S-oxiracetam protect against ischemic stroke via alleviating blood brain barrier dysfunction in rats

Eur J Pharm Sci. 2017 Nov 15;109:40-47. doi: 10.1016/j.ejps.2017.07.029. Epub 2017 Jul 29.

Abstract

The blood brain barrier (BBB) maintains the basic stability of the brain tissue under physiological conditions, while destroys and exaggerates brain edema and inflammatory response after ischemic stroke. In this study, we researched S-oxiracetam (S-ORC), a nootropic drug, alleviates BBB dysfunction and protects against ischemic stroke in rats. Middle cerebral artery occlusion(MCAO)/reperfusion in rats is applied to mimic ischemic stroke. One hour after reperfusion, rats are administered intravenously with different dose (0.12, 0.24, or 0.48g/kg) of S-ORC for continuative three days. Seventy-two hours after MCAO, TTC staining, hematoxylin and eosin (H&E) staining, brain water content, immunohistochemical staining, EB extravasation, western blot are provided to evaluate the protective effect and possible mechanism of S-ORC on BBB dysfunction. Furthermore, brain concentration of verapamil (P-glycoprotein substrate) and atenolol (paracellular transport marker) were assayed by UPLC-MS/MS co administration with or without S-ORC. The results show that post-treatment of S-ORC decreases cerebral infarct size, lessens brain edema, inhibits neutrophil infiltration and cytokines releasing. Furthermore, S-ORC treatment decreases EB leakage, downregulates MMP-9, upregulates occludin and claudin-5, and decreases brain concentration of verapamil and atenolol after MCAO surgery. In conclusion, the present study demonstrates that post-treatment of S-ORC alleviates BBB dysfunction by regulating tight junction proteins (TJPs), upregulating P-glycoprotein function, and protects against ischemic stroke as result.

Keywords: Blood brain barrier; Inflammation; Ischemic stroke; S-oxiracetam.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Atenolol / pharmacology
  • Blood-Brain Barrier / drug effects*
  • Blood-Brain Barrier / metabolism
  • Claudin-5 / metabolism
  • Cytokines / blood
  • Infarction, Middle Cerebral Artery / blood
  • Infarction, Middle Cerebral Artery / metabolism*
  • Male
  • Matrix Metalloproteinase 9 / metabolism
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Occludin / metabolism
  • Pyrrolidines / pharmacology*
  • Pyrrolidines / therapeutic use
  • Rats, Sprague-Dawley
  • Stroke / blood
  • Stroke / metabolism*
  • Verapamil / pharmacology

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Claudin-5
  • Cldn5 protein, rat
  • Cytokines
  • Neuroprotective Agents
  • Occludin
  • Ocln protein, rat
  • Pyrrolidines
  • Atenolol
  • Verapamil
  • Matrix Metalloproteinase 9
  • Mmp9 protein, rat
  • oxiracetam