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yogita dheer, Nitin Chitranshi, Stuart L Graham, Vivek Kumar Gupta; Bexarotene suppresses the retinal expression of ER stress marker proteins p-PERK and GADD153 in experimental model of glaucoma. Invest. Ophthalmol. Vis. Sci. 2018;59(9):6124.
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Bexarotene is a Retinoid-X-receptor (RxR) agonist used in treatment of cutaneous T-cell lymphoma and its protective role is being increasingly investigated in various neurodegenerative disorders. Protein misfolding and endoplasmic reticulum (ER) stress induced apoptosis has been shown to lead to retinal degenerative changes in glaucoma. In the present study, we investigated potential involvement of bexarotene in modulating ER stress response and apoptotic changes in mouse retina under experimental glaucoma conditions.
Excitotoxicity mediated glutamate model and microbead induced increased intraocular pressure model were generated in the lab. Oral administration of bexarotene (100 mg/kg) was started in mice for 1 week and 2 weeks in glutamate and microbead injection model respectively at the same time as experimental stress was initiated. Immunofluorescence staining was used to determine the expression of p-PERK and GADD153 in mice retinas (n=15). Western blot analysis was performed to determine changes in expression of ER stress markers and pro-apoptotic protein BAD in the retinas.
Quantification of western blot results revealed that there was significant decreased ER stress reactivity with bexarotene treatment as compared to glaucoma i.e. for p-PERK: mean± SD %;130.5 ± 5.37vs 182.9± 14.08 ; *p<0.05;n=3(glutamate model) and 123.6± 9.94 vs 216±11.13; ***p<0.001; n=3 (microbead model) and for GADD 153: 151.2±12.38 vs 204.7±14.09; *p<0.05; n=3 (glutamate model) and 155.2±10.08 vs 208.7±19.02; *p< 0.05; n=3 (microbead model). Also a significant decrease in BAD expression was observed (144± 10.19 vs 224.4± 9.55; **p< 0.05; n=3) in glutamate model and (127.2± 9.78 vs 227.1± 15.1; **p< 0.05; n=3) in microbead model. Immunostaining results also showed increased expression of p-PERK and GADD153 in mouse retinal layers in both models.
The results suggest bexarotene as an effective pharmacological agent in attenuating ER stress response and apoptosis in retina caused by experimental glaucoma models. However, targeting only one branch of the ER stress pathway might not be sufficient to prevent glaucoma induced cell death. Proteomics studies to understand the drug effects on expression of various ER stress markers and apoptotic pathways will further help to understand the mechanism of drug actions.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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