Protective effect of delayed treatment with low-dose glibenclamide in three models of ischemic stroke.
OBJECTIVE
Ischemia/hypoxia induces de novo expression of the sulfonylurea receptor 1-regulated NC(Ca-ATP) channel. In rodent models of ischemic stroke, early postevent administration of the sulfonylurea, glibenclamide, is highly effective in reducing edema, mortality, and lesion volume, and in patients with diabetes presenting with ischemic stroke, pre-event plus postevent use of sulfonylureas is associated with better neurological outcome. However, the therapeutic window for treatment with glibenclamide has not been studied.


METHODS
We examined the effect of low-dose (nonhypoglycemogenic) glibenclamide in 3 rat models of ischemic stroke, all involving proximal middle cerebral artery occlusion (MCAo): a thromboembolic model, a permanent suture occlusion model, and a temporary suture occlusion model with reperfusion (105 minutes occlusion, 2-day reperfusion). Treatment was started at various times up to 6 hours post-MCAo. Lesion volumes were measured 48 hours post-MCAo using 2,3,5-triphenyltetrazolium chloride.


RESULTS
Glibenclamide reduced total lesion volume by 53% in the thromboembolic MCAo model at 6 hours, reduced corrected cortical lesion volume by 51% in the permanent MCAo model at 4 hours, and reduced corrected cortical lesion volume by 41% in the temporary MCAo model at 5.75 hours (P<0.05 for all 3). Analysis of pooled data from the permanent MCAo and temporary MCAo series indicated a sigmoidal relationship between hemispheric swelling and corrected cortical lesion volume with the half-maximum cortical lesion volume being observed with 10% hemispheric swelling.


CONCLUSIONS
Low-dose glibenclamide has a strong beneficial effect on lesion volume and has a highly favorable therapeutic window in several models of ischemic stroke.
Simard
J Marc
JM
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201-1595, USA. msimard@smail.umaryland.edu
Yurovsky
Vladimir
V
Tsymbalyuk
Natalia
N
Melnichenko
Ludmila
L
Ivanova
Svetlana
S
Gerzanich
Volodymyr
V
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001921:Brain / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications*; D002544:Cerebral Infarction / Q000473:pathology; D003627:Data Interpretation, Statistical; D005905:Glyburide / Q000627:therapeutic use*; D006943:Hyperglycemia / Q000097:blood / Q000150:complications; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D008297:Male; D018696:Neuroprotective Agents; D024661:Potassium Channels, Inwardly Rectifying / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D011955:Receptors, Drug / Q000096:biosynthesis / Q000235:genetics; D020521:Stroke / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D013453:Sulfonylurea Compounds / Q000494:pharmacology; D064233:Sulfonylurea Receptors; D013923:Thromboembolism / Q000188:drug therapy / Q000473:pathology
D018528:ATP-Binding Cassette Transporters; D007004:Hypoglycemic Agents; D018696:Neuroprotective Agents; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors; D005905:Glyburide