July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
The Effects of KR-67607 on Intraocular Pressure and Glaucomatous Optic Neuropathy
Author Affiliations & Notes
  • Jee Young Kim
    T2B infrastructure Center for Ocular Disease, Inje University Busan Paik Hospital, Korea (the Republic of)
  • Yunjeong Kang
    T2B infrastructure Center for Ocular Disease, Inje University Busan Paik Hospital, Korea (the Republic of)
  • Yerin Shin
    T2B infrastructure Center for Ocular Disease, Inje University Busan Paik Hospital, Korea (the Republic of)
  • Eunyoung Park
    T2B infrastructure Center for Ocular Disease, Inje University Busan Paik Hospital, Korea (the Republic of)
  • Jin Soo Lee
    BIONETIX, INC, Korea (the Republic of)
  • Jaewook Yang
    T2B infrastructure Center for Ocular Disease, Inje University Busan Paik Hospital, Korea (the Republic of)
    Department of Ophthalmology, Inje University College of Medicine, Korea (the Republic of)
  • Footnotes
    Commercial Relationships   Jee Young Kim, None; Yunjeong Kang, None; Yerin Shin, None; Eunyoung Park, None; Jin Soo Lee, None; Jaewook Yang, None
  • Footnotes
    Support  the Ministry of Health & Welfare, Republic of Korea (grant number : HI15C1142)
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 643. doi:
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      Jee Young Kim, Yunjeong Kang, Yerin Shin, Eunyoung Park, Jin Soo Lee, Jaewook Yang; The Effects of KR-67607 on Intraocular Pressure and Glaucomatous Optic Neuropathy. Invest. Ophthalmol. Vis. Sci. 2019;60(9):643.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : KR-67607, a potent and highly selective 11β-Hydroxysteroid dehydrogenase type 1(11β-HSD1) inhibitor which is known to reduce the conversion of inactive cortisone to active cortisol, can decrease intraocular pressure and protect the damage on ocular tissue in glaucoma eye. This study was conducted to evaluate the effects of KR-67607 on intraocular pressure (IOP) reduction and retinal ganglion cells (RGC) degeneration in the DBA/2 mouse.

Methods : DBA/2 mice (n=15/group) were divided into four treatment groups, which were topically treated vehicle, two different concentrations of KR-67607 (0.75, 1.5mg/ml), or Alphagan twice a day per week over a period of 4 months. C57BL/6 mice (n=15) were used as a negative control group for glaucoma. Measurement of IOP was performed every four weeks until sacrifice. At endpoint, Eyes were enucleated for histopathology analyses.

Results : From the age of 5 months, the IOP of DBA/2mice begun to increase gradually compared to C57BL/6 mice. Elevated IOP in DBA/2 mice was reduced by 16.7(±7.4)% in the mice administered 0.75 mg/ml KR-67607 and by 26.1(±7.6)% in the mice administered 1.5 mg/ml KR-67607. The retinas in DBA/2 mice showed thinner retinal nerve fiber layer (RNFL) and severe excavation of the optic nerve head (ONH). After administration of KR-67607 recovered the normal thickness of RNFL and structure of ONH. The pathophysiology of glaucomatous optic nerve head damage was confirmed by cleaved Caspase-3, -9, and TUNEL staining. The increased apoptotic cells were decreased in the DBA/2 mice administered KR-67607 (DBA-KR). IOP elevation caused significant RGC loss of DBA/2 mice, but the administration of KR-67607 recovered RGCs. Attenuated RGC loss was confirmed by immunostaining of Brn3a on flat-mounted retinas. Furthermore, Caspase-3 and –9 staining confirmed that RGC loss was due to apoptosis. The glaucomatous injuries in DBA/2 mice showed intense GFAP localized to the ONH, but not in DBA-KR. This neuroprotective effect of KR-67607 might be related to the reduced RGC degeneration by astrocyte activation in ONH of DBA/2 mice.

Conclusions : These results suggest that KR-67607 reduces IOP and prevents glaucomatous optic neuropathy, which is achieved by attenuating RGC loss and suppressing astrocyte activation. Based on these data, KR-67607 has a potentiality to be used as a new neuroprotective therapeutic agent for glaucoma.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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