Glibenclamide reduces inflammation, vasogenic edema, and caspase-3 activation after subarachnoid hemorrhage.

Abstract

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 (TNFalpha) and nuclear factor (NF)kappaB signaling were prominent. In vitro experiments confirmed that Abcc8 transcription is stimulated by TNFalpha. 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 TNFalpha and NFkappaB, 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.

• Authors: J Marc Simard, Zhihua Geng, S Kyoon Woo, Svetlana Ivanova, Cigdem Tosun, Ludmila Melnichenko, Volodymyr Gerzanich
• Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (J Cereb Blood Flow Metab) Vol. 29 Issue 2 Pg. 317-30 (Feb 2009) ISSN: 1559-7016 [Electronic] United States
• PMID: 18854840 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• ATP-Binding Cassette Transporters
• Abcc8 protein, rat
• Potassium Channels, Inwardly Rectifying
• Receptors, Drug
• Sulfonylurea Receptors
• Tumor Necrosis Factor-alpha
• Caspase 3
• Glyburide

Topics

• ATP-Binding Cassette Transporters (genetics, metabolism)
• Animals
• Blood-Brain Barrier (drug effects)
• Brain Edema (drug therapy, enzymology, pathology)
• Carotid Artery Injuries
• Carotid Artery, Internal
• Caspase 3 (metabolism)
• Enzyme Activation (drug effects)
• Glyburide (therapeutic use)
• Hypoxia (pathology)
• Inflammation (drug therapy, enzymology, pathology)
• Male
• Potassium Channels, Inwardly Rectifying (genetics, metabolism)
• Rats
• Rats, Wistar
• Receptors, Drug (genetics, metabolism)
• Subarachnoid Hemorrhage (drug therapy, enzymology, pathology)
• Sulfonylurea Receptors
• Tumor Necrosis Factor-alpha (pharmacology)
• Up-Regulation (genetics)