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This Article Full Text Full Text (PDF) All Versions of this Article: 291/5/H2210    most recent 01270.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Hong, H. Articles by Chen, A. F. Search for Related Content PubMed PubMed Citation Articles by Hong, H. Articles by Chen, A. F.

Atorvastatin protects against cerebral infarction via inhibition of NADPH oxidase-derived superoxide in ischemic stroke

¹Departments of Pharmacology and Neurology, Neuroscience Program and Cell and Molecular Biology Program, Michigan State University, East Lansing, Michigan; and ²Department of Neurology and ³Cerebrovascular Research Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China

Submitted 1 December 2005 ; accepted in final form 10 May 2006

Statins have recently been shown to exert neuronal protection in ischemic stroke. Reactive oxygen species, specifically superoxide formed during the early phase of reperfusion, augment neuronal injury. NADPH oxidase is a key enzyme for superoxide production. The present study tested the hypothesis that atorvastatin protects against cerebral infarction via inhibition of NADPH oxidase-derived superoxide in transient focal ischemia. Transient focal ischemia was created in halothane-anesthetized adult male Sprague-Dawley rats (250–300 g) by middle cerebral artery occlusion (MCAO). Atorvastatin (Lipitor, 10 mg/kg sc) was administered three times before MCAO. Infarct volume was measured by triphenyltetrazolium chloride staining. NADPH oxidase enzymatic activity and superoxide levels were quantified in the ischemic core and penumbral regions by lucigenin (5 µM)-enhanced chemiluminescence. Expression of NADPH oxidase membrane subunit gp91^phox and membrane-translocated subunit p47^phox and small GTPase Rac-1 was analyzed by Western blot. NADPH oxidase activity and superoxide levels increased after reperfusion and peaked within 2 h of reperfusion in the penumbra, but not in the ischemic core, in MCAO rats. Atorvastatin pretreatment prevented these increases, blunted expression of membrane subunit gp91^phox, and prevented translocation of cytoplasmic subunit p47^phox to the membrane in the penumbra 2 h after reperfusion. Consequently, cerebral infarct volume was significantly reduced in atorvastatin-treated compared with nontreated MCAO rats 24 h after reperfusion. These results indicate that atorvastatin protects against cerebral infarction via inhibition of NADPH oxidase-derived superoxide in transient focal ischemia.

transient focal ischemia; neuronal injury; inducible nitric oxide synthase; oxidative stress; statins

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