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Dorota Skowronska-Krawczyk, Viet Anh Nguyen Huu, Lorena Raquel Rocha Jimenez, Mary Jabari; Removal of early senescent cells to protect retinal ganglion cells (RGCs) in glaucoma. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2509.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate whether the removal of early senescent retinal ganglion cells (RGCs) prevents progression of RGC and vision loss in mouse model of glaucoma. This project shall create a solid foundation for future studies on potential applications of senolytic drugs in glaucoma patients.
We used a unique transgenic mouse model that allows selective, reproducible, and time-dependent removal of senescent, p16Ink4a-positive cells. After unilateral intraocular pressure elevation mice were injected with small molecule to selectively remove senescent cells. RGC survival was assessed by fluoresecent microscopy of Brn3a stained whole retina flat-mounts. Loss of p16 expression was verified by RT-qPCR analysis. Visual function loss was studied using visual evoked potential (VEP) measurements.
We have applied experimental elevation of IOP to the transgenic mice . Four mice were treated with small molecule and a control group of four mice was sham-treated with PBS. Each mouse underwent unilateral hydrostatic pressure-induced IOP elevation t, with the contralateral eye left as untreated control. Fascinatingly, we have observed that five-day administration of small molecule after IOP elevation had a neuroprotective effect on RGC number in transgenic mice but not in WT animals . The effect was statistically significant as assessed using 1-way ANOVA and post-hoc Tukey tests (p<0.01). At the same time, we have looked at the p16Ink4a expression at day 3 post treatment and observed striking lack of upregulation of the gene upon treatment. Finally, we have tested the visual circuit integrity in the drug treated mice on day 7. We have found that eyes subjected to IOP elevation have decreased VEP P1-N1 amplitude, compared to contralateral non-IOP control eyes and observed dramatic rescue in VEP amplitude in transgenic animals treated with small molecule.
We concluded that the GCV treatment of transgenic animals has a protective effect on structure and function of the retina. This exploratory project provided preliminary data for future investigations aimed at screening senolytic drugs that can be used to treat glaucoma patients as well as to understand the process of neuroprotection.
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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