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NADPH oxidase plays a central role in blood-brain barrier damage in experimental stroke

Stroke (1970), 2007-11, Vol.38 (11), p.3000-3006 [Peer Reviewed Journal]

2007 INIST-CNRS ;ISSN: 0039-2499 ;EISSN: 1524-4628 ;DOI: 10.1161/strokeaha.107.489765 ;PMID: 17916764 ;CODEN: SJCCA7

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Title:
NADPH oxidase plays a central role in blood-brain barrier damage in experimental stroke
Author: KAHLES, Timo ; LUEDIKE, Peter ; ENDRES, Matthias ; GALLA, Hans-Joachim ; STEINMETZ, Helmuth ; BUSSE, Rudi ; NEUMANN-HAEFELIN, Tobias ; BRANDES, Ralf P
Subjects: Animals ; Biological and medical sciences ; Blood-Brain Barrier - enzymology ; Blood-Brain Barrier - physiopathology ; Brain Edema - enzymology ; Brain Edema - etiology ; Brain Edema - physiopathology ; Cell Hypoxia - physiology ; Cells, Cultured ; Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges ; Clostridium difficile ; Disease Models, Animal ; Endothelial Cells - metabolism ; Enzyme Activation - drug effects ; Enzyme Activation - physiology ; Enzyme Inhibitors - pharmacology ; Fundamental and applied biological sciences. Psychology ; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy ; Infarction, Middle Cerebral Artery - enzymology ; Infarction, Middle Cerebral Artery - physiopathology ; Male ; MAP Kinase Signaling System - drug effects ; MAP Kinase Signaling System - genetics ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NADH, NADPH Oxidoreductases - antagonists & inhibitors ; NADH, NADPH Oxidoreductases - genetics ; NADH, NADPH Oxidoreductases - metabolism ; NADPH Oxidase 1 ; Nervous system (semeiology, syndromes) ; Neurology ; Protein Transport - drug effects ; Protein Transport - physiology ; rac1 GTP-Binding Protein - antagonists & inhibitors ; rac1 GTP-Binding Protein - metabolism ; Reactive Oxygen Species - metabolism ; Reperfusion Injury - enzymology ; Reperfusion Injury - physiopathology ; rho-Associated Kinases - antagonists & inhibitors ; rho-Associated Kinases - metabolism ; Stroke - enzymology ; Stroke - physiopathology ; Sus scrofa ; Vascular diseases and vascular malformations of the nervous system ; Vertebrates: nervous system and sense organs
Is Part Of: Stroke (1970), 2007-11, Vol.38 (11), p.3000-3006
Description: Cerebral ischemia/reperfusion is associated with reactive oxygen species (ROS) generation, and NADPH oxidases are important sources of ROS. We hypothesized that NADPH oxidases mediate blood-brain barrier (BBB) disruption and contribute to tissue damage in ischemia/reperfusion. Ischemia was induced by filament occlusion of the middle cerebral artery in mice for 2 hours followed by reperfusion. BBB permeability was measured by Evans blue extravasation. Monolayer permeability was determined from transendothelial electrical resistance of cultured porcine brain capillary endothelial cells. BBB permeability was increased in the ischemic hemisphere 1 hour after reperfusion. In NADPH oxidase-knockout (gp91phox(-/-)) mice, middle cerebral artery occlusion-induced BBB disruption and lesion volume were largely attenuated compared with those in wild-type mice. Inhibition of NADPH oxidase by apocynin prevented BBB damage. In porcine brain capillary endothelial cells, hypoxia/reoxygenation induced translocation of the NADPH oxidase activator Rac-1 to the membrane. In vivo inhibition of Rac-1 by the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin or Clostridium difficile lethal toxin B also prevented the ischemia/reperfusion-induced BBB disruption. Stimulation of porcine brain capillary endothelial cells with H(2)O(2) increased permeability, an effect attenuated by inhibition of phosphatidyl inositol 3-kinase or c-Jun N-terminal kinase but not blockade of extracellular signal-regulated kinase-1/2 or p38 mitogen-activated protein kinase. Inhibition of Rho kinase completely prevented the ROS-induced increase in permeability and the ROS-induced polymerization of the actin cytoskeleton. Activation of Rac and subsequently of the gp91phox containing NADPH oxidase promotes cerebral ROS formation, which then leads to Rho kinase-mediated endothelial cell contraction and disruption of the BBB. Inhibition of NADPH oxidase is a promising approach to reduce brain injury after stroke.
Publisher: Hagerstown, MD: Lippincott Williams & Wilkins
Language: English
Identifier: ISSN: 0039-2499
EISSN: 1524-4628
DOI: 10.1161/strokeaha.107.489765
PMID: 17916764
CODEN: SJCCA7
Source: MEDLINE
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NADPH oxidase plays a central role in blood-brain barrier damage in experimental stroke

2007 INIST-CNRS ;ISSN: 0039-2499 ;EISSN: 1524-4628 ;DOI: 10.1161/strokeaha.107.489765 ;PMID: 17916764 ;CODEN: SJCCA7

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