Icariside II attenuates cerebral ischemia/reperfusion-induced blood-brain barrier dysfunction in rats via regulating the balance of MMP9/TIMP1

Acta Pharmacol Sin. 2020 Dec;41(12):1547-1556. doi: 10.1038/s41401-020-0409-3. Epub 2020 Jun 2.

Abstract

Cerebral ischemia/reperfusion (I/R) results in harmful consequences during ischemic stroke, especially the disruption of the blood-brain barrier (BBB), which leads to severe hemorrhagic transformation through aggravation of edema and brain hemorrhage. Our previous study demonstrated that icariside II (ICS II), which is derived from Herba Epimedii, attenuates cerebral I/R injury by inhibiting the GSK-3β-mediated activation of autophagy both in vitro and in vivo. However, the effect of ICS II on the BBB remains unclear. Thus, in this study, we investigated the regulation of BBB integrity by ICS II after cerebral I/R injury and further explored the underlying mechanism in rats. Cerebral I/R injury was induced by middle cerebral artery occlusion (MCAO), and the treatment groups were administered ICS II at a dose of 16 mg/kg by gavage twice a day for 3 days. The results showed that ICS II effectively prevented BBB disruption, as evidenced by Evans Blue staining. Moreover, ICS II not only significantly reduced the expression of MMP2/9 but also increased TIMP1 and tight junction protein (occludin, claudin 5, and ZO 1) expression. Intriguingly, ICS II may directly bind to both MMP2 and MMP9, as evidenced by molecular docking. In addition, ICS II also inhibited cerebral I/R-induced apoptosis and ameliorated the Bax/Bcl-2 ratio and cleaved-caspase 3 level. Collectively, our findings reveal that ICS II significantly ameliorates I/R-induced BBB disruption and neuronal apoptosis in MCAO rats by regulating the MMP9/TIMP1 balance and inhibiting the caspase 3-dependent apoptosis pathway.

Keywords: MCAO rats; Stroke; apoptosis; blood–brain barrier; cerebral ischemia/reperfusion; icariside II; molecular docking; tight junction.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Blood-Brain Barrier / drug effects*
  • Brain / pathology
  • Brain Ischemia / etiology
  • Brain Ischemia / metabolism*
  • Brain Ischemia / pathology
  • Claudin-5 / metabolism
  • Flavonoids / metabolism
  • Flavonoids / therapeutic use*
  • Infarction, Middle Cerebral Artery / complications
  • Infarction, Middle Cerebral Artery / pathology
  • Male
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / metabolism*
  • Molecular Docking Simulation
  • Neurons / drug effects
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / therapeutic use*
  • Occludin / metabolism
  • Protein Binding
  • Rats, Sprague-Dawley
  • Reperfusion Injury / etiology
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / pathology
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism*
  • Zonula Occludens-1 Protein / metabolism

Substances

  • Claudin-5
  • Cldn5 protein, rat
  • Flavonoids
  • Neuroprotective Agents
  • Occludin
  • Ocln protein, rat
  • TIMP1 protein, rat
  • Tissue Inhibitor of Metalloproteinase-1
  • Tjp1 protein, rat
  • Zonula Occludens-1 Protein
  • baohuoside I
  • Matrix Metalloproteinase 2
  • Mmp2 protein, rat
  • Matrix Metalloproteinase 9
  • Mmp9 protein, rat