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 1

l-DOPA/DDI treatment prevents choroidal neovascularization independently of subretinal inflammation and loss of central dopaminergic neurons in mice.

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l-DOPA/DDI treatment prevents choroidal neovascularization independentl...
(A and B) TH-stained SNpc (A) and quantification of dopaminergic TH+ neurons in SNpc (B) of 9-week-old C57BL/6J mice that received PBS or MPTP intoxication at 6 weeks of age and laser injury at 8 weeks and were treated with intraperitoneal PBS or l-DOPA (30 mg/kg/d) plus benserazide (bens) (12 mg/kg/d) from 1 week before injury until 7 days after injury. One-way ANOVA/Bonferroni’s test. (C–E) IBA-1– (green) and CD102– (red) stained choroidal flat mounts (C), quantification of number of subretinal IBA-1+ mononuclear phagocytes (MPs) counted on the RPE at a distance of 0–500 μm to CD102+ CNV (D), and quantification of CD102+ CNV area (E), 7 days after laser injury of mice that received MPTP intoxication and treatment regimens as for A. One-way ANOVA/Bonferroni’s test; control-PBS (Ctl-PBS) vs. MPTP-PBS 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, benserazide (12 mg/kg/d), or l-DOPA (30 mg/kg/d) plus benserazide (12 mg/kg/d) from 1 week before injury until sacrifice. (G) Quantification of subretinal IBA-1+ MPs counted on the RPE at a distance of 0–500 μm to CD102+ CNV, 4, 7, and 10 days after laser injury of 8-week-old C57BL/6J mice treated with PBS, benserazide (12 mg/kg/d), or l-DOPA (30 mg/kg/d) plus benserazide (12 mg/kg/d) from 1 week before laser injury until sacrifice. One-way ANOVA/Bonferroni’s test; P = nonsignificant for each group. (H) CD102– (red) stained choroidal flat mounts 7 days after laser injury of 8-week-old C57BL/6J mice treated with PBS, benserazide (12 mg/kg/d), or l-DOPA (30 mg/kg/d) plus benserazide (12 mg/kg/d) from 1 week before injury until sacrifice. (I) CD102+ CNV area 4, 7, and 10 days after laser injury of 8-week-old C57BL/6J mice treated with PBS, benserazide (12 mg/kg/d), or l-DOPA (30 mg/kg/d) plus benserazide (12 mg/kg/d) from 1 week before injury until sacrifice. One-way ANOVA/Bonferroni’s test. n is indicated in each column for each group. Scale bars: 200 μm.