Abstract
Glibenclamide is neuroprotective against cerebral ischemia in rats. We studied whether glibenclamide enhances long-term brain repair and improves behavioral recovery after stroke. Adult male Wistar rats were subjected to transient middle cerebral artery occlusion (MCAO) for 90 minutes. A low dose of glibenclamide (total 0.6 μg) was administered intravenously 6, 12, and 24 hours after reperfusion. We assessed behavioral outcome during a 30-day follow-up and animals were perfused for histological evaluation. In vitro specific binding of glibenclamide to microglia increased after pro-inflammatory stimuli. In vivo glibenclamide was associated with increased migration of doublecortin-positive cells in the striatum toward the ischemic lesion 72 hours after MCAO, and reactive microglia expressed sulfonylurea receptor 1 (SUR1) and Kir6.2 in the medial striatum. One month after MCAO, glibenclamide was also associated with increased number of NeuN-positive and 5-bromo-2-deoxyuridine-positive neurons in the cortex and hippocampus, and enhanced angiogenesis in the hippocampus. Consequently, glibenclamide-treated MCAO rats showed improved performance in the limb-placing test on postoperative days 22 to 29, and in the cylinder and water-maze test on postoperative day 29. Therefore, acute blockade of SUR1 by glibenclamide enhanced long-term brain repair in MCAO rats, which was associated with improved behavioral outcome.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP-Binding Cassette Transporters / antagonists & inhibitors
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ATP-Binding Cassette Transporters / metabolism
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Animals
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Antigens, Nuclear / metabolism
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Brain Ischemia* / drug therapy
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Brain Ischemia* / metabolism
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Brain Ischemia* / pathology
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Brain Ischemia* / physiopathology
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Cell Movement / drug effects
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Corpus Striatum / metabolism
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Corpus Striatum / pathology
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Corpus Striatum / physiopathology
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Dose-Response Relationship, Drug
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Doublecortin Domain Proteins
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Doublecortin Protein
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Glyburide* / pharmacokinetics
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Glyburide* / pharmacology
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Hippocampus / metabolism
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Hippocampus / pathology
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Hippocampus / physiopathology
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Hypoglycemic Agents* / pharmacokinetics
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Hypoglycemic Agents* / pharmacology
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Male
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Maze Learning / drug effects
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Microglia / metabolism
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Microglia / pathology
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Microtubule-Associated Proteins / metabolism
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Neovascularization, Physiologic / drug effects
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Nerve Tissue Proteins / metabolism
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Neurogenesis / drug effects*
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Neuropeptides / metabolism
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Potassium Channels, Inwardly Rectifying / antagonists & inhibitors
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Potassium Channels, Inwardly Rectifying / metabolism
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Rats
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Rats, Wistar
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Receptors, Drug / antagonists & inhibitors
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Receptors, Drug / metabolism
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Recovery of Function / drug effects*
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Sulfonylurea Receptors
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Time Factors
Substances
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ATP-Binding Cassette Transporters
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Abcc8 protein, rat
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Antigens, Nuclear
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Dcx protein, rat
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Doublecortin Domain Proteins
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Doublecortin Protein
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Hypoglycemic Agents
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Kir6.2 channel
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Microtubule-Associated Proteins
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Nerve Tissue Proteins
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Neuropeptides
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Potassium Channels, Inwardly Rectifying
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Rbfox3 protein, rat
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Receptors, Drug
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Sulfonylurea Receptors
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Glyburide