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Updated: Nov 23, 2025
A Protocol to Evaluate and Quantify Retinal Pigmented Epithelium Pathologies in Mouse Models of Age-Related Macular Degeneration
Published on: March 10, 2023
Protective effects of PARP1-inhibitory compound in dry age-related macular degeneration
Jeongmin Ho1, Ki-Hong Jang1, Tae-Sung Koo2
1Department of Biological Sciences, Chungnam National University, Daejeon, South Korea.
Abstract:
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.
Insights
A novel compound, PIC, effectively inhibits Poly (ADP-ribose) polymerase 1 (PARP1) in retinal cells. Administered via eye drops, PIC shows promise for treating dry age-related macular degeneration (AMD) by preserving retinal structure and function.
Area of Science:
- Ophthalmology
- Molecular Biology
- Pharmacology
Background:
- Poly (ADP-ribose) polymerase 1 (PARP1)-dependent cell death in retinal pigment epithelium (RPE) contributes to dry age-related macular degeneration (AMD).
- Current PARP1 inhibitors for dry AMD have suboptimal delivery routes.
- A novel PARP1-inhibitory compound (PIC) was developed to address these limitations.
Purpose of the Study:
- To evaluate the in vitro and in vivo efficacy of a novel PARP1-inhibitory compound (PIC).
- To assess PIC's potential as an eye drop therapeutic for dry AMD.
Main Methods:
- Enzyme-based assays and ARPE-19 cell-based assays were used to determine PIC's inhibitory profile against PARP isotypes.
- Mitochondrial function and cellular energy levels were assessed in ARPE-19 cells under oxidative stress.
- Corneal penetration, RPE morphology, outer nuclear layer thickness, and retinal function were evaluated in rat and rabbit models following topical PIC administration.
Main Results:
- PIC exhibited superior efficacy compared to existing PARP1 inhibitors, with low nanomolar IC50 and EC50 values.
- PIC effectively moderated mitochondrial fission, depolarization, and maintained cellular energy levels under oxidative stress.
- Topical PIC application in rat and rabbit models preserved RPE morphology, outer nuclear layer thickness, and retinal structural and functional integrity.
Conclusions:
- PIC demonstrates a distinctive inhibitory profile and potent efficacy against PARP1 activation.
- PIC effectively protects retinal cells from oxidative stress by preserving mitochondrial function and energy levels.
- PIC's good corneal penetration and efficacy as an eye drop formulation make it a promising therapeutic candidate for dry AMD.
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