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Kerstin Birke, Marco T Birke, Jessica F Garcias, Rajendra Kumar-Singh; Topical Application of a Purinergic P2X Antagonist Enables Structural and Functional Rescue of Blue Light Induced Photoreceptor Degeneration in a Model of Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4386.
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© ARVO (1962-2015); The Authors (2016-present)
Retinitis pigmentosa (RP) is an extremely heterogeneous disorder involving more than 50 different genes. Apoptosis is the final common pathway for photoreceptor degeneration in RP. We wished to examine whether topical application of PPADS, a purinergic P2X antagonist could attenuate blue light induced photoreceptor degeneration in a murine model of RP.
Dark adapted Balb/c mice were exposed to blue light (450nm; 10000 Lux) for 4h. After 16h, mice were treated with either 4.7mM PPADS or the solvent control 0.9% NaCl, applied topically as eye drops once a day for eight consecutive days. Thickness of the outer nuclear layer (ONL) was assessed by optical coherence tomography (OCT) on days 3 and 8 post blue light exposure. On day 9 post light exposure, retinal function was examined by electroretinogram (ERG), followed by enucleation of eyes that were processed for histology. ONL structure was microscopically analyzed in DAPI stained paraffin-sections of whole eyes. Balb/c mice that underwent blue light exposure but received no treatment served as light degeneration (LD) controls. Balb/c mice that were neither exposed to blue light nor received treatment served as wild-type (wt) controls.
OCT analysis showed that blue light exposure reduced the ONL thickness by 70.1 +/- 3.12% on day 3 and 46 +/- 3.6% on day 8 in the LD controls relative to wt controls. Mice treated with the solvent control (NaCl) indicated a reduction by 49.7 +/- 2.4% on day 3 and 51.6 +/- 11.1% on day 8. In contrast, mice receiving topical treatment of 4.7mM PPADS, showed an intact retina of 95.4 +/- 2.27% on day 3 and 88.8 +/- 2.03% on day 8 relative to wt eyes and a relative improvement in ONL thickness of 44.4% on day 3 and 41.2% on day 8 compared to NaCl controls, indicating a therapeutic effect of PPADS on degeneration of the ONL. In functional ERG analyses, wt mice and PPADS treated mice responded almost identically suggesting complete rescue of the ERG. Solvent control mice and LD mice displayed significantly reduced response. Histological analyses of the retina confirmed essentially complete rescue of the ONL in PPADS treated mice.
Antagonism of purinergic P2X receptors by PPADS attenuates blue light induced retinal degeneration in a murine model of RP.
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