Newly expressed SUR1-regulated NC(Ca-ATP) channel mediates cerebral edema after ischemic stroke.
Pathological conditions in the central nervous system, including stroke and trauma, are often exacerbated by cerebral edema. We recently identified a nonselective cation channel, the NC(Ca-ATP) channel, in ischemic astrocytes that is regulated by sulfonylurea receptor 1 (SUR1), is opened by depletion of ATP and, when opened, causes cytotoxic edema. Here, we evaluated involvement of this channel in rodent models of stroke. SUR1 protein and mRNA were newly expressed in ischemic neurons, astrocytes and capillaries. Upregulation of SUR1 was linked to activation of the transcription factor Sp1 and was associated with expression of functional NC(Ca-ATP) but not K(ATP) channels. Block of SUR1 with low-dose glibenclamide reduced cerebral edema, infarct volume and mortality by 50%, with the reduction in infarct volume being associated with cortical sparing. Our findings indicate that the NC(Ca-ATP) channel is crucially involved in development of cerebral edema, and that targeting SUR1 may provide a new therapeutic approach to stroke.
Department of Neurosurgery, School of Medicine, University of Maryland at Baltimore, 22 South Greene Street, Suite 12SD, Baltimore, Maryland 21201-1595, USA. msimard@surgery1.umaryland.edu
J Marc
JM
Simard
Mingkui
M
Chen
Kirill V
KV
Tarasov
Sergei
S
Bhatta
Svetlana
S
Ivanova
Ludmila
L
Melnitchenko
Natalya
N
Tsymbalyuk
G Alexander
GA
West
Volodymyr
V
Gerzanich
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001929:Brain Edema / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D002545:Brain Ischemia / Q000209:etiology / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007150:Immunohistochemistry; D007473:Ion Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D017078:Laser-Doppler Flowmetry; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011955:Receptors, Drug; D016329:Sp1 Transcription Factor / Q000378:metabolism; D020521:Stroke / Q000209:etiology / Q000473:pathology; D064233:Sulfonylurea Receptors; D015854:Up-Regulation
D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D002118:Calcium; D005905:Glyburide; D007004:Hypoglycemic Agents; D007473:Ion Channels; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016376:Oligonucleotides, Antisense; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger; D011955:Receptors, Drug; D016329:Sp1 Transcription Factor; D064233:Sulfonylurea Receptors; C577509:Abcc8 protein, rat