DRD2 activation inhibits choroidal neovascularization in patients with Parkinson’s disease and age-related macular degeneration
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
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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Research Article Neuroscience Ophthalmology

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 3

DRD2 activation mediates the CNV inhibition observed under l-DOPA/DDI treatment in vivo.

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DRD2 activation mediates the CNV inhibition observed under l-DOPA/DDI tr...
Quantitative RT-PCR of dopamine receptor (DR1–DR5) mRNAs normalized with β-actin of 8-week-old C57BL/6J mouse retina (A) or choroid (B) 7 days after laser injury compared with control mice. Mann-Whitney U test DRD2 in CNV group vs. DRD2 in Ctl group; P value indicated in the figure when statistically significant. (C) Quantitative RT-PCR of DRD2 mRNAs normalized with β-actin of fresh RPE from donor eye and HCECs. (D) Representative microphotographs of choroidal explants of 2-week-old C57BL/6J pups at day 6 after 3-day treatment with PBS or dopamine (1 μM) or pretreated 1 hour with eticlopride (10 μM) before addition of dopamine (1 μM). Scale bars: 1 mm. (E) Quantification of choroidal vascular sprouting from 2-week-old C57BL/6J pups at day 6 after 3 days of treatment with PBS or dopamine (1 μM) or pretreated for 1 hour with eticlopride (10 μM) before addition of dopamine (1 μM), quinpirole (10 μM), SKF38393 (10 μM), or PD168077 (10 μM). One-way ANOVA/Bonferroni’s test; P values indicated in the figure, PBS vs. SKF38393 and PD168077 P = nonsignificant. (F) IBA-1– (green) and CD102– (red) stained choroidal flat mounts 7 days after laser injury of 8-week-old C57BL/6J mice treated with PBS or quinpirole (5 mg/kg) from 1 week before injury until sacrifice. Scale bars: 200 μm. (G) Quantification of subretinal IBA-1+ MPs counted on the RPE at a distance of 0–500 μm to CD102+ CNV 7 days after laser injury of 8-week-old C57BL/6J mice and treated with PBS, l-DOPA (30 mg/kg) plus benserazide (12 mg/kg), l-DOPA (30 mg/kg) plus benserazide (12 mg/kg) plus eticlopride (1 mg/kg), or quinpirole (5 mg/kg) from 1 week before injury until sacrifice. One-way ANOVA/Bonferroni’s test; P = nonsignificant for each group. (H) CD102+ CNV area 7 days after laser injury of 8-week-old C57BL/6J mice and treated with PBS, l-DOPA (30 mg/kg) plus benserazide (12 mg/kg), l-DOPA (30 mg/kg) plus benserazide (12 mg/kg) plus eticlopride (1 mg/kg), or quinpirole (5 mg/kg) from 1 week before injury until sacrifice. One-way ANOVA/Bonferroni’s test; P values indicated in the figure. hRPE, fresh human retinal pigment epithelium. n is indicated in each column for each group.