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EV30 suppresses choroidal neovascularization associated with modulation of the mTOR/NF-κB/p38 MAPK signaling pathway
Songyu Xu1, Qiao Zhuo2, Jing Li2
1Eye Institute and Department of Ophthalmology, the Eye & ENT Hospital, Fudan University, Shanghai, 200031, China; Key Laboratory of Myopia and Related Eye Diseases, NHC, Shanghai, 200031, China; Key laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, 200031, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, 200031, China; School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China.
Abstract:
Wet age-related macular degeneration (wAMD) is a leading cause of irreversible vision loss characterized by pathological choroidal neovascularization (CNV). While anti-VEGF therapies are the standard of care, limitations such as treatment resistance and side effects necessitate novel therapeutic agents. This study evaluates the therapeutic efficacy and mechanism of EV30, a novel pterostilbene derivative, in suppressing CNV. EV30 was synthesized based on the pterostilbene template. In vitro, the effects of EV30 on human umbilical vein endothelial cells (HUVECs) proliferation, migration, and tube formation were assessed using Cell Counting Kit-8 (CCK-8), scratch wound, and tube formation assays, respectively. Mechanistic pathways were investigated via Western blotting and RT-qPCR. In vivo, a laser-induced CNV mouse model was treated with intravitreal EV30. Efficacy was evaluated utilizing fundus photography, fluorescein angiography (FFA), optical coherence tomography (OCT), and choroidal flat mounts (IB4 staining). Finally, biosafety was assessed through histology (H&E), electroretinography (ERG), and blood analysis. EV30 demonstrated potent anti-angiogenic properties in vitro, significantly inhibiting HUVEC proliferation, migration, and tube formation in a dose- and time-dependent manner. EV30 reduced vascular endothelial growth factor A (VEGFA) expression and modulated the phosphorylation status of proteins associated with the mTOR/NF-κB/p38 MAPK signaling pathway. In the laser-induced CNV model, EV30 effectively reduced lesion area and vascular leakage comparable to bevacizumab. Furthermore, ERG analysis revealed that EV30 partially preserved retinal electrophysiological function, as indicated by improved scotopic a-wave amplitudes, suggesting functional protection of the retina in the CNV model. EV30 exerted anti-angiogenic effects and was associated with modulation of mTOR/NF-κB/p38 MAPK signaling activity. Together, these findings suggest that EV30 represents a potential therapeutic candidate for CNV by suppressing pathological angiogenesis and modulating inflammation-associated signaling pathways.
Insights
A novel pterostilbene derivative, EV30, shows promise in treating wet age-related macular degeneration (wAMD). This compound effectively inhibits pathological choroidal neovascularization (CNV) and demonstrates biosafety, offering a potential new therapy for vision loss.
Area of Science:
- Ophthalmology
- Molecular Biology
- Pharmacology
Background:
- Wet age-related macular degeneration (wAMD) causes irreversible vision loss due to pathological choroidal neovascularization (CNV).
- Current anti-VEGF therapies for wAMD have limitations, including treatment resistance and side effects, highlighting the need for novel therapeutic agents.
Purpose of the Study:
- To evaluate the therapeutic efficacy of EV30, a novel pterostilbene derivative, in suppressing CNV.
- To elucidate the underlying mechanism of action of EV30 in inhibiting CNV.
Main Methods:
- In vitro studies assessed EV30's effects on human umbilical vein endothelial cells (HUVECs) proliferation, migration, and tube formation.
- Mechanistic pathways were investigated using Western blotting and RT-qPCR.
- In vivo efficacy was evaluated in a laser-induced CNV mouse model using fundus photography, FFA, OCT, and choroidal flat mounts; biosafety was assessed via histology, ERG, and blood analysis.
Main Results:
- EV30 exhibited potent anti-angiogenic properties in vitro, inhibiting HUVEC proliferation, migration, and tube formation.
- EV30 reduced vascular endothelial growth factor A (VEGFA) expression and modulated the mTOR/NF-κB/p38 MAPK signaling pathway.
- In vivo, EV30 effectively reduced CNV lesion area and vascular leakage, comparable to bevacizumab, and partially preserved retinal function.
Conclusions:
- EV30 demonstrates significant anti-angiogenic effects and modulates key signaling pathways involved in CNV.
- EV30 shows therapeutic potential for CNV by suppressing pathological angiogenesis and inflammation.
- The biosafety profile and efficacy suggest EV30 as a promising candidate for wAMD treatment.
