Abstract
Purpose :
Chronic inflammation significantly contributes to photoreceptor death in blinding retinal diseases such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD). The bromodomain and extraterminal domain (BET) proteins are epigenetic readers that act as key proinflammatory factors. Here, we investigated the effects and action mechanism of dBET6, a proteolysis-targeting chimera (PROTAC) small molecule that selectively degrades BET proteins by the ubiquitin-proteasome system during light-induced retinal degeneration.
Methods :
To induce the LIRD mouse model, BALB/c mice (6-8 weeks, male) were exposed to 15000 lux white light for 2 h. mice were intraperitoneally injected without (control group, n=15) or with 10 mg/kg of dBET6 (n=25-30) or vehicle (n=25-30) 1 h before LD and 24 h after LD, and retinal function and morphology were evaluated 48 h after LD. Hematoxylin and eosin staining and immunofluorescence access retinal morphology. Western blot assay determines the expression of proinflammatory cytokine in retinas. Optical Coherence Tomography and Electroretinogram evaluate retinal morphology and function in vivo.
Results :
Intraperitoneal injection of dBET6 led to the rapid degradation of BET proteins in the retina without detectable toxicity. dBET6 improved retinal responsiveness and visual acuity after LD. dBET6 also repressed LD-induced retinal macrophages/microglia activation, Müller cell gliosis, photoreceptor death and retinal degeneration. Finally, dBET6 suppressed expression of proinflammatory factors, such as CD86, GFAP, IL1β in retina in response to LD.
Conclusions :
In summary, our study shows that dBET6 prevents light-induced retinal degeneration through inhibiting retinal inflammation. The results suggest that the dBET6 may be a potential therapeutic drug for retinal degeneration.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.