Format

Send to

Choose Destination
Cell Mol Life Sci. 2019 Aug 26. doi: 10.1007/s00018-019-03283-2. [Epub ahead of print]

Drug repurposing studies of PARP inhibitors as a new therapy for inherited retinal degeneration.

Author information

1
Division of Experimental Ophthalmology, Institute for Ophthalmic Research, Tübingen, Germany. aysesahaboglu@hotmail.com.
2
Departamento Ciencias Biomédicas, Universidad Cardenal Herrera-CEU Universities, Valencia, Spain.
3
Department of Thoracic and Cardiovascular Surgery, University Hospital Tübingen, Tübingen, Germany.
4
German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
5
Department of Medical Genetics, Erciyes University, Kayseri, Turkey.
6
Universidad Nacional Autónoma de México, Ciudad de México, México.
7
Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey.
8
Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey. serdar.durdagi@med.bau.edu.tr.

Abstract

The enzyme poly-ADP-ribose-polymerase (PARP) has important roles for many forms of DNA repair and it also participates in transcription, chromatin remodeling and cell death signaling. Currently, some PARP inhibitors are approved for cancer therapy, by means of canceling DNA repair processes and cell division. Drug repurposing is a new and attractive aspect of therapy development that could offer low-cost and accelerated establishment of new treatment options. Excessive PARP activity is also involved in neurodegenerative diseases including the currently untreatable and blinding retinitis pigmentosa group of inherited retinal photoreceptor degenerations. Hence, repurposing of known PARP inhibitors for patients with non-oncological diseases might provide a facilitated route for a novel retinitis pigmentosa therapy. Here, we demonstrate and compare the efficacy of two different PARP inhibitors, BMN-673 and 3-aminobenzamide, by using a well-established retinitis pigmentosa model, the rd1 mouse. Moreover, the mechanistic aspects of the PARP inhibitor-induced protection were also investigated in the present study. Our results showed that rd1 rod photoreceptor cell death was decreased by about 25-40% together with the application of these two PARP inhibitors. The wealth of human clinical data available for BMN-673 highlights a strong potential for a rapid clinical translation into novel retinitis pigmentosa treatments. Remarkably, we have found that the efficacy of 3 aminobenzamide was able to decrease PARylation at the nanomolar level. Our data also provide a link between PARP activity with the Wnt/β-catenin pathway and the major intracellular antioxidant concentrations behind the PARP-dependent retinal degeneration. In addition, molecular modeling studies were integrated with experimental studies for better understanding of the role of PARP1 inhibitors in retinal degeneration.

KEYWORDS:

Drug repurposing; Molecular modeling; Neuroprotection; PARP; Retinal degeneration

PMID:
31451894
DOI:
10.1007/s00018-019-03283-2

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center