Endothelial sulfonylurea receptor 1-regulated NC Ca-ATP channels mediate progressive hemorrhagic necrosis following spinal cord injury.
Acute spinal cord injury (SCI) causes progressive hemorrhagic necrosis (PHN), a poorly understood pathological process characterized by hemorrhage and necrosis that leads to devastating loss of spinal cord tissue, cystic cavitation of the cord, and debilitating neurological dysfunction. Using a rodent model of severe cervical SCI, we tested the hypothesis that sulfonylurea receptor 1-regulated (SUR1-regulated) Ca(2+)-activated, [ATP](i)-sensitive nonspecific cation (NC(Ca-ATP)) channels are involved in PHN. In control rats, SCI caused a progressively expansive lesion with fragmentation of capillaries, hemorrhage that doubled in volume over 12 hours, tissue necrosis, and severe neurological dysfunction. SUR1 expression was upregulated in capillaries and neurons surrounding necrotic lesions. Patch clamp of cultured endothelial cells exposed to hypoxia showed that upregulation of SUR1 was associated with expression of functional SUR1-regulated NC(Ca-ATP) channels. Following SCI, block of SUR1 by glibenclamide or repaglinide or suppression of Abcc8, which encodes for SUR1 by phosphorothioated antisense oligodeoxynucleotide essentially eliminated capillary fragmentation and progressive accumulation of blood, was associated with significant sparing of white matter tracts and a 3-fold reduction in lesion volume, and resulted in marked neurobehavioral functional improvement compared with controls. We conclude that SUR1-regulated NC(Ca-ATP) channels in capillary endothelium are critical to development of PHN and constitute a major target for therapy in SCI.
Simard
J Marc
JM
Department of Neurosurgery, School of Medicine, University of Maryland at Baltimore, Baltimore, Maryland 21201-1595, USA. msimard@smail.umaryland.edu
Tsymbalyuk
Orest
O
Ivanov
Alexander
A
Ivanova
Svetlana
S
Bhatta
Sergei
S
Geng
Zhihua
Z
Woo
S Kyoon
SK
Gerzanich
Volodymyr
V
D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015220:Calcium Channels / Q000378:metabolism*; D002196:Capillaries / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005905:Glyburide / Q000494:pharmacology; D006470:Hemorrhage / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D009336:Necrosis / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D020319:Oligodeoxyribonucleotides, Antisense; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D020318:Rats, Long-Evans; D011955:Receptors, Drug; D015222:Sodium Channels / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D064233:Sulfonylurea Receptors; D013997:Time Factors
D018528:ATP-Binding Cassette Transporters; D015220:Calcium Channels; D005905:Glyburide; D007004:Hypoglycemic Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D015222:Sodium Channels; D064233:Sulfonylurea Receptors; C577509:Abcc8 protein, rat