June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Topical Ketotifen fumarate inhibits mast cell degranulation and loss of retinal pigment epithelial cells in rat model for geographic atrophy
Author Affiliations & Notes
  • Tomohiro Niizawa
    Johns Hopkins Medicine Wilmer Eye Institute, Baltimore, Maryland, United States
  • Imran Ahmed Bhutto
    Johns Hopkins Medicine Wilmer Eye Institute, Baltimore, Maryland, United States
  • Anupama Tiwari
    Johns Hopkins Medicine Wilmer Eye Institute, Baltimore, Maryland, United States
  • Rhonda R. Grebe
    Johns Hopkins Medicine Wilmer Eye Institute, Baltimore, Maryland, United States
  • Jesse Alt
    Johns Hopkins University Brain Science Institute, Baltimore, Maryland, United States
  • Rana Rais
    Johns Hopkins University Brain Science Institute, Baltimore, Maryland, United States
  • Malia Michelle Edwards
    Johns Hopkins Medicine Wilmer Eye Institute, Baltimore, Maryland, United States
  • Gerard A Lutty
    Johns Hopkins Medicine Wilmer Eye Institute, Baltimore, Maryland, United States
  • Footnotes
    Commercial Relationships   Tomohiro Niizawa, None; Imran Bhutto, None; Anupama Tiwari, None; Rhonda Grebe, None; Jesse Alt, None; Rana Rais, None; Malia Edwards, None; Gerard Lutty, None
  • Footnotes
    Support  Global Ophthalmology Awards Program (GOAP) 2019
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 252. doi:
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      Tomohiro Niizawa, Imran Ahmed Bhutto, Anupama Tiwari, Rhonda R. Grebe, Jesse Alt, Rana Rais, Malia Michelle Edwards, Gerard A Lutty; Topical Ketotifen fumarate inhibits mast cell degranulation and loss of retinal pigment epithelial cells in rat model for geographic atrophy. Invest. Ophthalmol. Vis. Sci. 2021;62(8):252.

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

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Abstract

Purpose : We have reported that subconjunctival slow-released 48/80 stimulated continuous degranulation of choroidal Mast cells (MCs) and resulted in loss of retinal pigment epithelium (RPE), reduced electroretinogram (ERG) and thinning of retina and choroid, i.e. a geographic atrophy (GA)-like phenotypes in the rat. Moreover, quiescing MCs with oral administration of the MC stabilizer, ketotifen fumarate (KTF), prevented these changes. We herein evaluated whether topical administration of KTF has the potential to prevent these GA-like changes.

Methods : First, we analyzed the levels of KTF in plasma, RPE/choroid/sclera, retina and brain, administered orally and topically twice daily for 5 days, in the eye tissues of normal Sprague Dawley rats. Second, the rats were divided into three groups: group 1, the rats were implanted 48/80 in a hydrogel in the superior subconjunctival space and treated with 1% (10mg/ml) of KTF eye drops; group 2, rats were implanted with 48/80 hydrogel and treated with phosphate buffer saline (PBS); and group 3, rats were implanted with an empty hydrogel only and treated with 1% KTF eye drops. KTF and PBS was topically administered twice daily for 8 weeks. Rats were sacrificed 1, 2, 4 and 8 weeks (w) after implantation. MCs were stained with nonspecific esterase (NSE), RPE labeled with RPE65 in whole mount choroids, and retinal and choroidal area determined in cryosections stained with picrosirius red. Dark-adapted ERG was also performed to evaluate retinal function.

Results : We found the highest level of KTF (average 5.6 nM/mg) in the RPE/choroid/sclera of the rats given topical administration in the pharmacokinetic study. At 1w and 2w after implantation, daily treatment with KTF prevented MC from degranulation (38 % reduction at 1w and 38.5 % at 2w of PBS treated, n=6 and n=3, p<0.001 and p<0.01, respectively). The RPE loss with 48/80 was significantly prevented by KTF treatment at 2w and 4w compared to PBS treatment (59.8 % and 34.8 %, n=3 and n=6, both p<0.001). There was a significant difference for preventing the ERG amplitude declining in KTF treated rat at 8w (n=6 per group).

Conclusions : Topical KTF eye drops had efficacy in preventing MCs degranulation and loss of RPE in our GA-like rat model. These data suggest that topical KTF eye drops might be a new therapeutic drug for treating GA.

This is a 2021 ARVO Annual Meeting abstract.

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