April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
Topical Application of Rho Kinase Inhibitor Decreases Intraocular Pressure and Prevents the Loss of Retinal Ganglion Cells in the Aging DBA/2J Mice
Author Affiliations & Notes
  • Vasanth Rao
    Ophthal & Pharmacology,
    Duke University, Durham, North Carolina
  • Robert Lalane, III
    Ophthalmology,
    Duke University, Durham, North Carolina
  • Corey Morris
    Ophthalmology,
    Duke University, Durham, North Carolina
  • Padma Iyer
    Ophthalmology,
    Duke University, Durham, North Carolina
  • Footnotes
    Commercial Relationships  Vasanth Rao, None; Robert Lalane, III, None; Corey Morris, None; Padma Iyer, None
  • Footnotes
    Support  NIH Grant EY018590
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 3080. doi:
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      Vasanth Rao, Robert Lalane, III, Corey Morris, Padma Iyer; Topical Application of Rho Kinase Inhibitor Decreases Intraocular Pressure and Prevents the Loss of Retinal Ganglion Cells in the Aging DBA/2J Mice. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3080.

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Abstract

Purpose: : To determine the long-term effects of Rho kinase inhibitors (RKIs) on intraocular pressure (IOP), retinal ganglion cell (RGC) survival and optic nerve axons in the DBA/2J mouse model of glaucoma.

Methods: : Four month-old female DBA/2J mice were divided into two groups (n=8 in each) and treated daily (Monday to Friday) with topical applications of either RKI-H1152 (2 drops {1.5 µl} of 25 mM drug, single dose) or with PBS (vehicle) for 6 months. C57BL/6 mice were used as controls. IOP was measured once in 3 to 4 weeks using a rebound tonometer under anesthesia (ketamin/xylazine) after one hr of drug application. After 5-6 months of treatment, the enucleated eyes were processed for retinal whole mount ganglion cell count (based on Brn-3 immunofluorescence) and histological analysis. The optic nerve sections were processed to determine the axon count with toluidine blue stain. The RGC and axons were quantitated using metamorph and Zeiss KS400 imaging system, respectively.

Results: : The DBA/2J mice from 6 months of age showed a significant and exponential elevation in IOP starting from ~13 to 28 mm Hg by 9 months of age (n=12-16 eyes). Compared to this vehicle treated group of mice, the RKI treated mice showed steadily lower IOP values starting from 6 months of age and at 9 months, IOP was 20 mm Hg, and reduced significantly by 30% (P<0.0025). IOP of the BL6 control mice at 9 months of age was less than 15 mm Hg. The RGC count in the central and peripheral retina was decreased significantly (by 75%, P<0.001, n=11) in the vehicle treated 9 month-old DBA/2J mice as compared the age-matched BL6 normal mice. On the other hand, the RGC count in the RKI treated DBA/2J mice was increased significantly (~100%, P<0.001, n=11) compared to the vehicle treated DBA/2J mice, but still 50% less compared to the BL6 normal mice. The optic nerve axons were decreased significantly by 50% (P<0.01) in both vehicle and RKI treated DBA/2J mice compared to the BL6 normal mice.

Conclusions: : This is the first study to demonstrate that topical application of RKI lowers IOP and prevents partially the loss of RGCs in the DBA/2J mouse model of glaucoma revealing the versatility of ocular hypotensive response of the Rho kinase inhibitors.

Keywords: intraocular pressure • signal transduction: pharmacology/physiology • neuroprotection 
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