Novel vascular endothelial growth factor blocker improves cellular viability and reduces hypobaric hypoxia‐induced vascular leakage and oedema in rat brain

Publisher： John Wiley & Sons Inc

E-ISSN： 1440-1681|42|5|475-484

ISSN： 0305-1870

Source： CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY (ELECTRONIC), Vol.42, Iss.5, 2015-05, pp. : 475-484

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Abstract

SummaryVascular endothelial growth factor (VEGF) is an important cerebral angiogenic and permeability factor under hypoxia. There is a need to find effective molecules that may ameliorate hypoxia‐induced cerebral oedema. In silico identification of novel candidate molecules that block VEGF‐A site were identified and validated with a Ramachandran plot. The active site residues of VEGF‐A were detected by Pocketfinder, CASTp, and DogSiteScorer. Based on in silico data, three VEGF‐A blocker (VAB) candidate molecules (VAB1, VAB2, and VAB3) were checked for improvement in cellular viability and regulation of VEGF levels in N2a cells under hypoxia (0.5% O2). Additionally, the best candidate molecule's efficacy was assessed in male Sprague‐Dawley rats for its ameliorative effect on cerebral oedema and vascular leakage under hypobaric hypoxia 7260 m. All experimental results were compared with the commercially available VEGF blocker sunitinib. Vascular endothelial growth factor‐A blocker 1 was found most effective in increasing cellular viability and maintaining normal VEGF levels under hypoxia (0.5% oxygen) in N2a cells. Vascular endothelial growth factor‐A blocker 1 effectively restored VEGF levels, decreased cerebral oedema, and reduced vascular leakage under hypobaric hypoxia when compared to sunitinib‐treated rats. Vascular endothelial growth factor‐A blocker 1 may be a promising candidate molecule for ameliorating hypobaric hypoxia‐induced vasogenic oedema by regulating VEGF levels.