Anti-angiogenic activities of hypericin in vivo: Potential for ophthalmologic applications

Gad Lavie, Mathilda Mandel, Sadick Hazan, Tilda Barliya, Michael Blank, Aaron Grunbaum, Daniel Meruelo, Arieh Solomon

Research output: Contribution to journalArticlepeer-review

Abstract

Hypericin, a perihydroxylated dianthraquinone is shown here to be a highly potent inhibitor of angiogenesis in several ocular models examined in rat eyes. Extensive angiogenesis induced in the cornea and iris by intra-ocular administration of FGF-2 was effectively inhibited by a minimum of four dose regimens of hypericin (2 mg/kg) administered via the intraperitoneal route at 48 h intervals. Maximal inhibition was achieved when animal treatment with hypericin was initiated 48 h prior to inoculation of FGF-2. The molecular basis for the hypericin-mediated inhibition of angiogenesis in the anterior eye compartment appears to involve several sites in the cascade leading to angiogenesis. We show that the activating phosphorylation of extracellular signal-regulated MAP kinases (ERK1/2) is inhibited by hypericin in human retinal pigment epithelial cells and in EA.hy926 cells, an endothelial hybridoma expressing endothelial cell properties. ERK1/2 activity is required for the transactivation of hypoxia-inducible factor 1 alpha (HIF-1α) and in VEGF-induced blood vessel sprouting. MT1-MMP activity in human microvascular endothelial cells was also inhibited. The findings identify hypericin as a potentially useful agent in the treatment of ophthalmic neovascularization pathogeneses.

Original languageEnglish
Pages (from-to)35-42
Number of pages8
JournalAngiogenesis
Volume8
Issue number1
DOIs
StatePublished - Mar 2005

Keywords

  • Agiogenesis
  • Hsp90
  • Hypericin
  • MAP kinases
  • Neovascularization

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