Glibenclamide enhances neurogenesis and improves long-term functional recovery after transient focal cerebral ischemia

J Cereb Blood Flow Metab. 2013 Mar;33(3):356-64. doi: 10.1038/jcbfm.2012.166. Epub 2012 Nov 14.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / antagonists & inhibitors
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Antigens, Nuclear / metabolism
  • Brain Ischemia* / drug therapy
  • Brain Ischemia* / metabolism
  • Brain Ischemia* / pathology
  • Brain Ischemia* / physiopathology
  • Cell Movement / drug effects
  • Corpus Striatum / metabolism
  • Corpus Striatum / pathology
  • Corpus Striatum / physiopathology
  • Dose-Response Relationship, Drug
  • Doublecortin Domain Proteins
  • Doublecortin Protein
  • Glyburide* / pharmacokinetics
  • Glyburide* / pharmacology
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Hippocampus / physiopathology
  • Hypoglycemic Agents* / pharmacokinetics
  • Hypoglycemic Agents* / pharmacology
  • Male
  • Maze Learning / drug effects
  • Microglia / metabolism
  • Microglia / pathology
  • Microtubule-Associated Proteins / metabolism
  • Neovascularization, Physiologic / drug effects
  • Nerve Tissue Proteins / metabolism
  • Neurogenesis / drug effects*
  • Neuropeptides / metabolism
  • Potassium Channels, Inwardly Rectifying / antagonists & inhibitors
  • Potassium Channels, Inwardly Rectifying / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, Drug / antagonists & inhibitors
  • Receptors, Drug / metabolism
  • Recovery of Function / drug effects*
  • Sulfonylurea Receptors
  • Time Factors

Substances

  • ATP-Binding Cassette Transporters
  • Abcc8 protein, rat
  • Antigens, Nuclear
  • Dcx protein, rat
  • Doublecortin Domain Proteins
  • Doublecortin Protein
  • Hypoglycemic Agents
  • Kir6.2 channel
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • Neuropeptides
  • Potassium Channels, Inwardly Rectifying
  • Rbfox3 protein, rat
  • Receptors, Drug
  • Sulfonylurea Receptors
  • Glyburide