期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 29, 期 2, 页码 317-330出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/jcbfm.2008.120
关键词
caspase-3; inflammation; subarachnoid hemorrhage; sulfonylurea receptor 1; vasogenic edema; zona occludens 1
资金
- National Heart, Lung and Blood Institute [HL082517]
- National Institute of Neurological Disorders and Stroke [NS048260, NS061808]
- Department of Veterans Affairs (Baltimore, MD, USA)
Subarachnoid hemorrhage (SAH) causes secondary brain injury due to vasospasm and inflammation. Here, we studied a rat model of mild-to-moderate SAH intended to minimize ischemia/hypoxia to examine the role of sulfonylurea receptor 1 (SUR1) in the inflammatory response induced by SAH. mRNA for Abcc8, which encodes SUR1, and SUR1 protein were abundantly upregulated in cortex adjacent to SAH, where tumor-necrosis factor-alpha (TNF alpha) and nuclear factor (NF)kappa B signaling were prominent. In vitro experiments confirmed that Abcc8 transcription is stimulated by TNF alpha. To investigate the functional consequences of SUR1 expression after SAH, we studied the effect of the potent, selective SUR1 inhibitor, glibenclamide. We examined barrier permeability ( immunoglobulin G, IgG extravasation), and its correlate, the localization of the tight junction protein, zona occludens 1 (ZO-1). SAH caused a large increase in barrier permeability and disrupted the normal junctional localization of ZO-1, with glibenclamide significantly reducing both effects. In addition, SAH caused large increases in markers of inflammation, including TNF alpha and NF kappa B, and markers of cell injury or cell death, including IgG endocytosis and caspase-3 activation, with glibenclamide significantly reducing these effects. We conclude that block of SUR1 by glibenclamide may ameliorate several pathologic effects associated with inflammation that lead to cortical dysfunction after SAH.
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