Purchase this article with an account.
Pakize Nur Akkaya, Dragana Trifunovic, Cigdem Elmas, Eberhart Zrenner, Ayse Sahaboglu; Repurposing of PARP inhibitors as neuroprotective agents in slow retinal degeneration. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2484.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
In hereditary retinal degenerations, rod and cone photoreceptors lose their functions and as a result irreversible vision loss occurs. Mutations in peripherin-2 gene (PRPH2) in human are associated with slow retinal degeneration similar to that caused by the mouse Prph2/rd2 mutation. The rd2 mouse is characterized by slow degeneration of the rod and cone photoreceptors. Excessive Poly-ADP-ribose polymerase (PARP) activity is causatively linked with retinal degeneration in different mice and rat models for hereditary retinal diseases. Here we compare the neuroprotective effects of three different clinically used PARP inhibitors on rd2 slow retinal degeneration.
rd2 mouse retinae together with retinal pigment epithelium (RPE) were explanted for ex vivo retinal cultures at postnatal day (PN) 9. Retinal explants were treated with three different concentrations of PARP inhibitors (PI1, PI2 and PI3) starting at PN11. One retina was used for the treatment, while the contralateral retina was used as control. Treatment was terminated at the peak of photoreceptor degeneration PN18. TUNEL, PAR and Cone-Arrestin (CAR) staining were performed for the assessment of dying cells, PAR accumulation and number of cone photoreceptors respectively.
The TUNEL assay assessment of dying photoreceptors showed that all PARP inhibitors (PI1, PI2, PI3) decreased the number of dying photoreceptors in rd2 retinae. The maximal level of photoreceptor protection was detected with 100nM PI1, 3nM PI2 and 10nM PI3 (untreated: 1.3 ± 0.6 SEM, n=9, PI1: 0.6 ± 0.04 SEM, n=4, PI2: 0.4 ± 0.04 SEM, n=5, PI3: 0.9 ± 0.1 SEM, n=7, p ≤0.0001). The most effective doses for PARP inhibition were assessed by the number of PAR+ cells in ONL (PAR; untreated: 0.2 ± 0.01 SEM, n=4, PI1: 0.1 ± 0.01 SEM, n=5, PI2: 0.1 ± 0.03 SEM n=5, p ≤0.01). In addition, 100nM PI1 treatment led to a significant increase in CAR positive photoreceptor density and percentage in ONL (CAR density; untreated: 1.1 ± 0.1 SEM n=4, PI1: 1.4 ± 0.1 SEM n=4 p ≤0.05, CAR percentage; untreated: 4.1 ± 0.4 SEM n=4, PI1: 5.6 ± 0.2 SEM n=4, p ≤0.05).
Excessive PARP activation is associated with rd2 photoreceptor cell death. As shown here, application of PARP inhibitors can reduce the number of dying photoreceptors in mice. Repurposing of PARP inhibitors may be worthwhile to be investigated as treatment strategy in human hereditary photoreceptor dystrophies.
This is a 2020 ARVO Annual Meeting abstract.
This PDF is available to Subscribers Only