Engeletin is a natural derivative of Smilax glabra rhizomilax that exhibits anti-inflammatory activity and suppresses lipid peroxidation. In the present study, we sought to elucidate the mechanistic basis for the neuroprotective and pro-angiogenic activity of engeltin in a human umbilical vein endothelial cells (HUVECs)
oxygen-
glucose deprivation and reoxygenation (OGD/R) model system and a
middle cerebral artery occlusion (MCAO) rat model of
cerebral ischemia and
reperfusion injury. These analyses revealed that
engeletin (10, 20, or 40 mg/kg) was able to reduce the
infarct volume, increase cerebral blood flow, improve neurological function, and bolster the expression of
vascular endothelial growth factor (
VEGF), vasohibin-2 (Vash-2),
angiopoietin-1 (Ang-1), phosphorylated human
angiopoietin receptor tyrosine kinase 2 (p-Tie2), and
platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) in MCAO rats. Similarly,
engeletin (100, 200, or 400 nM) markedly enhanced the migration, tube formation, and
VEGF expression of HUVECs in an OGD/R model system, while the
VEGF receptor (R) inhibitor
axitinib reversed the observed changes in HUVEC tube formation activity and Vash-2,
VEGF, and CD31 expression. These data suggested that
engeletin exhibited significant
neuroprotective effects against
cerebral ischemia and
reperfusion injury in rats, and improved cerebrovascular angiogenesis by modulating the
VEGF/vasohibin and Ang-1/Tie-2 pathways.