Olaparib significantly delays photoreceptor loss in a model for hereditary retinal degeneration
| Autor: | Sahaboglu, Ayse, Barth, Melanie, Secer, Enver, del Amo, Eva M., Urtti, Arto, Arsenijevic, Yvan, Zrenner, Eberhart, Paquet-Durand, Francois |
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| Přispěvatelé: | Faculty of Pharmacy, Division of Pharmaceutical Biosciences, Drug Delivery, Drug Research Program, Drug Delivery Unit |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
ROD CGMP-PHOSPHODIESTERASE
Cell Survival Quantitative Structure-Activity Relationship POLY(ADP-RIBOSE) POLYMERASE Poly(ADP-ribose) Polymerase Inhibitors PIGMENTOSA Article Piperazines ACTIVATION Mice Neoplasms Animals BETA-SUBUNIT Cyclic GMP MOUSE RETINA Mice Inbred C3H Retinal Degeneration PARP INHIBITORS 3112 Neurosciences 1184 Genetics developmental biology physiology THERAPEUTIC OPPORTUNITIES Immunohistochemistry Chromatin eye diseases Neuroprotective Agents DNA-DAMAGE CELL-DEATH 317 Pharmacy Phthalazines Rabbits sense organs Poly(ADP-ribose) Polymerases Photoreceptor Cells Vertebrate Protein Binding |
| Zdroj: | Sahaboglu, A, Barth, M, Secer, E, Del Amo, E M, Urtti, A, Arsenijevic, Y, Zrenner, E & Paquet-Durand, F 2016, ' Olaparib significantly delays photoreceptor loss in a model for hereditary retinal degeneration ', Scientific Reports, vol. 6 . https://doi.org/10.1038/srep39537 Scientific reports, vol. 6, pp. 39537 Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep39537 |
| Popis: | The enzyme poly-ADP-ribose-polymerase (PARP) mediates DNA-repair and rearrangements of the nuclear chromatin. Generally, PARP activity is thought to promote cell survival and in recent years a number of PARP inhibitors have been clinically developed for cancer treatment. Paradoxically, PARP activity is also connected to many diseases including the untreatable blinding disease Retinitis Pigmentosa (RP), where PARP activity appears to drive the pathogenesis of photoreceptor loss. We tested the efficacy of three different PARP inhibitors to prevent photoreceptor loss in the rd1 mouse model for RP. In retinal explant cultures in vitro, olaparib had strong and long-lasting photoreceptor neuroprotective capacities. We demonstrated target engagement by showing that olaparib reduced photoreceptor accumulation of poly-ADP-ribosylated proteins. Remarkably, olaparib also reduced accumulation of cyclic-guanosine-monophosphate (cGMP), a characteristic marker for photoreceptor degeneration. Moreover, intravitreal injection of olaparib in rd1 animals diminished PARP activity and increased photoreceptor survival, confirming in vivo neuroprotection. This study affirms the role of PARP in inherited retinal degeneration and for the first time shows that a clinically approved PARP inhibitor can prevent photoreceptor degeneration in an RP model. The wealth of human clinical data available for olaparib highlights its strong potential for a rapid clinical translation into a novel RP treatment. |
| Databáze: | OpenAIRE |
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