Nito Chikako, Kamada Hiroshi, Endo Hidenori, Niizuma Kuniyasu, Myer D Jeannie, Chan Pak H
Department of Neurosurgery, Stanford University School of Medicine, Stanford, California 94305-5487, USA.
J Cereb Blood Flow Metab. 2008 Oct;28(10):1686-96. doi: 10.1038/jcbfm.2008.60. Epub 2008 Jun 11.
Cytosolic phospholipase A(2) (cPLA(2)) 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 cPLA(2) and release of arachidonic acid. However, involvement of the p38 MAPK pathway in cPLA(2) activation and of reactive oxygen species in expression of p38 MAPK/cPLA(2) 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-cPLA(2) in rat brain cortex after tFCI. Activity assays showed that both p38 MAPK and cPLA(2) activation markedly increased 1 day after reperfusion. Intraventricular administration of SB203580 significantly suppressed activation and phosphorylation of cPLA(2) and attenuated BBB extravasation and subsequent edema. Moreover, overexpression of copper/zinc-superoxide dismutase remarkably diminished activation and phosphorylation of both p38 MAPK and cPLA(2) after reperfusion. These findings suggest that the p38 MAPK/cPLA(2) pathway may promote BBB disruption with secondary vasogenic edema and that superoxide anions can stimulate this pathway after ischemia-reperfusion injury.
胞质型磷脂酶A2（cPLA2）是介导花生四烯酸代谢的关键酶，花生四烯酸代谢会导致脑缺血诱导的氧化损伤、血脑屏障（BBB）功能障碍和水肿。最近的报道表明，p38丝裂原活化蛋白激酶（MAPK）与cPLA2的磷酸化和激活以及花生四烯酸的释放有关。然而，p38 MAPK信号通路在cPLA2激活中的作用以及活性氧在脑缺血再灌注损伤后p38 MAPK/cPLA2表达中的作用仍不清楚。为了解决这些问题，我们使用了大鼠短暂性局灶性脑缺血（tFCI）模型。蛋白质免疫印迹分析显示，tFCI后大鼠脑皮质中磷酸化p38 MAPK和磷酸化cPLA2的表达显著增加。活性测定表明，再灌注1天后p38 MAPK和cPLA2的激活均显著增加。脑室内注射SB203580可显著抑制cPLA2的激活和磷酸化，并减轻BBB渗漏及随后的水肿。此外，铜/锌超氧化物歧化酶的过表达显著减少了再灌注后p38 MAPK和cPLA2的激活和磷酸化。这些发现表明，p38 MAPK/cPLA2信号通路可能促进BBB破坏并引发继发性血管源性水肿，并且超氧阴离子可在缺血再灌注损伤后刺激该信号通路。
