Purchase this article with an account.
Shuntaro Ogura, Rajkumar Baldeosingh, Siva Pramodh Kambhampati, Gerard A Lutty; The efficacy of mast cell stabilizer in the experiment rat model of geographic atrophy. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5380.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Blindness from geographic atrophy (GA) remains unaddressed due to the lacking of distinct animal models and there is no proven drug treatment to date. Previously, we have reported that continuous choroidal mast cell (MC) degranulation contributed to a GA-like phenotype in our rat model (ARVO, 2018). We herein evaluated whether a generic MC stabilizer, ketotifen fumarate has the potential to prevent these changes.
Sprague Dawley (SD) rats, KIT mutant (WsRC-Ws/Ws) rats (lacks in MCs) and wild-type (WsRC-+/+) rats were used. Two approaches, ex vivo and in vivo, were evaluated in this study. Ex vivo, rat eye cups (anterior segments and retina excised) were incubated for 3 hours with compound 48/80, a MC stimulator. MC degranulation and choroidal macrophage activation (sphericity and volume) were evaluated (ARVO, 2018). Ketotifen or phosphate buffered saline (PBS) were administered orally to SD rats twice daily for 4 days (10 mg/day) prior to treating with 48/80 ex vivo. In vivo, we implanted 48/80 in a hydrogel slow release pellet subconjunctivally in all rats. Ketotifen or PBS was orally administered twice daily to SD rats for 6 weeks (10 mg/day) . Area of retinal pigment epithelium (RPE) loss, MC degranulation and macrophage morphology were assessed post-implantation. Electroretinogram (ERG) was also performed to evaluate retinal function.
Ex vivo, choroidal macrophages were activated (sphericity increase and volume decrease) in WsRC-+/+ rats but not in WsRC-Ws/Ws rats (p<0.001, respectively). Ketotifen pretreatment inhibited MC degranulation from 48/80 in SD rats by 36.6% (p=0.004) and significantly prevented macrophage activation (p<0.001). In vivo, at 6 weeks after subconjunctival 48/80 hydrogel implantation, daily treatment of ketotifen prevented MC degranulation (46.1% of PBS treated, p=0.008). Macrophages were less activated, RPE loss was prevented, and ERG amplitude declined less in ketotifen treated SD rats and in WsRC-Ws/Ws rats (SD rats, RPE: p=0.002, ERG: p=0.002; WsRC rats, RPE: p<0.001, ERG: p=0.012).
These data suggest that 48/80 only stimulated MCs not macrophages in choroid. Cytokine release from MCs activated macrophages, and MC degranulation directly contributed to RPE loss, which resembles the phenotype of human GA. Quiescing MCs with oral administration of ketotifen prevented these changes and, therefore, might be a new therapeutic agent for treating GA.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
This PDF is available to Subscribers Only