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Sulfonylurea receptor 1 in central nervous system injury: a focused review

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      Abstract

      The sulfonylurea receptor 1 (Sur1)-regulated NCCa-ATP channel is a nonselective cation channel that is regulated by intracellular calcium and adenosine triphosphate. The channel is not constitutively expressed, but is transcriptionally upregulated de novo in all cells of the neurovascular unit, in many forms of central nervous system (CNS) injury, including cerebral ischemia, traumatic brain injury (TBI), spinal cord injury (SCI), and subarachnoid hemorrhage (SAH). The channel is linked to microvascular dysfunction that manifests as edema formation and delayed secondary hemorrhage. Also implicated in oncotic cell swelling and oncotic (necrotic) cell death, the channel is a major molecular mechanism of ‘accidental necrotic cell death' in the CNS. In animal models of SCI, pharmacological inhibition of Sur1 by glibenclamide, as well as gene suppression of Abcc8, prevents delayed capillary fragmentation and tissue necrosis. In models of stroke and TBI, glibenclamide ameliorates edema, secondary hemorrhage, and tissue damage. In a model of SAH, glibenclamide attenuates the inflammatory response due to extravasated blood. Clinical trials of an intravenous formulation of glibenclamide in TBI and stroke underscore the importance of recent advances in understanding the role of the Sur1-regulated NCCa-ATP channel in acute ischemic, traumatic, and inflammatory injury to the CNS.

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      Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials.

      Malignant infarction of the middle cerebral artery (MCA) is associated with an 80% mortality rate. Non-randomised studies have suggested that decompressive surgery reduces this mortality without increasing the number of severely disabled survivors. To obtain sufficient data as soon as possible to reliably estimate the effects of decompressive surgery, results from three European randomised controlled trials (DECIMAL, DESTINY, HAMLET) were pooled. The trials were ongoing when the pooled analysis was planned. Individual data for patients aged between 18 years and 60 years, with space-occupying MCA infarction, included in one of the three trials, and treated within 48 h after stroke onset were pooled for analysis. The protocol was designed prospectively when the trials were still recruiting patients and outcomes were defined without knowledge of the results of the individual trials. The primary outcome measure was the score on the modified Rankin scale (mRS) at 1 year dichotomised between favourable (0-4) and unfavourable (5 and death) outcome. Secondary outcome measures included case fatality rate at 1 year and a dichotomisation of the mRS between 0-3 and 4 to death. Data analysis was done by an independent data monitoring committee. 93 patients were included in the pooled analysis. More patients in the decompressive-surgery group than in the control group had an mRS
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        Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications.

        Focal cerebral ischaemia and post-ischaemic reperfusion cause cerebral capillary dysfunction, resulting in oedema formation and haemorrhagic conversion. There are substantial gaps in understanding the pathophysiology, especially regarding early molecular participants. Here, we review physiological and molecular mechanisms involved. We reaffirm the central role of Starling's principle, which states that oedema formation is determined by the driving force and the capillary "permeability pore". We emphasise that the movement of fluids is largely driven without new expenditure of energy by the ischaemic brain. We organise the progressive changes in osmotic and hydrostatic conductivity of abnormal capillaries into three phases: formation of ionic oedema, formation of vasogenic oedema, and catastrophic failure with haemorrhagic conversion. We suggest a new theory suggesting that ischaemia-induced capillary dysfunction can be attributed to de novo synthesis of a specific ensemble of proteins that determine osmotic and hydraulic conductivity in Starling's equation, and whose expression is driven by a distinct transcriptional program.
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          Structure and mechanism of ABC transporter proteins.

          ATP-binding cassette (ABC) transporters are ubiquitous membrane proteins that couple the transport of diverse substrates across cellular membranes to the hydrolysis of ATP. The crystal structures of four ABC transporters have recently been determined. They reveal similar arrangements of the conserved ATP-hydrolyzing nucleotide-binding domains, but unrelated architectures of the transmembrane domains, with the notable exception of a common 'coupling helix' that is essential for transmitting conformational changes. The structures suggest a mechanism that rationalizes ATP-driven transport: While binding of ATP appears to trigger an outward-facing conformation, dissociation of the hydrolysis products may promote an inward-facing conformation. This basic scheme can, in principle, explain nutrient import by ABC importers and drug extrusion by ABC exporters.
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            Author and article information

            Affiliations
            [1 ]simpleDepartment of Neurosurgery, University of Maryland School of Medicine , Baltimore, Maryland, USA
            [2 ]simpleDepartment of Pathology, University of Maryland School of Medicine , Baltimore, Maryland, USA
            [3 ]simpleDepartment of Physiology, University of Maryland School of Medicine , Baltimore, Maryland, USA
            Author notes
            [* ]simpleDepartment of Neurosurgery, University of Maryland School of Medicine , 22 S. Greene Street, Suite S12D, Baltimore, MD 21201-1595, USA. E-mail: msimard@ 123456smail.umaryland.edu
            Journal
            J Cereb Blood Flow Metab
            J. Cereb. Blood Flow Metab
            Journal of Cerebral Blood Flow & Metabolism
            Nature Publishing Group
            0271-678X
            1559-7016
            September 2012
            20 June 2012
            1 September 2012
            : 32
            : 9
            : 1699-1717
            3434627
            jcbfm201291
            10.1038/jcbfm.2012.91
            22714048
            Copyright © 2012 International Society for Cerebral Blood Flow & Metabolism, Inc.

            This work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

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