Imidazole-based alkaloid derivative LCB54-0009 suppresses ocular angiogenesis and lymphangiogenesis in models of experimental retinopathy and corneal neovascularization.
OBJECTIVE
Abnormally induced angiogenesis and lymphangiogenesis are associated with human diseases, including neovascular eye disease. Substances that inhibit these processes may have potential as an attractive therapeutic strategy for these diseases.


METHODS
In vitro and in vivo angiogenesis and/or lymphangiogenesis were assessed in VEGF- or hypoxia-stimulated endothelial and retinal cells and in animal models of oxygen-induced retinopathy (OIR), streptozotocin-induced diabetic retinopathy (SIDR), suture-induced inflammatory corneal neovascularization (SICNV) and silver nitrate-induced corneal neovascularization. HUVECs and retinal cells were cultured under hypoxic conditions or incubated with VEGF to identify the molecular mechanisms involved.


RESULTS
The imidazole-based alkaloid derivative LCB54-0009 inhibited capillary-like tube formation in VEGF-induced HUVECs without inducing cytotoxic effects. Intravitreal injection of LCB54-0009 into retinas suppressed the formation of the pathological neovascular tufts and increased vascular permeability in both OIR of mice and SIDR of rats. Furthermore, subconjunctival injection of LCB54-0009 into the cornea suppressed corneal inflammation and inflammation-associated angiogenesis and lymphangiogenesis in SICNV of mice and silver nitrate cauterization of rats. These pharmacological activities were associated with effects on HIF-1α protein stability and HIF-1α/NF-κB redox sensitivity through its antioxidant activities. LCB54-0009 also inhibited the hypoxia-induced expression of angiopoietin-2, and VEGF-induced VEGFR-2 activation and downstream signalling, resulting in the down-regulation of the expression of pro-angiogenic factors and pro-inflammatory mediators and an up-regulation of the expression of anti-angiogenic factors.


CONCLUSIONS
LCB54-0009 is a potential candidate molecule for blocking pathological angiogenesis and lymphangiogenesis mediated by HIF-1α- angiopoietin-2 expression and VEGFR-2 activation.
Department of Dermatology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Byung-Hak
BH
Kim
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
Junyeop
J
Lee
Catholic Institute for Visual Science, Department of Ophthalmology and Visual Science, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Jun-Sub
JS
Choi
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
Dae Young
DY
Park
LegoChem Biosciences, Inc., Daejeon, Korea.
Ho Young
HY
Song
LegoChem Biosciences, Inc., Daejeon, Korea.
Tae Kyo
TK
Park
Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
Chung-Hyun
CH
Cho
Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
Sang-Kyu
SK
Ye
Catholic Institute for Visual Science, Department of Ophthalmology and Visual Science, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Choun-Ki
CK
Joo
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
Gou Young
GY
Koh
Department of Dermatology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Tae-Yoon
TY
Kim
D000470:Alkaloids / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology / Q000627:therapeutic use*; D016510:Corneal Neovascularization / Q000139:chemically induced / Q000188:drug therapy*; D003930:Diabetic Retinopathy / Q000139:chemically induced / Q000188:drug therapy*; D004195:Disease Models, Animal; D015536:Down-Regulation; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D042583:Lymphangiogenesis / Q000187:drug effects*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000188:drug therapy*; D010100:Oxygen; D061251:Primary Cell Culture; D051381:Rats; D012160:Retina / Q000187:drug effects / Q000378:metabolism; D012835:Silver Nitrate; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
C000607981:3-(2-((3,4-dihydroxyphenyl)-(4-(2-dimethylaminoethyl)imidazol-1-yl)methyl)benzo(1,3)dioxol-5-yl)propionic acid; D000470:Alkaloids; D020533:Angiogenesis Inhibitors; D042702:Angiopoietin-2; D052117:Benzodioxoles; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007093:Imidazoles; D016328:NF-kappa B; D042461:Vascular Endothelial Growth Factor A; D012835:Silver Nitrate; D040301:Vascular Endothelial Growth Factor Receptor-2; D010100:Oxygen