Protective effects of PARP1-inhibitory compound in dry age-related macular degeneration

• Published in: Biomedicine & pharmacotherapy Vol. 133; p. 111041
• Main Authors: Ho, Jeongmin, Jang, Ki-Hong, Koo, Tae-Sung, Park, Changmin, Kim, Young-Hoon, Lee, Juhee, Kim, Eunhee
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.01.2021; Elsevier
• Subjects: Administration, Ophthalmic; Animals; Antioxidants - pharmacology; Cell Line; Disease Models, Animal; Dry AMD; Electroretinogram; Funduscopy; Humans; Iodates; Macular Degeneration - chemically induced; Macular Degeneration - drug therapy; Macular Degeneration - enzymology; Macular Degeneration - pathology; Male; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - pathology; Ocular Absorption; Ophthalmic Solutions; Oxidative Stress - drug effects; PARP1; PARP1-inhibitory compound; Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors; Poly (ADP-Ribose) Polymerase-1 - metabolism; Poly(ADP-ribose) Polymerase Inhibitors - administration & dosage; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Rabbits; Rats; Rats, Sprague-Dawley; Retinal Pigment Epithelium - drug effects; Retinal Pigment Epithelium - enzymology; Retinal Pigment Epithelium - pathology; RPE; PARP1; ARPE-19; H&E; INL; RPE; I.P; PIC; Dry AMD; RGA; Funduscopy; I.V; P.O; GCL; Electroretinogram; SI; IC50; AMD; EC50; RIPK1; ERG; PARP1-inhibitory compound
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2020.111041

[Display omitted] •PARP1-inhibitory compound (PIC) shows superior protective effect in RPE cells from oxidative stress-induced death compared to FDA-approved PARP1 inhibitors.•The eye drop application of PIC prevents RPE degeneration in in vivo models of dry AMD.•PIC has plausible candidate in development of eye drops as [5–10] dry AMD therapy. Poly (ADP-ribose) polymerase 1 (PARP1)-dependent cell death in the retinal pigment epithelium (RPE) is implicated in dry age-related macular degeneration (AMD). Although PARP1 inhibitors are available for treating dry AMD, their delivery route is not ideal for patients. The aim of this study was to test the efficacy of a novel PARP1-inhibitory compound (PIC) in vitro and in vivo. This study presents PIC, a novel small molecule, with superior efficacy to PARP1 inhibitors in the market. PIC demonstrated a distinctive inhibitory profile against PARP isotypes than the FDA-approved PARP1 inhibitors. PIC inhibited PARP1 activation at an IC50 of 0.41 ± 0.15 nM in an enzyme-based assay in vitro and at IC50 and EC50 in ARPE-19 cells of 0.11 ± 0.02 nM and 0.22 ± 0.02 nM, respectively, upon H2O2 insult. PIC also moderated mitochondrial fission and depolarization and maintained cellular energy levels under oxidative stress in ARPE-19 cells. Furthermore, PIC demonstrated good corneal penetration in a rat model, presenting PIC as a promising candidate for eye drop therapeutics for dry AMD. When PIC was administered as an eye drop formulation, RPE morphology was preserved, maintaining the thickness of the outer nuclear layers under sodium iodate (SI) treatment in rats. In SI-treated rabbits, eye drop administration of PIC also retained the structural and functional integrity when analyzed using funduscopy and electroretinogram. Collectively, our data portray PIC as an attractive treatment measure for dry AMD.