Investigative ophthalmology & visual science · 2026
Levodopa Suppresses Choroidal Neovascularization Through a Tyrosinase-Dependent Dual Mechanism.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Veernala Induvahi, Cuamatzi-Castelan Andrea Sara, Rajesh Amrita, Gong Joyce, D'Souza Godlyn J, Lavine Jeremy A
Аннотация
PURPOSE: Levodopa (L-DOPA), a precursor for melanin and dopamine, has been linked to reduced intravitreal injection burden and delayed onset of neovascular age-related macular degeneration (AMD). Further, L-DOPA and dopamine receptor D2 (DRD2) agonists inhibit laser-induced choroidal neovascularization (CNV). However, the contributions of endogenous versus exogenous L-DOPA signaling, their effects in alternative CNV models, and the contributions of DRD2 versus GPR143, the receptor for L-DOPA, signaling remain unresolved.
METHODS: Choroidal sprouting assays (CSA) were performed using wild-type (WT) and tyrosinase-mutant (Tyr-/-) mice with and without dopamine pathway agonists and antagonists. CNV number and area were measured in pigmented Vldlr-/- and albino Vldlr-/-Tyr-/- mice with and without L-DOPA or the DRD2 agonist quinpirole.
RESULTS: Endogenous L-DOPA deficiency (Tyr-/-) did not affect CSA sprouting or CNV in Vldlr-/- mice. Exogenous L-DOPA suppressed angiogenesis ex vivo in both WT and Tyr-/- choroidal explants in a dose-dependent manner. In vivo, L-DOPA reduced CNV lesion number, lesion area, and macrophage infiltration in albino but not pigmented Vldlr-/- mice. Dopamine and quinpirole produced modest anti-angiogenic effects, and eticlopride partially reversed L-DOPA inhibition in choroidal explants. Quinpirole suppressed CNV lesion number, lesion area, and macrophage infiltration in pigmented Vldlr-/- mice.
CONCLUSIONS: Our findings show that L-DOPA's anti-angiogenic effects are exogenous, more effective in tyrosinase-mutant mice, and mediated by both the DRD2 and non-DRD2 pathways, potentially GPR143. The saturation of GPR143 signaling in pigmented eyes provides a mechanistic basis for reduced responsiveness, highlighting the importance of pigmentation biology in the development of L-DOPA-based therapeutics.
METHODS: Choroidal sprouting assays (CSA) were performed using wild-type (WT) and tyrosinase-mutant (Tyr-/-) mice with and without dopamine pathway agonists and antagonists. CNV number and area were measured in pigmented Vldlr-/- and albino Vldlr-/-Tyr-/- mice with and without L-DOPA or the DRD2 agonist quinpirole.
RESULTS: Endogenous L-DOPA deficiency (Tyr-/-) did not affect CSA sprouting or CNV in Vldlr-/- mice. Exogenous L-DOPA suppressed angiogenesis ex vivo in both WT and Tyr-/- choroidal explants in a dose-dependent manner. In vivo, L-DOPA reduced CNV lesion number, lesion area, and macrophage infiltration in albino but not pigmented Vldlr-/- mice. Dopamine and quinpirole produced modest anti-angiogenic effects, and eticlopride partially reversed L-DOPA inhibition in choroidal explants. Quinpirole suppressed CNV lesion number, lesion area, and macrophage infiltration in pigmented Vldlr-/- mice.
CONCLUSIONS: Our findings show that L-DOPA's anti-angiogenic effects are exogenous, more effective in tyrosinase-mutant mice, and mediated by both the DRD2 and non-DRD2 pathways, potentially GPR143. The saturation of GPR143 signaling in pigmented eyes provides a mechanistic basis for reduced responsiveness, highlighting the importance of pigmentation biology in the development of L-DOPA-based therapeutics.