Abstract
Purpose:
Age related macular degeneration (AMD) is the leading cause of blindness among the elderly population and oxidative stress has been implicated as a major cause of this ocular disorder. Previously we had reported that sulindac protects cultured RPE cells (ARPE19) against reactive oxygen species (ROS) induced stress. The purpose of this current study is to understand the protective mechanism involved in protection by sulindac of RPE from oxidative stress induced by either tert-butyl hydrogen peroxide (TBHP) or ultraviolet light (UVB). Protection of RPE cells against ROS was also observed with fenofibrate, a known agonist of PPARα. The results support a mechanism in which the protection of RPE cells against oxidative stress is through a preconditioning mechanism involving activation of PPAR α.
Methods:
RPE cells were incubated with sulindac or fenofibrate for 24 hours, following which the cells were either exposed to a range of TBHP concentrations or 1200mj UVB light. Cell viability was determined by the MTT assay and upregulation of preconditioning markers was detected using western blotting. In a light damage mouse model, sulindac was administered by intravitreal injection and evaluation of the retinal tissues for photoreceptor damage was performed.
Results:
The results indicate that sulindac confers >30 % protection of cultured ARPE19 cells against oxidative damage. The sulindac protection in vitro could be replaced by fenofibrate and was inhibited by an antagonist of PPARα, indicating a role of PPARα in the sulindac effect. Other results indicated that the protective effect of sulindac was through an IPC mechanism. In a preliminary in vivo study, sulindac protected photoreceptors against photooxidative damage in a light damage model in mice.
Conclusions:
Our findings indicate that preconditioning pathways and activation of PPARα play key roles in sulindac’s protective mechanism. A more extensive in vivo study is planned to establish therapeutic efficacy and other modes of administration. Implementing pharmacological preconditioning to deter oxidative stress outlined here represents a possible clinical approach to treat AMD and other oxidative stress induced disorders.
Keywords: 412 age-related macular degeneration •
701 retinal pigment epithelium •
656 protective mechanisms