Ligustilide Ameliorates the Permeability of the Blood-Brain Barrier Model In Vitro During Oxygen-Glucose Deprivation Injury Through HIF/VEGF Pathway

J Cardiovasc Pharmacol. 2019 May;73(5):316-325. doi: 10.1097/FJC.0000000000000664.


Chuanxiong rhizome has been widely used for the treatment of cerebral vascular disease in traditional Chinese medicine. The integrity of blood-brain barrier (BBB) is closely linked to the cerebral vascular disease. The protective effects of ligustilide, the major bioactive component in Chuanxiong rhizome, on cerebral blood vessels have been reported previously, but its effects and potential mechanism on BBB have not been entirely clarified. In the current work, the effects of ligustilide on BBB permeability and the underlying molecular mechanisms had been investigated using the model of BBB established by coculturing astrocytes and brain microvascular endothelial cells isolated from the rat brain. The ischemia-damaged model of BBB has been established with oxygen and glucose deprivation (OGD). Our results indicated that OGD significantly increased the permeability in the coculture BBB model. This OGD-induced increase in permeability could suppress by ligustilide in a concentration-dependent manner. Also, ligustilide promoted both gene and protein expression of tight junction proteins. Ligustilide suppressed the upregulation of HIF-1α, vascular endothelial growth factor, and AQP-4 in the BBB model induced by OGD. Collectively, all results have demonstrated that ligustilide is capable of reducing the permeability of BBB in vitro model induced by OGD through HIF-1α/vascular endothelial growth factor pathway and AQP-4, which provide a new target for the clinical application of ligustilide on BBB after stroke in future.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Butyrolactone / analogs & derivatives*
  • 4-Butyrolactone / pharmacology
  • Animals
  • Aquaporin 4 / metabolism
  • Astrocytes / drug effects*
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Blood-Brain Barrier / drug effects*
  • Blood-Brain Barrier / metabolism
  • Blood-Brain Barrier / pathology
  • Capillary Permeability / drug effects*
  • Cell Hypoxia
  • Cells, Cultured
  • Coculture Techniques
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Glucose / deficiency*
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Male
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Tight Junctions / drug effects
  • Tight Junctions / metabolism
  • Tight Junctions / pathology
  • Vascular Endothelial Growth Factor A / metabolism*
  • Zonula Occludens-1 Protein / genetics
  • Zonula Occludens-1 Protein / metabolism


  • Aqp4 protein, rat
  • Aquaporin 4
  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Tjp1 protein, rat
  • Vascular Endothelial Growth Factor A
  • Zonula Occludens-1 Protein
  • vascular endothelial growth factor A, rat
  • ligustilide
  • Glucose
  • 4-Butyrolactone