Role of the p38 mitogen-activated protein kinase/cytosolic phospholipase A2 signaling pathway in blood-brain barrier disruption after focal cerebral ischemia and reperfusion

Chikako Nito, Hiroshi Kamada, Hidenori Endo, Kuniyasu Niizuma, D. Jeannie Myer, Pak H. Chan

Research output: Contribution to journalArticlepeer-review

98 Citations (Scopus)

Abstract

Cytosolic phospholipase A2 (cPLA2) is a key enzyme that mediates arachidonic acid metabolism, which causes cerebral ischemia-induced oxidative injury, blood-brain barrier (BBB) dysfunction, and edema. Recent reports have shown that p38 mitogen-activated protein kinase (MAPK) is related to phosphorylation and activation of cPLA2 and release of arachidonic acid. However, involvement of the p38 MAPK pathway in cPLA2 activation and of reactive oxygen species in expression of p38 MAPK/cPLA2 after ischemia-reperfusion injury in the brain remains unclear. To address these issues, we used a model of transient focal cerebral ischemia (tFCI) in rats. Western blot analysis showed a significant increase in expression of phospho-p38 MAPK and phospho-cPLA2 in rat brain cortex after tFCI. Activity assays showed that both p38 MAPK and cPLA2 activation markedly increased 1 day after reperfusion. Intraventricular administration of SB203580 significantly suppressed activation and phosphorylation of cPLA2 and attenuated BBB extravasation and subsequent edema. Moreover, overexpression of copper/zinc-superoxide dismutase remarkably diminished activation and phosphorylation of both p38 MAPK and cPLA2 after reperfusion. These findings suggest that the p38 MAPK/cPLA2 pathway may promote BBB disruption with secondary vasogenic edema and that superoxide anions can stimulate this pathway after ischemia-reperfusion injury.

Original languageEnglish
Pages (from-to)1686-1696
Number of pages11
JournalJournal of Cerebral Blood Flow and Metabolism
Volume28
Issue number10
DOIs
Publication statusPublished - 2008 Oct

Keywords

  • Blood-brain barrier
  • Cytosolic phospholipase A
  • Focal cerebral ischemia
  • Mitogen-activated protein kinase
  • Oxidative stress
  • Superoxide dismutase

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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