DRD2 activation inhibits choroidal neovascularization in patients with Parkinson’s disease and age-related macular degeneration
Thibaud Mathis, … , Stéphane Hunot, Florian Sennlaub
Thibaud Mathis, … , Stéphane Hunot, Florian Sennlaub
Published July 16, 2024
Citation Information: J Clin Invest. 2024;134(17):e174199. https://doi.org/10.1172/JCI174199.
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DRD2 activation inhibits choroidal neovascularization in patients with Parkinson’s disease and age-related macular degeneration

Abstract

Neovascular age-related macular degeneration (nAMD) remains a major cause of visual impairment and puts considerable burden on patients and health care systems. l-DOPA–treated Parkinson’s disease (PD) patients have been shown to be partially protected from nAMD, but the mechanism remains unknown. Using murine models that combine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine–induced (MPTP-induced) PD and laser-induced nAMD with standard PD treatment of l-DOPA/DOPA-decarboxylase inhibitor or specific dopamine receptor inhibitors, we here demonstrate that l-DOPA treatment–induced increase of dopamine-mediated dopamine receptor D2 (DRD2) signaling inhibits choroidal neovascularization independently of MPTP-associated nigrostriatal pathway lesion. Analyzing a retrospective cohort of more than 200,000 patients with nAMD receiving anti-VEGF treatment from the French nationwide insurance database, we show that DRD2 agonist–treated PD patients have a significantly delayed age of onset of nAMD and reduced need for anti-VEGF therapies, similar to the effects of the l-DOPA treatment. While providing a mechanistic explanation for an intriguing epidemiological observation, our findings suggest that systemic DRD2 agonists might constitute an adjuvant therapy to delay and reduce the need for anti-VEGF therapy in patients with nAMD.

Authors

Thibaud Mathis, Florian Baudin, Anne-Sophie Mariet, Sébastien Augustin, Marion Bricout, Lauriane Przegralek, Christophe Roubeix, Éric Benzenine, Guillaume Blot, Caroline Nous, Laurent Kodjikian, Martine Mauget-Faÿsse, José-Alain Sahel, Robin Plevin, Christina Zeitz, Cécile Delarasse, Xavier Guillonneau, Catherine Creuzot-Garcher, Catherine Quantin, Stéphane Hunot, Florian Sennlaub

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Figure 2

The decarboxylation of l-DOPA to dopamine is necessary for its anti-angiogenic effect on CNV ex vivo and in vitro.

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The decarboxylation of l-DOPA to dopamine is necessary for its anti-angi...
(A) Quantitative RT-PCR of mouse DOPA-decarboxylase (Ddc) mRNAs normalized with β-actin of fresh neuroretina, RPE/choroid, and choroid from 8-week-old C57BL/6J mice. (B) Quantitative RT-PCR of human Ddc mRNAs normalized with β-actin of fresh human RPE from donor eye and HCECs. (C) Representative microphotographs of choroidal explants from 2-week-old C57BL/6J pups at day 6 after 3-day treatment with PBS, l-DOPA (1 μM), or dopamine (1 μM). Scale bars: 1 mm. (D) Quantification of vascular sprouting area between days 3 and 6 from choroidal explants prepared from 2-week-old C57BL/6J pups and treated with dopamine (1 μM), benserazide (10 μM), or l-DOPA (1 μM) or preincubated 1 hour with benserazide (10 μM) before addition of l-DOPA (1 μM). One-way ANOVA/Bonferroni’s test. (E) Quantification of vascular sprouting area between days 3 and 6 from choroidal explants prepared from 2-week-old C57BL/6J pups and treated with increasing concentrations of dopamine. (F) Representative microphotographs of DAPI+ HCECs after a 24-hour treatment with PBS, l-DOPA (1 μM), or dopamine (1 μM) with or without VEGF exposure (10 ng/mL). Scale bars: 200 μm. (G) Quantification of DAPI+ HCECs after a 24-hour treatment with PBS, l-DOPA (1 μM), or dopamine (1 μM) with VEGF exposure (10 ng/mL). One-way ANOVA/Bonferroni’s test, PBS vs. l-DOPA P = nonsignificant. (H) Volcano plot of differentially expressed genes and scatterplot of DUSP4 read counts of FACS-sorted CD31+CD11b+ endothelial cells from day 4 choroidal explants that had or had not been incubated with 1 μM dopamine for 24 hours. The volcano plot shows the log2(fold change) (x axis) versus the significance [–log10(P value); y axis] of the 2,276 genes with a log2(fold change) greater than ±1.0. Vertical lines indicate the cutoff of fold change = ±1.0. Adjusted P value, indicated for the difference in DUSP4 transcription, was calculated by Benjamini and Hochberg false discovery rate correction method. (I) Representative microphotographs and quantification of vascular sprouting area between days 3 and 6 of choroidal explants from 2-week-old C57BL/6J Dusp4+/+ and Dusp4–/– pups. Mann-Whitney U test. Scale bars: 1 mm. hRPE, fresh human retinal pigment epithelium; ND, not detected. n is indicated in each column for each group.