Simard, J.M. et al. Endothelial sulfonylurea receptor 1-regulated NC Ca-ATP channels mediate progressive hemorrhagic necrosis following spinal cord injury. J. Clin. Invest. 117, 2105-2113

Department of Neurosurgery, School of Medicine, University of Maryland at Baltimore, Baltimore, Maryland 21201-1595, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 09/2007; 117(8):2105-13. DOI: 10.1172/JCI32041
Source: PubMed


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.

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Available from: Volodymyr Gerzanich
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    • "Blood–spinal cord barrier breakdown occurs soon after injury leading to progressive hemorrhagic necrosis at the lesion epicenter (Noble and Wrathall, 1989; Popovich et al., 1996; Schnell et al., 1999; Simard et al., 2007, 2010). Blood-derived immune cells (leukocytes ) invade the spinal cord in waves, regulated in part by newly-formed ECM molecules that act as chemoattractants. "
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    ABSTRACT: Throughout the body, the extracellular matrix (ECM) provides structure and organization to tissues and also helps regulate cell migration and intercellular communication. In the injured spinal cord (or brain), changes in the composition and structure of the ECM undoubtedly contribute to regeneration failure. Less appreciated is how the native and injured ECM influences intraspinal inflammation and, conversely, how neuroinflammation affects the synthesis and deposition of ECM after CNS injury. In all tissues, inflammation can be initiated and propagated by ECM disruption. Molecules of ECM newly liberated by injury or inflammation include hyaluronan fragments, tenascins, and sulfated proteoglycans. These act as “damage-associated molecular patterns” or “alarmins”, i.e., endogenous proteins that trigger and subsequently amplify inflammation. Activated inflammatory cells, in turn, further damage the ECM by releasing degradative enzymes including matrix metalloproteinases (MMPs). After spinal cord injury (SCI), destabilization or alteration of the structural and chemical compositions of the ECM affects migration, communication, and survival of all cells – neural and non-neural – that are critical for spinal cord repair. By stabilizing ECM structure or modifying their ability to trigger the degradative effects of inflammation, it may be possible to create an environment that is more conducive to tissue repair and axon plasticity after SCI.
    Full-text · Article · Aug 2014 · Experimental Neurology
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    • "Key words: combinatorial treatment; spinal cord injury; cervical SCI; mechanism of action; time window After acute spinal cord injury (SCI), the initial mechanical insult to the spinal cord triggers a complex cascade of multiple secondary injury mechanisms that exacerbate the primary damage. These pathophysiological processes are initiated within minutes, hours, or days and include ischemia from disrupted microvasculature (Mautes et al., 2000; Whetstone et al., 2003; Habgood et al., 2007) and inflammation (Blight, 1992; Sroga et al., 2003; Fleming et al., 2006; Donnelly and Popovich, 2008), hemorrhagic necrosis (Zhang et al., 1996; Guth et al., 1999; Simard et al., 2007), and oxidative stress (Azbill et al., 1997; Xu et al., 2005; Sullivan et al., 2007; Xiong et al., 2007). The primary mechanical damage and secondary injury mechanisms ultimately leave disrupted axons that have a modest regenerative capacity and are further limited by inhibitory substrates in the CNS such as chondroitin sulfate proteoglycans and myelin-associated inhibitors (McGee and Strittmatter, 2003; Bradbury and Carter, 2011). "
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    ABSTRACT: Because of the complex, multifaceted nature of spinal cord injury (SCI), it is widely believed that a combination of approaches will be superior to individual treatments. Therefore, we employed a rat model of cervical SCI to evaluate the combination of four noninvasive treatments that individually have been reported to be effective for acute SCI during clinically relevant therapeutic time windows. These treatments included ghrelin, ibuprofen, C16, and ketogenic diet (KD). These were selected not only because of their previously reported efficacy in SCI models but also for their potentially different mechanisms of action. The administration of ghrelin, ibuprofen, C16, and KD several hours to days postinjury was based on previous observations by others that each treatment had profound effects on the pathophysiology and functional outcome following SCI. Here we showed that, with the exception of a modest improvement in performance on the Montoya staircase test at 8–10 weeks postinjury, the combinatorial treatment with ghrelin, ibuprofen, C16, and KD did not result in any significant improvements in the rearing test, grooming test, or horizontal ladder. Histologic analysis of the spinal cords did not reveal any significant differences in tissue sparing between treatment and control groups. Although single approaches of ghrelin, ibuprofen, C16, and KD have been reported to be beneficial after SCI, our results show that the combination of the four interventions did not confer significant functional or histological improvements in a cervical model of SCI. Possible interactions among the treatments may have negated their beneficial effects, emphasizing the challenges that have to be addressed when considering combinatorial drug therapies for SCI. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Jul 2014 · Journal of Neuroscience Research
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    • "Indeed, mechanical injury to the spinal cord rapidly damages the spinal microvasculature resulting in acute intraspinal bleeding with progressive hemorrhagic necrosis (PHN), which is highly destructive. In fact, interventions that prevent or reduce PHN after SCI are markedly protective (Benton and Hagg, 2011; Hill, 2001; Noble and Wrathall, 1989a, 1989b; Popovich et al., 2011; Simard et al., 2007, 2010, 2012, 2013). However, bleeding can have conflicting effects on glia, especially oligodendrocyte lineage cells. "
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    ABSTRACT: Spinal cord injury (SCI) evokes rapid deleterious and reparative glial reactions. Understanding the triggers for these responses is necessary for designing strategies to maximize repair. This study examined lesion formation and glial responses to vascular disruption and hemorrhage, a prominent feature of acute SCI. The specific role of hemorrhage is difficult to evaluate in trauma-induced lesions, because mechanical injury initiates many downstream responses. To isolate vascular disruption from trauma-induced effects, we created a novel and reproducible model of collagenase-induced intraspinal hemorrhage (ISH) and compared glial reactions between unilateral ISH and a hemi-contusion injury. Similar to contusion injuries, ISH lesions caused loss of myelin and axons and became filled with iron-laden macrophages. We hypothesized that intraspinal hemorrhage would also initiate reparative cellular responses including NG2 + oligodendrocyte progenitor cell (OPC) proliferation and oligodendrocyte genesis. Indeed, ISH induced OPC proliferation within 1d post-injury (dpi), which continued throughout the first week and resulted in a sustained elevation of NG2 + OPCs. ISH also caused oligodendrocyte loss within 4 h that was sustained through 3d post-ISH. However, oligodendrogenesis, as determined by bromo-deoxyuridine (BrdU) positive oligodendrocytes, restored oligodendrocyte numbers by 7dpi, revealing that proliferating OPCs differentiated into new oligodendrocytes after ISH. The signaling molecules pERK1/2 and pSTAT3 were robustly increased acutely after ISH, with pSTAT3 being expressed in a portion of OPCs, suggesting that activators of this signaling cascade may initiate OPC responses. Aside from subtle differences in timing of OPC responses, changes in ISH tissue closely mimicked those in hemi-contusion tissue. These results are important for elucidating the contribution of hemorrhage to lesion formation and endogenous cell-mediated repair, and will provide the foundation for future studies geared toward identifying the role of specific blood components on injury and repair mechanisms. This understanding may provide new clinical targets for SCI and other devastating conditions such as intracerebral hemorrhage.
    Full-text · Article · May 2014 · Experimental Neurology
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