Topical Ketotifen Fumarate Inhibits Choroidal Mast Cell Degranulation and Loss of Retinal Pigment Epithelial Cells in
Tomohiro Nizawa1, Imran A Bhutto1, Anupama Tiwari1
1Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Purpose:
This study evaluates whether topical ketotifen fumarate (KTF) can prevent geographic atrophy (GA)-like phenotypes in a rat model.
Methods:
Pharmacokinetics (PKs) of KTF after topical administration twice daily for 5 days was analyzed in rat retina, retinal pigment epithelium (RPE)/choroid/sclera, and in plasma by an liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Rats were then given hydrogel implants +/- 48/80 in the superior subconjunctival space and topically treated with 1% and 0.25% of KTF or phosphate buffer saline (PBS) twice daily. Rats were euthanized at 1, 2, 4, and 8 weeks postinjection. Choroidal mast cells (MCs) were stained with nonspecific esterase and the RPE monolayer was labeled with RPE65 and ZO-1 in whole mount choroids. Retinal and choroidal areas were determined in cryosections stained with picrosirius red. Dark-adapted electroretinogram (ERG) was also performed to evaluate retinal function.
Results:
PK results showed the highest level of KTF (average 5.6 nM/mg) in the RPE/choroid/sclera in rats given topical 1% KTF. Topical 1% KTF significantly reduced choroidal MC degranulation at 1 week and 2 weeks (both P < 0.001) and RPE loss at 4 weeks (P < 0.001) as well as retinal and choroidal thinning (both P < 0.001) and reduction in ERG amplitude at 8 weeks (P < 0.05) compared to PBS. Similar results were obtained with 0.25% KTF.
Conclusions:
Both 1% and 0.25% KTF eye drops effectively reduced MC degranulation, RPE loss, and retinal and choroidal thinning while preventing the decline of ERG amplitude in a GA-like rat model. These data suggest that topical KTF might be a new therapeutic drug for treating GA.
Translational Relevance:
The results of this study demonstrate that topical KTF successfully reduced GA-like phenotypes in a rat model and may provide a novel therapy for GA.
Insights
Topical ketotifen fumarate (KTF) eye drops effectively reduced geographic atrophy (GA)-like phenotypes in a rat model. This suggests KTF may be a promising new therapy for treating GA.
Area of Science:
- Ophthalmology
- Pharmacology
Background:
- Geographic atrophy (GA) is a leading cause of vision loss.
- Current therapeutic options for GA are limited.
Purpose of the Study:
- To evaluate the efficacy of topical ketotifen fumarate (KTF) in preventing GA-like phenotypes in a rat model.
- To assess the pharmacokinetic profile of topical KTF in ocular tissues.
Main Methods:
- Rats were treated with topical KTF (1% and 0.25%) or vehicle after subconjunctival injection.
- Pharmacokinetics of KTF were analyzed in ocular tissues and plasma.
- Histological analysis assessed mast cell degranulation, RPE loss, and retinal/choroidal thinning.
- Electroretinography (ERG) evaluated retinal function.
Main Results:
- Topical KTF achieved significant concentrations in the RPE/choroid/sclera.
- KTF treatment significantly reduced mast cell degranulation, RPE loss, and retinal/choroidal thinning.
- KTF prevented the decline in ERG amplitude, indicating preserved retinal function.
Conclusions:
- Topical ketotifen fumarate eye drops demonstrated significant efficacy in reducing GA-like phenotypes in a rat model.
- KTF may represent a novel therapeutic strategy for geographic atrophy.
