Investigative Ophthalmology & Visual Science 2015-03-01

Poly(ADP-Ribose) Polymerase Inhibition Improves Corneal Epithelial Innervation and Wound Healing in Diabetic Rats.

Yong-Soo Byun, Borami Kang, Young-Sik Yoo, Choun-Ki Joo

Index: Invest. Ophthalmol. Vis. Sci. 56(3) , 1948-55, (2015)

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Abstract

We evaluated the effect of poly(ADP-ribose) polymerase (PARP) inhibition by using 1,5-isoquinolinediol (ISO) on corneal epithelial innervation in diabetic rats.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.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.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.Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.