Endothelial sulfonylurea receptor 1–regulated NCCa-ATP channels mediate progressive hemorrhagic necrosis following spinal cord injury
J. Marc Simard, Orest Tsymbalyuk, Alexander Ivanov, Svetlana Ivanova, Sergei Bhatta, Zhihua Geng, S. Kyoon Woo, Volodymyr Gerzanich
J. Marc Simard, Orest Tsymbalyuk, Alexander Ivanov, Svetlana Ivanova, Sergei Bhatta, Zhihua Geng, S. Kyoon Woo, Volodymyr Gerzanich
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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 5

Gene suppression of SUR1 blocks expression of functional NCCa-ATP channels and improves outcome in SCI.

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Gene suppression of SUR1 blocks expression of functional NCCa-ATP channe...
(A) Western blots for SUR1 in gliotic capsule from rats with infusion of scrambled ODN (Scr-ODN) or antisense ODN (AS-ODN) directly into the brain injury site for 10–12 days prior to tissue harvest. Also shown is densitometric analysis of Western blots from the same groups of rats (n = 3 per group). (B) Membrane potential of astrocytes from gliotic capsules of the same groups of rats as in A during application of Na azide to deplete ATP. Mean depolarization of 3 cells per group is shown. (C) Cord sections immunolabeled for SUR1, 1 day after SCI, from rats treated with i.v. infusion of scrambled ODN or antisense ODN. Scale bar: 0.5 mm. Also shown is quantitative immunofluorescence for the same groups of rats (n = 3 per group). ROI, region of interest. (D) Blood in cord homogenates, performance on angled plane, and rearing, 1 day after SCI, for rats treated with i.v. infusion of scrambled ODN or antisense ODN. Error bars indicate SEM. *P < 0.05, **P < 0.01 versus scrambled ODN.