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Ayse Sahaboglu, Stavros Vagionitis, Alaa Sharif, Melanie Barth, kangwei jiao, Manoj Kulkarni, Dragana Trifunovic, Marius Ueffing, Eberhart Zrenner, Francois Paquet-Durand; The neuroprotective effects of PARP inhibition in different types of photoreceptor degeneration. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
Inherited retinal degenerations (RD) such as Retinitis Pigmentosa (RP) or Achromatopsia are often caused by gene defects in rod or cone photoreceptors, and lead to an irreversible loss in visual function. Recently, it was shown that dying photoreceptor cells display strong activation of poly-ADP-ribose polymerase (PARP) in ten different RD animal models. These results suggested PARP as a common denominator for different RD types and thus PARP inhibition as potentially beneficial for the course of disease. Here, we investigated the neuroprotective effect of PARP inhibition on different photoreceptor degeneration in mouse models for rod-cone, and cone degeneration.
rd2 and cpfl1 mouse retinae were explanted together with retinal pigment epithelium at postnatal day (PN) 9 and PN14, respectively. Retinal explants were treated with PARP inhibitor (PJ34, 6µM) starting at PN11 (rd2) and PN16 (cpfl1). One retina was used for the treatment, while the other retina was used as control. Treatment was terminated at the peak of degeneration (rd2, PN18; cpfl1, PN24) for each model. TUNEL, neuron specific enolase (NSE), and PAR staining were performed for the assessment of dying cells, cone photoreceptor cells, and PAR accumulation, respectively.
Detection of degenerating cells using the TUNEL assay showed a treatment induced decrease in the number of dying cells in rd2 retinae (treated:0.6 ± 0.1 SEM, n=8; untreated:1.05 ± 0.1 SEM, n=10, p=0.013). Although the percentage of TUNEL positive cells was higher in the cpfl1 treated group (treated:4.86 ± 0.2 SEM, n=5; untreated:3.77 ± 0.3 SEM, n=5, p=0.026), the numbers of preserved cone photoreceptors were higher in treated (2.43 ± 0.3 SEM, n=5) than untreated (1.52 ± 0.2 SEM, n=5, p=0.022).
PARP inhibition shows neuroprotective effects in the rd2 retinae and preserves cones in cpfl1 retinae. PARP may have important functions during cell death in rod and cone photoreceptors. PARP inhibition could open new treatment strategies for a variety of hereditary photoreceptor dystrophies.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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