Dopamine D2 receptor activation inhibits choroidal neovascularization in Parkinson patients with age related macular degeneration.. Dopamine D2 receptor activation inhibits choroidal neovascularization in Parkinson patients with age related macular degeneration.

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 Disease (PD) patients have been shown to be partially protected from nAMD, but the mechanism remains unknown. Using murine models combining 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD and laser-induced nAMD, 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 receptor D2 (DRD2) signaling inhibits choroidal neovascularization independently of MPTP-associated nigrostriatal pathway lesion. Analyzing a retrospective cohort of more than two hundred thousand nAMD patients 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 for nAMD (81.4 (±7.0) vs 79.4 (±8.1) years old, respectively, p<0.0001) and reduced need for anti-VEGF therapies (-0.6 injections per 100 mg/day daily dose of DRD2 agonists the second year of treatment), similar to 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 nAMD patients. Overall design: To gain insight into the transcriptionnal modification induced by dopanime in endothelial cells, we cultured choroidal explants for 3 days and then stimulated them with 1µM dopamine. After 24 hours, choroidal explants were collected and dissociated with collagenase. Two hundred CD31+CD11b- cells were sorted on a BD FACS melody. RNA-seq libraries were prepared using the Smartseq V4 kit from Takara.