DRD2 activation inhibits choroidal neovascularization in patients with Parkinson's disease and age-related macular degeneration

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Mathis, Thibaud and Baudin, Florian and Mariet, Anne-Sophie and Augustin, Sébastien and Bricout, Marion and Przegralek, Lauriane and Roubeix, Christophe and Benzenine, Éric and Blot, Guillaume and Nous, Caroline and Kodjikian, Laurent and Mauget-Faÿsse, Martine and Sahel, José-Alain and Plevin, Robin and Zeitz, Christina and Delarasse, Cécile and Guillonneau, Xavier and Creuzot-Garcher, Catherine and Quantin, Catherine and Hunot, Stéphane and Sennlaub, Florian (2024) DRD2 activation inhibits choroidal neovascularization in patients with Parkinson's disease and age-related macular degeneration. Journal of Clinical Investigation, 134 (17). e174199. ISSN 0021-9738 (https://doi.org/10.1172/JCI174199)

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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.

ORCID iDs

Mathis, Thibaud, Baudin, Florian, Mariet, Anne-Sophie, Augustin, Sébastien, Bricout, Marion, Przegralek, Lauriane, Roubeix, Christophe, Benzenine, Éric, Blot, Guillaume, Nous, Caroline, Kodjikian, Laurent, Mauget-Faÿsse, Martine, Sahel, José-Alain, Plevin, Robin ORCID logoORCID: https://orcid.org/0000-0002-7849-1220, Zeitz, Christina, Delarasse, Cécile, Guillonneau, Xavier, Creuzot-Garcher, Catherine, Quantin, Catherine, Hunot, Stéphane and Sennlaub, Florian;
CORE (COnnecting REpositories)