corneal epithelium in the diabetic rats.
authors.affiliation: Department of Ophthalmology and Visual Science, Seoul St. Mary's Hospital, Catholic University of Korea, College of Medicine, Seoul, Korea Catholic Institute for Visual Science, Catholic University of Korea, College of Medicine, Seoul, Korea.
authors.forename: Yong-Soo
authors.initials: YS
authors.lastname: Byun
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, Catholic University of Korea, College of Medicine, Seoul, Korea.
authors.forename: Borami
authors.initials: B
authors.lastname: Kang
authors.affiliation: Catholic Institute for Visual Science, Catholic University of Korea, College of Medicine, Seoul, Korea.
authors.forename: Young-Sik
authors.initials: YS
authors.lastname: Yoo
authors.affiliation: Department of Ophthalmology and Visual Science, Seoul St. Mary's Hospital, Catholic University of Korea, College of Medicine, Seoul, Korea Catholic Institute for Visual Science, Catholic University of Korea, College of Medicine, Seoul, Korea.
authors.forename: Choun-Ki
authors.initials: CK
authors.lastname: Joo
mesh_terms: D000818:Animals; D003315:Cornea / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003930:Diabetic Retinopathy / Q000378:metabolism / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019573:Epithelium, Corneal / Q000187:drug effects / Q000294:innervation*; D007150:Immunohistochemistry; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C095653:1,5-dihydroxyisoquinoline; D011065:Poly(ADP-ribose) Polymerases
keywords: PARP; diabetic keratopathy; diabetic neuropathy; epithelial innervation