Role of the p38 Mitogen-Activated Protein Kinase/Cytosolic Phospholipase A2 Signaling Pathway in Blood—Brain Barrier Disruption after Focal Cerebral Ischemia and Reperfusion

• Published in: Journal of cerebral blood flow and metabolism Vol. 28; no. 10; pp. 1686 - 1696
• Main Authors: Nito, Chikako, Kamada, Hiroshi, Endo, Hidenori, Niizuma, Kuniyasu, Myer, D Jeannie, Chan, Pak H
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.10.2008; Lippincott Williams & Wilkins; Sage Publications Ltd
• Subjects: Animals; Animals, Genetically Modified; Biological and medical sciences; Blood-Brain Barrier - physiology; Brain Edema - metabolism; Brain Edema - pathology; Brain Ischemia - metabolism; Brain Ischemia - pathology; Cerebral Infarction - metabolism; Cerebral Infarction - pathology; Cyclooxygenase 2 - metabolism; Enzyme Inhibitors - pharmacology; Humans; Imidazoles - pharmacology; Male; Medical sciences; Neurology; Neuropharmacology; Neuroprotective agent; Oxidative Stress - physiology; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; Pharmacology. Drug treatments; Phospholipases A2, Cytosolic - metabolism; Phosphorylation; Pyridines - pharmacology; Rats; Rats, Sprague-Dawley; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Signal Transduction - physiology; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Superoxide Dismutase-1; Superoxides - metabolism; Vascular diseases and vascular malformations of the nervous system; mitogen-activated protein kinase; focal cerebral ischemia; blood—brain barrier; superoxide dismutase; oxidative stress; cytosolic phospholipase A2; blood-brain barrier; Oxidative stress; Nervous system diseases; Enzyme; Transferases; Ischemia reperfusion; Mitogen-activated protein kinase; Cardiovascular disease; Superoxide dismutase; Esterases; Blood brain barrier; Phospholipase A; Carboxylic ester hydrolases; Cerebral disorder; Vascular disease; Central nervous system disease; Brain ischemia; p38 Mitogen activated protein kinase; Hydrolases; Oxidoreductases; Cerebrovascular disease
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.2008.60

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.