The Inhibitory Effect of Selected D2 Dopaminergic Receptor Agonists on VEGF-Dependent Neovascularization in Zebrafish Larvae: Potential New Therapy in Ophthalmic Diseases

Abstract

Pathological angiogenesis is correlated with many ophthalmic diseases. The most common are exudative age-related macular degeneration and proliferative diabetic retinopathy. The current treatment for these diseases is based on regularly administered anti-VEGF antibodies injections. In the study, we investigated selected D2 dopaminergic receptor agonists, namely bromocriptine, cabergoline and pergolide, on hypoxia-induced neovascularization. We used the zebrafish laboratory model, specifically three-day post fertilization (dpf) Tg(fli-1: EGFP) zebrafish larvae. To induce abnormal angiogenesis of hyaloid-retinal vessels (HRVs) and intersegmental vessels (ISVs), the larvae were treated with cobalt chloride (II) (CoCl2) (a hypoxia-inducing agent) from 24 h post fertilization. The inhibitory role of D2 dopaminergic receptor agonists was investigated using confocal microscopy and qPCR. Additionally, the results were compared to those obtained in the group treated with CoCl2 followed by bevacizumab, the well-known antiangiogenic agent. Confocal microscopy analyses revealed severe deformation of vessels in the CoCl2 treated group, while co-incubation with bromocriptine, cabergoline, pergolide and bevacizumab, respectively, significantly inhibited abnormalities of angiogenesis. The qPCR analyses supported the protective role of the chosen dopaminergic agonists by demonstrating their influence on CoCl2-derived upregulation of vegfaa expression. The present results suggest that the D2 receptor agonists can be considered as a new direction in research for antiangiogenic therapy.

Retinal Toxicity Induced by Chemical Agents

“…In a study with a zebrafish animal model, retinal neovascularization induced by cobalt chloride promoted hypoxia. Pre-incubation with bromocriptine, cabergoline, pergolide, and all ergot-derived D2 dopamine receptor agonists significantly inhibited abnormalities of angiogenesis, decreasing mRNA expression levels of vascular endothelial growth factor Aa (VEGFAA) [ 130 ].…”

Effects of endogenous dopamine induced by low concentration atropine eye drops on choroidal neovascularization in high myopia mice

“…This study also showed that DRD2 expression was increased in the low concentration atropine group compared with the control group, and the indirect activation of DRD2 resulted in the decrease of CNV area and VEGFA expression. Recently published a study on fundus neovascularization found that D2 dopaminergic receptor agonists can downregulate VEGF overexpression and should be taken under consideration as new anti-VEGF drug used in ophthalmological vasculature diseases, such as age-related macular degeneration and proliferative form of diabetic retinopathy and diabetic macular edema [9] . Although the level of VEGF in myopia CNV eyes was lower than that in normal…”

“…Dopamine functions through its corresponding membrane receptors, a family of seven transmembrane regions of G-protein-coupled receptors that dopamine receptor into five major subtypes, they were D1-class receptors (D1, D5) and D2-class receptors (D2, D3, D4) [8] . D2 dopaminergic receptor agonists can downregulate VEGF overexpression and should be taken under consideration as new anti-VEGF drug used in ophthalmological vasculature diseases, such as agerelated macular degeneration and proliferative form of diabetic retinopathy and diabetic macular edema [9] . Therefore, low concentrations of atropine may indirectly affect pathological neovascularization of the ocular fundus.…”

Recent Advancement in Breast Cancer Research: Insights from Model Organisms—Mouse Models to Zebrafish

“…As tumor cells injected into the yolk can enter the circulation, go to the tailfin, and create micro-metastases, intravasation has also been observed [128]. Important discoveries regarding the mechanics of sprouting angiogenesis [138][139][140][141], vessel guidance [135][136][137][138][139][140][141][142], and vascular endothelial growth factor signaling [143,144], among other angiogenic processes [145], have been made thanks to the use of zebrafish. Time-lapse imaging can reveal information on the activities of cancer cells and suggest pathways for invasion, proliferation, and metastasis.…”