Acute NADPH oxidase activation potentiates cerebrovascular permeability response to bradykinin in ischemia-reperfusion

Abigail Woodfin, De-En Hu, Mosharraf Sarker, Tsuyoshi Kurokawa, Paul Fraser

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)


Free radical generation is a key event in cerebral reperfusion injury. Bradykinin (Bk) and interleukin-1 beta (IL-1 beta) have both been implicated in edema formation after stroke, although acute Bk application itself results in only a modest permeability increase. We have investigated the molecular mechanism by assessing the permeability of single pial venules in a stroke model. Increased permeability on reperfusion was dependent on the duration of ischemia and was prevented by applying the B-2 receptor antagonist HOE 140. Postreperfusion permeability increases were mimicked by applying Bk (5 mu M) for 10 min and blocked by coapplying the IL-1 receptor antagonist with Bk. Furthermore, 10 min pretreatment with IL-1 beta resulted in a 3 orders of magnitude leftward shift of the acutely applied Bk concentration-response curve. The left shift was abolished by scavenging free radicals with superoxide dismutase and catalase. Apocynin coapplied with IL-1 beta completely blocked the potentiation, implying that NADPH oxidase assembly is the immediate target of IL-1 beta, In conclusion, this is first demonstration that bradykinin, released during cerebral ischemia, leads to IL-1 beta release, which in turn activates NADPH oxidase leading to blood-brain barrier breakdown. (C) 2010 Elsevier Inc. All rights reserved.
Original languageEnglish
Pages (from-to)518 - 524
Number of pages7
JournalFree Radical Biology and Medicine
Issue number4
Publication statusPublished - 15 Feb 2011


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