Endothelial sulfonylurea receptor 1–regulated NCCa-ATP channels mediate progressive hemorrhagic necrosis following spinal cord injury
J. Marc Simard, … , S. Kyoon Woo, Volodymyr Gerzanich
J. Marc Simard, … , S. Kyoon Woo, Volodymyr Gerzanich
Published August 1, 2007
Citation Information: J Clin Invest. 2007;117(8):2105-2113. https://doi.org/10.1172/JCI32041.
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Research Article Neuroscience

Endothelial sulfonylurea receptor 1–regulated NCCa-ATP channels mediate progressive hemorrhagic necrosis following spinal cord injury

Abstract

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) Ca2+-activated, [ATP]i-sensitive nonspecific cation (NCCa-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 NCCa-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 NCCa-ATP channels in capillary endothelium are critical to development of PHN and constitute a major target for therapy in SCI.

Authors

J. Marc Simard, Orest Tsymbalyuk, Alexander Ivanov, Svetlana Ivanova, Sergei Bhatta, Zhihua Geng, S. Kyoon Woo, Volodymyr Gerzanich

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Figure 1

SUR1 is upregulated in SCI.

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SUR1 is upregulated in SCI. (A) Immunohistochemical localization of SUR1...
(A) Immunohistochemical localization of SUR1 in control rats (CTR) and at different times after SCI as indicated, with montages constructed from multiple individual images and positive labeling shown in black pseudocolor. (B) Magnified views of SUR1-immunolabeled sections taken from control and from the core (heavily labeled area in A at 6 hours). (C and D) Immunolabeling of capillaries with vimentin (Vim) and colabeling with SUR1 in control rats (C) and from the penumbra of SCI rats (tissue adjacent to the heavily labeled core in A, 6 hours) (D). (E) Western blots for SUR1 of spinal cord tissue from control rats (50 μg protein), from rats 6 hours after SCI (50 μg protein), and from an equivalent amount of blood (BL; 2 μl) as is present in the injured cord. Blots are representative of 5–6 control and SCI rats. (F and G) In situ hybridization for Abcc8 in control rats and in whole cords (F) or in the penumbra (G) 6 hours after SCI using antisense (AS) and sense (SE) as indicated. Immunohistochemistry and in situ hybridization images are representative of findings in 3–5 rats per group. Scale bars: 1 mm (A); 100 μM (B–D and G, top panels and bottom left panel); 50 μM (G, bottom right panel).