The P2X4 receptor is required for neuroprotection via ischemic preconditioning

Sci Rep. 2016 May 13:6:25893. doi: 10.1038/srep25893.


Ischemic preconditioning (IPC), a procedure consisting of transient ischemia and subsequent reperfusion, provides ischemic tolerance against prolonged ischemia in the brain. Although the blood flow changes mediated by IPC are primarily perceived by vascular endothelial cells, the role of these cells in ischemic tolerance has not been fully clarified. In this study, we found that the P2X4 receptor, which is abundantly expressed in vascular endothelial cells, is required for ischemic tolerance following middle artery occlusion (MCAO) in mice. Mechanistically, the P2X4 receptor was stimulated by fluid shear stress, which mimics reperfusion, thus promoting the increased expression of osteopontin, a neuroprotective molecule. Furthermore, we found that the intracerebroventricular administration of osteopontin was sufficient to exert a neuroprotective effect mediated by preconditioning-stimulated P2X4 receptor activation. These results demonstrate a novel mechanism whereby vascular endothelial cells are involved in ischemic tolerance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / blood supply*
  • Brain / cytology
  • Brain / metabolism
  • Brain Ischemia / etiology
  • Brain Ischemia / genetics
  • Brain Ischemia / metabolism
  • Brain Ischemia / prevention & control*
  • Disease Models, Animal
  • Endothelial Cells / metabolism
  • Ischemic Preconditioning / methods*
  • Mice
  • Mice, Inbred C57BL
  • Osteopontin / metabolism
  • Receptors, Purinergic P2X4 / genetics
  • Receptors, Purinergic P2X4 / metabolism*
  • Transcriptional Activation


  • P2rx4 protein, mouse
  • Receptors, Purinergic P2X4
  • Spp1 protein, mouse
  • Osteopontin