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

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.