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Drug development in targeting ion channels for brain edema

Abstract

Cerebral edema is a pathological hallmark of various central nervous system (CNS) insults, including traumatic brain injury (TBI) and excitotoxic injury such as stroke. Due to the rigidity of the skull, edema-induced increase of intracranial fluid significantly complicates severe CNS injuries by raising intracranial pressure and compromising perfusion. Mortality due to cerebral edema is high. With mortality rates up to 80% in severe cases of stroke, it is the leading cause of death within the first week. Similarly, cerebral edema is devastating for patients of TBI, accounting for up to 50% mortality. Currently, the available treatments for cerebral edema include hypothermia, osmotherapy, and surgery. However, these treatments only address the symptoms and often elicit adverse side effects, potentially in part due to non-specificity. There is an urgent need to identify effective pharmacological treatments for cerebral edema. Currently, ion channels represent the third-largest target class for drug development, but their roles in cerebral edema remain ill-defined. The present review aims to provide an overview of the proposed roles of ion channels and transporters (including aquaporins, SUR1-TRPM4, chloride channels, glucose transporters, and proton-sensitive channels) in mediating cerebral edema in acute ischemic stroke and TBI. We also focus on the pharmacological inhibitors for each target and potential therapeutic strategies that may be further pursued for the treatment of cerebral edema.

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Fig. 1: Status of the blood–brain barrier (BBB) at different phases of cerebral edema.
Fig. 2: Schematic depiction of the main channels and transporters that have been implicated in facilitating cerebral edema and excitotoxicity during moderate and severe acute brain injuries.

References

  1. 1.

    Donkin JJ, Vink R. Mechanisms of cerebral edema in traumatic brain injury: therapeutic developments. Curr Opin Neurol. 2010;23:293–9.

    CAS  PubMed  Google Scholar 

  2. 2.

    Klatzo I. Pathophysiological aspects of brain edema. Acta Neuropathol. 1987;72:236–9.

    CAS  PubMed  Google Scholar 

  3. 3.

    Rungta RL, Choi HB, Tyson JR, Malik A, Dissing-Olesen L, Lin PJC, et al. The cellular mechanisms of neuronal swelling underlying cytotoxic edema. Cell. 2015;161:610–21.

    CAS  PubMed  Google Scholar 

  4. 4.

    Berrouschot J, Sterker M, Bettin S, Köster J, Schneider D. Mortality of space-occupying (‘malignant’) middle cerebral artery infarction under conservative intensive care. Intensive Care Med. 1998;24:620–3.

    CAS  PubMed  Google Scholar 

  5. 5.

    Hacke W, Schwab S, Horn M, Spranger M, De Georgia M, von Kummer R. ‘Malignant’ middle cerebral artery territory infarction: clinical course and prognostic signs. Arch Neurol. 1996;53:309–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Hill MD, Hachinski V. Stroke treatment: time is brain. Lancet. 1998;352:SIII10–4.

    PubMed  Google Scholar 

  7. 7.

    Ayata C, Ropper AH. Ischaemic brain oedema. J Clin Neurosci. 2002;9:113–24.

    PubMed  Google Scholar 

  8. 8.

    Thrane AS, Thrane VR, Nedergaard M. Drowning stars: reassessing the role of astrocytes in brain edema. Trends Neurosci. 2014;37:620–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Hinson HE, Stein D, Sheth KN. Hypertonic saline and mannitol therapy in critical care neurology. J Intensive Care Med. 2013;28:3–11.

    PubMed  Google Scholar 

  10. 10.

    Ziai WC, Toung TJK, Bhardwaj A. Hypertonic saline: first-line therapy for cerebral edema? J Neurol Sci. 2007;261:157–66.

    CAS  PubMed  Google Scholar 

  11. 11.

    Polin RS, Shaffrey ME, Bogaev CA, Tisdale N, Germanson T, Bocchicchio B, et al. Decompressive bifrontal craniectomy in the treatment of severe refractory posttraumatic cerebral edema. Neurosurgery. 1997;41:84–92.

    CAS  PubMed  Google Scholar 

  12. 12.

    Moritz ML, Ayus JC. Hyperosmolar therapy for raised intracranial pressure. N Engl J Med. 2012;367:2555–6.

    PubMed  Google Scholar 

  13. 13.

    Jha RM, Kochanek PM, Simard JM. Pathophysiology and treatment of cerebral edema in traumatic brain injury. Neuropharmacology. 2019;145:230–46.

    CAS  PubMed  Google Scholar 

  14. 14.

    Stokum JA, Gerzanich V, Simard JM. Molecular pathophysiology of cerebral edema. J Cereb Blood Flow Metab. 2016;36:513–38.

    CAS  PubMed  Google Scholar 

  15. 15.

    Liang D, Bhatta S, Gerzanich V, Simard JM. Cytotoxic edema: mechanisms of pathological cell swelling. Neurosurg Focus. 2007;22:E2.

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Simard JM, Kent TA, Chen M, Tarasov KV, Gerzanich V. Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications. Lancet Neurol. 2007;6:258–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Wang Y, Hu W, Perez-Trepichio AD, Ng TC, Furlan AJ, Majors AW, et al. Brain tissue sodium is a ticking clock telling time after arterial occlusion in rat focal cerebral ischemia. Stroke. 2000;31:1386–91.

    CAS  PubMed  Google Scholar 

  18. 18.

    Ito U, Ohno K, Nakamura R, Suganuma F, Inaba Y. Brain edema during ischemia and after restoration of blood flow: Measurement of water, sodium, potassium content and plasma protein permeability. Stroke. 1979;10:542–7.

    CAS  PubMed  Google Scholar 

  19. 19.

    Mestre H, Du T, Sweeney AM, Liu G, Samson AJ, Peng W, et al. Cerebrospinal fluid influx drives acute ischemic tissue swelling. Science. 2020;367:eaax7171.

    CAS  PubMed  Google Scholar 

  20. 20.

    Muller WA. Leukocyte-endothelial-cell interactions in leukocyte transmigration and the inflammatory response. Trends Immunol. 2003;24:327–34.

    CAS  PubMed  Google Scholar 

  21. 21.

    Romanic AM, White RF, Arleth AJ, Ohlstein EH, Barone FC. Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke. 1998;29:2010–30.

    Google Scholar 

  22. 22.

    Gerstner ER, Duda DG, di Tomaso E, Ryg PA, Loeffler JS, Sorensen AG, et al. VEGF inhibitors in the treatment of cerebral edema in patients with brain cancer. Nat Rev Clin Oncol. 2009;6:229–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Kovács Z, Ikezaki K, Samoto K, Inamura T, Fukui M. VEGF and flt: expression time kinetics in rat brain infarct. Stroke. 1996;27:1865–72.

    PubMed  Google Scholar 

  24. 24.

    Aslam M, Ahmad N, Srivastava R, Hemmer B. TNF-alpha induced NFκB signaling and p65 (RelA) overexpression repress Cldn5 promoter in mouse brain endothelial cells. Cytokine. 2012;57:269–75.

    CAS  PubMed  Google Scholar 

  25. 25.

    Masada T, Hua Y, Xi G, Yang GY, Hoff JT, Keep RF. Attenuation of intracerebral hemorrhage and thrombin-induced brain edema by overexpression of interleukin-1 receptor antagonist. J Neurosurg. 2009;95:680–6.

    Google Scholar 

  26. 26.

    Donkin JJ, Turner RJ, Hassan I, Vink R. Substance P in traumatic brain injury. Prog Brain Res. 2007;161:97–109.

    CAS  PubMed  Google Scholar 

  27. 27.

    Marmarou A. A review of progress in understanding the pathophysiology and treatment of brain edema. Neurosurg Focus. 2007;22:E1.

    PubMed  Google Scholar 

  28. 28.

    Lai TW, Zhang S, Wang YT. Excitotoxicity and stroke: identifying novel targets for neuroprotection. Prog Neurobiol. 2014;115:157–88.

    CAS  PubMed  Google Scholar 

  29. 29.

    Guerriero RM, Giza CC, Rotenberg A. Glutamate and GABA imbalance following traumatic brain injury. Curr Neurol Neurosci Rep. 2015;15:27. https://doi.org/10.1007/s11910-015-0545-1.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Leis JA, Bekar LK, Walz W. Potassium homeostasis in the ischemic brain. Glia. 2005;50:407–16.

    PubMed  Google Scholar 

  31. 31.

    Besancon E, Guo S, Lok J, Tymianski M, Lo EH. Beyond NMDA and AMPA glutamate receptors: emerging mechanisms for ionic imbalance and cell death in stroke. Trends Pharmacol Sci. 2008;29:268–75.

    CAS  PubMed  Google Scholar 

  32. 32.

    Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 1999;22:1–7.

    Google Scholar 

  33. 33.

    Tymianski M. Emerging mechanisms of disrupted cellular signaling in brain ischemia. Nat Neurosci. 2011;14:1369–73.

    CAS  PubMed  Google Scholar 

  34. 34.

    Sun HS, Feng ZP, Barber PA, Buchan AM, French RJ. Kir6.2-containing ATP-sensitive potassium channels protect cortical neurons from ischemic/anoxic injury in vitro and in vivo. Neuroscience. 2007;144:1509–15.

    CAS  PubMed  Google Scholar 

  35. 35.

    Sun HS, Feng ZP, Miki T, Seino S, French RJ. Enhanced neuronal damage after ischemic insults in mice lacking Kir6.2-containing ATP-sensitive K+ channels. J Neurophysiol. 2006;95:2590–601.

    CAS  PubMed  Google Scholar 

  36. 36.

    Sun HS, Jackson MF, Martin LJ, Jansen K, Teves L, Cui H, et al. Suppression of hippocampal TRPM7 protein prevents delayed neuronal death in brain ischemia. Nat Neurosci. 2009;12:1300–7.

    CAS  PubMed  Google Scholar 

  37. 37.

    Xiong ZG, Zhu XM, Chu XP, Minami M, Hey J, Wei WL. Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels. Cell. 2004;118:687–98.

    CAS  PubMed  Google Scholar 

  38. 38.

    Wong R, Abussaud A, Leung JW, Xu BF, Li FY, Huang S, et al. Blockade of the swelling-induced chloride current attenuates the mouse neonatal hypoxic-ischemic brain injury in vivo. Acta Pharmacol Sin. 2018;39:858–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Thompson RJ, Zhou N, MacVicar BA. Ischemia opens neuronal gap junction hemichannels. Science. 2006;312:924–7.

    CAS  PubMed  Google Scholar 

  40. 40.

    Thompson RJ, Jackson MF, Olah ME, Rungta RL, Hines DJ, Beazely MA, et al. Activation of pannexin-1 hemichannels augments aberrant bursting in the hippocampus. Science. 2008;322:1555–9.

    CAS  PubMed  Google Scholar 

  41. 41.

    Yang B. Aquaporins. Advances in experimental medicine and biology book series 969. Dordrecht: Springer Nature; 2017.

    Google Scholar 

  42. 42.

    Amiry-Moghaddam M, Ottersen OP. The molecular basis of water transport in the brain. Nat Rev Neurosci. 2003;4:991–1001.

    CAS  PubMed  Google Scholar 

  43. 43.

    Frydenlund DS, Bhardwaj A, Otsuka T, Mylonakou MN, Yasumura T, Davidson KGV, et al. Temporary loss of perivascular aquaporin-4 in neocortex after transient middle cerebral artery occlusion in mice. Proc Natl Acad Sci USA. 2006;103:13532–6.

    CAS  PubMed  Google Scholar 

  44. 44.

    Steiner E, Enzmann GU, Lin S, Ghavampour S, Hannocks MJ, Zuber B, et al. Loss of astrocyte polarization upon transient focal brain ischemia as a possible mechanism to counteract early edema formation. Glia. 2012;60:646–59.

    Google Scholar 

  45. 45.

    Agre P, King LS, Yasui M, Guggino WB, Ottersen OP, Fujiyoshi Y, et al. Aquaporin water channels—from atomic structure to clinical medicine. J Physiol. 2002;542:3–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Andrew RD, Labron MW, Boehnke SE, Carnduff L, Kirov SA. Physiological evidence that pyramidal neurons lack functional water channels. Cereb Cortex. 2007;17:787–802.

    PubMed  Google Scholar 

  47. 47.

    Fukuda AM, Pop V, Spagnoli D, Ashwal S, Obenaus A, Badaut J. Delayed increase of astrocytic aquaporin 4 after juvenile traumatic brain injury: possible role in edema resolution? Neuroscience. 2012;222:366–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Taniguchi M, Yamashita T, Kumura E, Tamatani M, Kobayashi A, Yokawa T, et al. Induction of aquaporin-4 water channel mRNA after focal cerebral ischemia in rat. Brain Res Mol Brain Res. 2000;78:131–7.

    CAS  PubMed  Google Scholar 

  49. 49.

    Ke C, Poon WS, Ng HK, Pang JCS, Chan Y. Heterogeneous responses of aquaporin-4 in oedema formation in a replicated severe traumatic brain injury model in rats. Neurosci Lett. 2001;301:21–4.

    CAS  PubMed  Google Scholar 

  50. 50.

    de Castro Ribeiro M, Hirt L, Bogousslavsky J, Regli L, Badaut J. Time course of aquaporin expression after transient focal cerebral ischemia in mice. J Neurosci Res. 2006;83:1231–40.

    Google Scholar 

  51. 51.

    Manley GT, Fujimura M, Ma T, Noshita N, Filiz F, Bollen AW, et al. Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med. 2000;6:159–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Yao X, Derugin N, Manley GT, Verkman AS. Reduced brain edema and infarct volume in aquaporin-4 deficient mice after transient focal cerebral ischemia. Neurosci Lett. 2015;584:368–72.

    CAS  PubMed  Google Scholar 

  53. 53.

    Hirt L, Fukuda AM, Ambadipudi K, Rashid F, Binder D, Verkman A, et al. Improved long-term outcome after transient cerebral ischemia in aquaporin-4 knockout mice. J Cereb Blood Flow Metab. 2017;37:277–90.

    CAS  PubMed  Google Scholar 

  54. 54.

    Akdemir G, Ratelade J, Asavapanumas N, Verkman AS. Neuroprotective effect of aquaporin-4 deficiency in a mouse model of severe global cerebral ischemia produced by transient 4-vessel occlusion. Neurosci Lett. 2014;574:70–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Stokum JA, Mehta RI, Ivanova S, Yu E, Gerzanich V, Simard JM. Heterogeneity of aquaporin-4 localization and expression after focal cerebral ischemia underlies differences in white versus grey matter swelling. Acta Neuropathol Commun. 2015;6:61.

    Google Scholar 

  56. 56.

    Sato S, Umenishi F, Inamasu G, Sato M, Ishikawa M, Nishizawa M, et al. Expression of water channel mRNA following cerebral ischemia. Acta Neurochir Suppl. 2000;76:239–41.

    CAS  PubMed  Google Scholar 

  57. 57.

    Shi WZ, Qi LL, Fang SH, Lu YB, Zhang WP, Wei EQ. Aggravated chronic brain injury after focal cerebral ischemia in aquaporin-4-deficient mice. Neurosci Lett. 2012;520:121–5.

    CAS  PubMed  Google Scholar 

  58. 58.

    Liang F, Luo C, Xu G, Su F, He X, Long S, et al. Deletion of aquaporin-4 is neuroprotective during the acute stage of micro traumatic brain injury in mice. Neurosci Lett. 2015;598:29–35.

    CAS  PubMed  Google Scholar 

  59. 59.

    Yao X, Uchida K, Papadopoulos MC, Zador Z, Manley GT, Verkman AS. Mildly reduced brain swelling and improved neurological outcome in aquaporin-4 knockout mice following controlled cortical impact brain injury. J Neurotrauma. 2015;32:1458–64.

    PubMed  PubMed Central  Google Scholar 

  60. 60.

    Fukuda AM, Adami A, Pop V, Bellone JA, Coats JS, Hartman RE, et al. Posttraumatic reduction of edema with aquaporin-4 RNA interference improves acute and chronic functional recovery. J Cereb Blood Flow Metab. 2013;33:1621–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Kiening KL, van Landeghem FKH, Schreiber S, Thomale UW, von Deimling A, Unterberg AW, et al. Decreased hemispheric Aquaporin-4 is linked to evolving brain edema following controlled cortical impact injury in rats. Neurosci Lett. 2002;324:105–8.

    CAS  PubMed  Google Scholar 

  62. 62.

    Aoki K, Uchihara T, Tsuchiya K, Nakamura A, Ikeda K, Wakayama Y. Enhanced expression of aquaporin 4 in human brain with infarction. Acta Neuropathol. 2003;106:121–4.

    CAS  PubMed  Google Scholar 

  63. 63.

    Hu H, Yao HT, Zhang WP, Zhang L, Ding W, Zhang SH, et al. Increased expression of aquaporin-4 in human traumatic brain injury and brain tumors. J Zhejiang Univ Sci B. 2005;6:33–7.

    PubMed  Google Scholar 

  64. 64.

    Lo Pizzo M, Schiera G, Di Liegro I, Di Liegro CM, Pál J, Czeiter E, et al. Aquaporin-4 distribution in control and stressed astrocytes in culture and in the cerebrospinal fluid of patients with traumatic brain injuries. Neurol Sci. 2013;34:1309–14.

    PubMed  Google Scholar 

  65. 65.

    Verkman AS, Binder DK, Bloch O, Auguste K, Papadopoulos MC. Three distinct roles of aquaporin-4 in brain function revealed by knockout mice. Biochim Biophys Acta. 2006;1758:1085–93.

    CAS  PubMed  Google Scholar 

  66. 66.

    Li YK, Wang F, Wang W, Luo Y, Wu PF, Xiao JL, et al. Aquaporin-4 deficiency impairs synaptic plasticity and associative fear memory in the lateral amygdala: involvement of downregulation of glutamate transporter-1 expression. Neuropsychopharmacology. 2012;37:1867–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Zhang H, Verkman AS. Aquaporin-4 independent Kir4.1 K+ channel function in brain glial cells. Mol Cell Neurosci. 2008;37:1–10.

    PubMed  Google Scholar 

  68. 68.

    Huber VJ, Tsujita M, Nakada T. Identification of Aquaporin 4 inhibitors using in vitro and in silico methods. Bioorg Med Chem. 2009;17:411–7.

    CAS  PubMed  Google Scholar 

  69. 69.

    Tanimura Y, Hiroaki Y, Fujiyoshi Y. Acetazolamide reversibly inhibits water conduction by aquaporin-4. J Struct Biol. 2009;166:16–21.

    CAS  PubMed  Google Scholar 

  70. 70.

    Yang B, Zhang H, Verkman AS. Lack of aquaporin-4 water transport inhibition by antiepileptics and arylsulfonamides. Bioorg Med Chem. 2008;16:7489–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Glober NK, Sprague S, Ahmad S, Mayfield KG, Fletcher LM, Digicaylioglue MH, et al. Acetazolamide treatment prevents redistribution of astrocyte aquaporin 4 after murine traumatic brain injury. Neurosci J. 2019;2019:2831501.

    PubMed  PubMed Central  Google Scholar 

  72. 72.

    Igarashi H, Huber VJ, Tsujita M, Nakada T. Pretreatment with a novel aquaporin 4 inhibitor, TGN-020, significantly reduces ischemic cerebral edema. Neurol Sci. 2011;32:113–6.

    PubMed  Google Scholar 

  73. 73.

    Pirici I, Balsanu TA, Bogdan C, Margaritescu C, Divan T, Vitalie V, et al. Inhibition of aquaporin-4 improves the outcome of ischaemic stroke and modulates brain paravascular drainage pathways. Int J Mol Sci. 2017;19:46.

    PubMed Central  Google Scholar 

  74. 74.

    Kamegawa A, Hiroaki Y, Tani K, Fujiyoshi Y. Two-dimensional crystal structure of aquaporin-4 bound to the inhibitor acetazolamide. MicroscOPY. 2016;65:177–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Farr GW, Hall CH, Farr SM, Wade R, Detzel JM, Adams AG, et al. Functionalized phenylbenzamides inhibit aquaporin-4 reducing Cerebral edema and improving outcome in two models of CNS injury. Neuroscience. 2019;404:484–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Wallisch J, Jha R, Vagni V, Feldman K, Dixon C, Farr G, et al. Effect of the novel aquaporin-4 antagonist AER-271 in combined TBI plus hemorrhagic shock in mice. Crit Care Med. 2015;43:6–7.

    Google Scholar 

  77. 77.

    Kochanek PM, Bramlett HM, Dixon CE, Dietrich WD, Mondello S, Wang KKW, et al. Operation brain trauma therapy: 2016 update. Mil Med. 2018;183:303–12.

    PubMed  Google Scholar 

  78. 78.

    Migliati ER, Amiry-Moghaddam M, Froehner SC, Adams ME, Ottersen OP, Bhardwaj A. Na+-K+-2Cl- cotransport inhibitor attenuates cerebral edema following experimental stroke via the perivascular pool of aquaporin-4. Neurocrit Care. 2010;13:123–31.

    CAS  PubMed  Google Scholar 

  79. 79.

    Migliati E, Meurice N, DuBois P, Fang JS, Somasekharan S, Eeckett B, et al. Inhibition of aquaporin-1 and aquaporin-4 water permeability by a derivative of the loop diuretic bumetanide acting at an internal pore-occluding binding site. Mol Pharmacol. 2009;76:105–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    O’Donnell ME, Tran L, Lam TI, Liu XB, Anderson SE. Bumetanide inhibition of the blood-brain barrier Na-K-Cl cotransporter reduces edema formation in the rat middle cerebral artery occlusion model of stroke. J Cereb Blood Flow Metab. 2004;24:1046–56.

    PubMed  Google Scholar 

  81. 81.

    Fazzina G, Amorini AM, Marmarou CR, Fukui S, Okuno K, Dunbar JG, et al. The protein kinase C activator phorbol myristate acetate decreases brain edema by aquaporin 4 downregulation after middle cerebral artery occlusion in the rat. J Neurotrauma. 2010;27:453–61.

    PubMed  PubMed Central  Google Scholar 

  82. 82.

    Okuno K, Taya K, Marmariu CR, Ozisik P, Fazzina G, Kleindienst A, et al. The modulation of aquaporin-4 by using PKC-activator (phorbol myristate acetate) and V1a receptor antagonist (SR49059) following middle cerebral artery occlusion/reperfusion in the rat. Acta Neurochir Suppl. 2008;102:431–6.

    PubMed  Google Scholar 

  83. 83.

    Marmarou CR, Liang X, Abidi NH, Parveen S, Taya K, Henderson SC, et al. Selective vasopressin-1a receptor antagonist prevents brain edema, reduces astrocytic cell swelling and GFAP, V1aR and AQP4 expression after focal traumatic brain injury. Brain Res. 2014;1581:89–102.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Papadopoulos MC, Verkman AS. Aquaporin 4 and neuromyelitis optica. Lancet Neurol. 2012;11:535–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Kitchen P, Salman MM, Halsey AM, Clarke-Bland C, MacDonald JA, Ishida H, et al. Targeting aquaporin-4 subcellular localization to treat central nervous system edema. Cell. 2020;181:784–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Chen M, Simard JM. Cell swelling and a nonselective cation channel regulated by internal Ca2+ and ATP in native reactive astrocytes from adult rat brain. J Neurosci. 2001;21:6512–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Aittoniemi J, Fotinou C, Craig TJ, de Wet H, Proks P, Ashcroft FM. SUR1: a unique ATP-binding cassette protein that functions as an ion channel regulator. Philos Trans R Soc Lond B Biol Sci. 2009;364:257–67.

    CAS  PubMed  Google Scholar 

  88. 88.

    Simard JM, Chen M, Tarasov KV, Bhatta S, Ivanoca S, Melnitchenko L, et al. Newly expressed SUR1-regulated NCCa-ATPchannel mediates cerebral edema after ischemic stroke. Nat Med. 2006;12:433–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Patel AD, Gerzanich V, Geng Z, Simard JM. Glibenclamide reduces hippocampal injury and preserves rapid spatial learning in a model of traumatic brain injury. J Neuropathol Exp Neurol. 2010;69:1177–90.

    CAS  PubMed  Google Scholar 

  90. 90.

    Jha RM, Puccio AM, Chou SHY, Chang CCH, Wallisch JS, Molyneaux BJ, et al. Sulfonylurea receptor-1: a novel biomarker for cerebral edema in severe traumatic brain injury. Crit Care Med. 2017;45:e255–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Jha RM, Puccio AM, Okonkwo DO, Zusman BE, Park SY, Wallisch J, et al. ABCC8 single nucleotide polymorphisms are associated with cerebral edema in severe TBI. Neurocrit Care. 2017;26:213–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Woo SK, Tsymbalyuk N, Tsymbalyuk O, Ivanova S, Gerzanich V, Simard JM. SUR1-TRPM4 channels, not KATP, mediate brain swelling following cerebral ischemia. Neurosci Lett. 2020;718:134729.

    PubMed  Google Scholar 

  93. 93.

    Zerangue N, Schwappach B, Yuh NJ, Lily YJ. A new ER trafficking signal regulates the subunit stoichiometry of plasma membrane KATP channels. Neuron. 1999;22:537–48.

    CAS  PubMed  Google Scholar 

  94. 94.

    Simard JM, Woo SK, Schwartzbauer GT, Gerzanich V. Sulfonylurea receptor 1 in central nervous system injury: A focused review. J Cereb Blood Flow Metab. 2012;32:1699–717.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Stokum JA, Kwon MS, Woo SK, Tsymbalyuk O, Vennekens R, Gerzanich V, et al. SUR1-TRPM4 and AQP4 form a heteromultimeric complex that amplifies ion/water osmotic coupling and drives astrocyte swelling. Glia. 2018;66:108–25.

    PubMed  Google Scholar 

  96. 96.

    Simard JM, Yurovsky V, Tsymbalyuk N, Melnichenko L, Ivanova S, Gerzanich V. Protective effect of delayed treatment with low-dose glibenclamide in three models of ischemic stroke. Stroke. 2009;40:604–9.

    CAS  PubMed  Google Scholar 

  97. 97.

    Zweckberger K, Hackenberg K, Jung CS, Hertle DN, Kiening KL, Unterberg AW, et al. Glibenclamide reduces secondary brain damage after experimental traumatic brain injury. Neuroscience. 2014;272:199–206.

    CAS  PubMed  Google Scholar 

  98. 98.

    Sheth KN, Elm JJ, Molyneaux BJ, Hinson H, Beslow LA, Sze GK, et al. Safety and efficacy of intravenous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2016;15:1160–9.

    CAS  PubMed  Google Scholar 

  99. 99.

    Kimberly WT, Battey TWK, Pham L, Wu O, Yoo AJ, Furie KL, et al. Glyburide is associated with attenuated vasogenic edema in stroke patients. Neurocrit Care. 2014;20:193–201.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Sheth KN, Petersen NH, Cheung K, Elm JJ, Hinson HE, Molyneaux BJ, et al. Long-term outcomes in patients aged ≥70 years with intravenous glyburide from the Phase II GAMES-RP study of large hemispheric infarction an exploratory analysis. Stroke. 2018;49:1457–63.

    PubMed  PubMed Central  Google Scholar 

  101. 101.

    Sun HS, Xu B, Chen W, Xiao A, Turvola E, Alibraham A, et al. Neuronal KATP channels mediate hypoxic preconditioning and reduce subsequent neonatal hypoxic-ischemic brain injury. Exp Neurol. 2015;263:161–71.

    CAS  PubMed  Google Scholar 

  102. 102.

    Liu R, Wang H, Xu B, Chen W, Turlova E, Dong N, et al. Cerebrovascular safety of sulfonylureas: the role of KATP channels in neuroprotection and the risk of stroke in patients with type 2 diabetes. Diabetes. 2016;65:2795–809.

    CAS  PubMed  Google Scholar 

  103. 103.

    Glykys J, Dzhala V, Egawa K, Kahle KT, Delpire E, Staley K. Chloride dysregulation, seizures, and cerebral edema: a relationship with therapeutic potential. Trends Neurosci. 2017;40:276–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Geck P, Pietrzyk C, Burckhardt BC, Pfeifferl B, Heinz E. Electrically silent cotransport of Na+, K+ and Cl in ehrlich cells. Biochim Biophys Acta. 1980;600:432–47.

    CAS  PubMed  Google Scholar 

  105. 105.

    Chen H, Sun D. The role of Na–K–Cl co–transporter in cerebral ischemia. Neurol Res. 2005;27:280–6.

    CAS  PubMed  Google Scholar 

  106. 106.

    Chew TA, Orlando BJ, Zhang J, Latorraca NR, Wang A, Hollingsworth SA, et al. Structure and mechanism of the cation–chloride cotransporter NKCC1. Nature. 2019;572:488–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Pacheco-Alvarez D, San Cristóbal P, Meade P, Moreno E, Vazquez N, Díaz A, et al. The Na+:Cl cotransporter is activated and phosphorylated at the amino-terminal domain upon intracellular chloride depletion. J Biol Chem. 2006;281:28755–63.

    CAS  PubMed  Google Scholar 

  108. 108.

    Su G, Haworth RA, Dempsey RJ, Sun D. Regulation of Na+-K+-Cl cotransporter in primary astrocytes by dibutyryl cAMP and high [K+](o). Am J Physiol Cell Physiol. 2000;279:C1710–21.

    CAS  PubMed  Google Scholar 

  109. 109.

    Huang WD, Pan J, Xu M, Su W, Lu YQ, Chen ZJ, et al. Changes and effects of plasma arginine vasopressin in traumatic brain injury. J Endocrinol Invest. 2008;31:996–1000.

    CAS  PubMed  Google Scholar 

  110. 110.

    Chen H, Luo J, Kintner DB, Shull GE, Sun D. Na+-dependent chloride transporter (NKCC1)-null mice exhibit less gray and white matter damage after focal cerebral ischemia. J Cereb Blood Flow Metab. 2005;25:54–66.

    PubMed  Google Scholar 

  111. 111.

    Su G, Kintner DB, Sun D. Contribution of Na+-K+-Cl cotransporter to high-[K+] o-induced swelling and EAA release in astrocytes. Am J Physiol Cell Physiol. 2002;282:C1136–46.

    CAS  PubMed  Google Scholar 

  112. 112.

    Su G, Kintner DB, Flagella M, Shull GE, Sun D. Astrocytes from Na+-K+-Cl cotransporter-null mice exhibit absence of swelling and decrease in EAA release. Am J Physiol Cell Physiol. 2002;282:C1147–60.

    CAS  PubMed  Google Scholar 

  113. 113.

    Foroutan S, Brillault J, Forbush B, O’Donnell ME. Moderate-to-severe ischemic conditions increase activity and phosphorylation of the cerebral microvascular endothelial cell Na+-K+-Cl cotransporter. Am J Physiol Cell Physiol. 2005;289:C1492–501.

    CAS  PubMed  Google Scholar 

  114. 114.

    Yan Y, Dempsey RJ, Sun D. Na+-K+-Cl cotransporter in rat focal cerebral ischemia. J Cereb Blood Flow Metab. 2001;21:711–21.

    CAS  PubMed  Google Scholar 

  115. 115.

    Lu KT, Huang TC, Tsai YH, Yang YL. TRPV4 channels mediate Na-K-Cl-co-transporter-induced brain edema after traumatic brain injury. J Neurochem. 2017;140:718–27.

    CAS  PubMed  Google Scholar 

  116. 116.

    Lu KT, Wu CY, Yen HH, Peng JHF, Wang CL, Yang YL. Bumetanide administration attenuated traumatic brain injury through IL-1 overexpression. Neurol Res. 2007;29:404–9.

    PubMed  Google Scholar 

  117. 117.

    Löscher W, Puskarjov M, Kaila K. Cation-chloride cotransporters NKCC1 and KCC2 as potential targets for novel antiepileptic and antiepileptogenic treatments. Neuropharmacology. 2013;69:62–74.

    PubMed  Google Scholar 

  118. 118.

    Hampel P, Römermann K, MacAulay N, Löscher W. Azosemide is more potent than bumetanide and various other loop diuretics to inhibit the sodium-potassium-chloride-cotransporter human variants hNKCC1A and hNKCC1B. Sci Rep. 2018;8:9877.

    PubMed  PubMed Central  Google Scholar 

  119. 119.

    Töllner K, Brandt C, Töpfer M, Brunhofer G, Erker T, Gabriel M, et al. A novel prodrug-based strategy to increase effects of bumetanide in epilepsy. Ann Neurol. 2014;75:550–62.

    PubMed  Google Scholar 

  120. 120.

    Erker T, Brandt C, Töllner K, Schreppel P, Twele F, Schidlitzki A, et al. The bumetanide prodrug BUM5, but not bumetanide, potentiates the antiseizure effect of phenobarbital in adult epileptic mice. Epilepsia. 2016;57:698–705.

    CAS  PubMed  Google Scholar 

  121. 121.

    Huang H, Bhuiyan MIH, Jiang T, Song S, Shankar S, Taheri T, et al. A novel Na+-K+-Cl cotransporter 1 inhibitor STS66 reduces brain damage in mice after ischemic stroke. Stroke. 2019;50:1021–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Lauf PK, Bauer J, Adragna NC, Fujise H, Zade-Oppen AM, Ryu KH, et al. Erythrocyte K-Cl cotransport: properties and regulation. Am J Physiol. 1992;263:C917–32.

    CAS  PubMed  Google Scholar 

  123. 123.

    Shen MR, Chou CY, Ellory JC. Volume-sensitive KCL transport associated with human cervical carcinogenesis. Pflügers Arch. 2000;440:751–60.

    CAS  PubMed  Google Scholar 

  124. 124.

    Ernest NJ, Weaver AK, Van Duyn LB, Sontheimer HW. Relative contribution of chloride channels and transporters to regulatory volume decrease in human glioma cells. Am J Physiol Cell Physiol. 2005;288:C1451–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Lauf PK, Di Fulvio M, Srivastava V, Sharma N, Adragna NC. KCC2a expression in a human fetal lens epithelial cell line. Cell Physiol Biochem. 2012;29:303–12.

    CAS  PubMed  Google Scholar 

  126. 126.

    Wei WC, AkermanCJ, Newey SE, Pan J, Clinch NWV, Jacob Y, et al. The potassium-chloride cotransporter 2 promotes cervical cancer cell migration and invasion by an ion transport-independent mechanism. J Physiol. 2011;589:5349–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127.

    Kahle KT, Staley KJ, Nahed BV, Gamba G, Hebert SC, Lifton RP, et al. Roles of the cation–chloride cotransporters in neurological disease. Nat Clin Pr Neurol. 2008;4:490–503.

    CAS  Google Scholar 

  128. 128.

    Kahle KT, Deeb TZ, Puskarjov M, Silayeva L, Liang B, Kaila K, et al. Modulation of neuronal activity by phosphorylation of the K-Cl cotransporter KCC2. Trends Neurosci. 2013;36:726–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129.

    Rivera C, Voipio J, Payne JA, Ruusuvuori E, Lahtinen H, Lamsa K, et al. The K+/Cl co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature. 1999;397:251–5.

    CAS  PubMed  Google Scholar 

  130. 130.

    Arion D, Lewis DA. Altered expression of regulators of the cortical chloride transporters NKCC1 and KCC2 in schizophrenia. Arch Gen Psychiatry. 2011;69:21–31.

    Google Scholar 

  131. 131.

    Di Cristo G, Awad PN, Hamidi S, Avoli M. KCC2, epileptiform synchronization, and epileptic disorders. Prog Neurobiol. 2018;162:1–16.

    PubMed  Google Scholar 

  132. 132.

    Coull JAM, Boudreau D, Bachand K, Prescott SA, Nault F, Sík A, et al. Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature. 2003;424:938–42.

    CAS  PubMed  Google Scholar 

  133. 133.

    Galeffi F, Sah R, Pond BB, George A, Schwartz-Bloom RD. Changes in intracellular chloride after oxygen-glucose deprivation of the adult hippocampal slice: effect of diazepam. J Neurosci. 2004;24:4478–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Jaenisch N, Witte OW, Frahm C. Downregulation of potassium chloride cotransporter KCC2 after transient focal cerebral ischemia. Stroke. 2010;41:e151–9.

    CAS  PubMed  Google Scholar 

  135. 135.

    Bonislawski DP, Schwarzbach EP, Cohen AS. Brain injury impairs dentate gyrus inhibitory efficacy. Neurobiol Dis. 2007;25:163–9.

    CAS  PubMed  Google Scholar 

  136. 136.

    Wu H, Shao A, Zhao M, Chen S, Yu J, Zhou J, et al. Melatonin attenuates neuronal apoptosis through up-regulation of K+-Cl- cotransporter KCC2 expression following traumatic brain injury in rats. J Pineal Res. 2016;61:241–50.

    CAS  PubMed  Google Scholar 

  137. 137.

    Lee HHC, Deeb TZ, Walker JA, Davies PA, Moss SJ. NMDA receptor activity downregulates KCC2 resulting in depolarizing GABAAreceptor-mediated currents. Nat Neurosci. 2011;14:736–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Puskarjov M, Ahmad F, Kaila K, Blaesse P. Activity-dependent cleavage of the K-Cl Cotransporter KCC2 Mediated by calcium-activated protease calpain. J Neurosci. 2012;32:11356–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Rivera C, Li H, Thomas-Crusells J, Lahtinen H, Viitanen T, Nanobashvili A, et al. BDNF-induced TrkB activation down-regulates the K+-Cl cotransporter KCC2 and impairs neuronal Cl- extrusion. J Cell Biol. 2002;159:747–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Aguado F. BDNF regulates spontaneous correlated activity at early developmental stages by increasing synaptogenesis and expression of the K+/Cl co-transporter KCC2. Development. 2003;130:1267–80.

    CAS  PubMed  Google Scholar 

  141. 141.

    Shulga A, Thomas-Crusells J, Sigl T, Blaesse A, Mestres P, Meyer M, et al. Posttraumatic GABAA-mediated [Ca2+]i increase is essential for the induction of brain-derived neurotrophic factor-dependent survival of mature central neurons. J Neurosci. 2008;28:6996–7005.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Hübner CA, Stein V, Hermans-Borgmeyer I, Meyer T, Ballanyi K, Jentsch TJ. Disruption of KCC2 reveals an essential role of K-Cl cotransport already in early synaptic inhibition. Neuron. 2001;30:515–24.

    PubMed  Google Scholar 

  143. 143.

    Woo NS, Lu J, England R, McClellan R, Dufour S, Mount DB, et al. Hyperexcitability and epilepsy associated with disruption of the mouse neuronal-specific K-Cl cotransporter gene. Hippocampus. 2002;12:258–68.

    CAS  PubMed  Google Scholar 

  144. 144.

    Tornberg J, Voikar V, Savilahti H, Rauvala H, Airaksinen MS. Behavioural phenotypes of hypomorphic KCC2-deficient mice. Eur J Neurosci. 2005;21:1327–37.

    PubMed  Google Scholar 

  145. 145.

    Pellegrino C, Gubkina O, Schaefer M, Becq H, Ludwig A, Mukhtarov M, et al. Knocking down of the KCC2 in rat hippocampal neurons increases intracellular chloride concentration and compromises neuronal survival. J Physiol. 2011;589:2475–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Sivakumaran S, Cardarelli RA, Maguire J, Kelley MR, Silayeva L, Morrow DH, et al. Selective inhibition of KCC2 leads to hyperexcitability and epileptiform discharges in hippocampal slices and in vivo. J Neurosci. 2015;35:8291–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147.

    Delpire E, Baranczak A, Waterson AG, Kim K, Kett N, Morrison RD, et al. Further optimization of the K-Cl cotransporter KCC2 antagonist ML077: development of a highly selective and more potent in vitro probe. Bioorg Med Chem Lett. 2012;22:4532–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Kimelberg HK. Volume activated anion channel and astrocytic cellular edema in traumatic brain injury and stroke. Adv Exp Med Biol. 2004;559:157–67.

    CAS  PubMed  Google Scholar 

  149. 149.

    Mongin AA. Volume-regulated anion channel—a frenemy within the brain. Pflug Arch. 2016;468:421–41.

    CAS  Google Scholar 

  150. 150.

    Cahalan MD, Lewis RS. Role of potassium and chloride channels in volume regulation by T lymphocytes. Soc Gen Physiol Ser. 1988;43:281–301.

    CAS  PubMed  Google Scholar 

  151. 151.

    Hazama A, Okada Y. Ca2+ sensitivity of volume-regulatory K+ and Cl channels in cultured human epithelial cells. J Physiol. 1988;402:687–702.

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152.

    Qiu Z, Dubin AE, Mathur J, Tu B, Reddy K, Miraglia LJ, et al. SWELL1, a plasma membrane protein, is an essential component of volume-regulated anion channel. Cell. 2014;157:447–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153.

    Voss FK, Ullrich F, Münch J, Lazarow K, Lutter D, Mah N, et al. Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC. Science. 2014;344:634–8.

    CAS  PubMed  Google Scholar 

  154. 154.

    Deneka D, Sawicka M, Lam AKM, Paulino C, Dutzler R. Structure of a volume-regulated anion channel of the LRRC8 family. Nature. 2018;558:254–9.

    CAS  PubMed  Google Scholar 

  155. 155.

    Kern DM, Oh S, Hite RK, Brohawn SG. Cryo-EM structures of the DCPIB- inhibited volume-regulated anion channel LRRC8A in lipid nanodiscs. Elife. 2019;8:e42636.

    PubMed  PubMed Central  Google Scholar 

  156. 156.

    Syeda R, Qiu Z, Dubin AE, Murthy SE, Florendo MN, Mason DE, et al. LRRC8 proteins form volume-regulated anion channels that sense ionic strength. Cell. 2016;164:499–511.

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157.

    Zhang H, Cao HJ, Kimelberg HK, Zhou M. Volume regulated anion channel currents of rat hippocampal neurons and their contribution to oxygen-and-glucose deprivation induced neuronal death. PLoS ONE. 2011;6:e16803.

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 158.

    Yang J, Vitery MDC, Chen J, Osei-Owusu J, Chu J, Qiu Z. Glutamate-releasing SWELL1 channel in astrocytes modulates synaptic transmission and promotes brain damage in stroke. Neuron. 2019;102:813–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159.

    Feustel PJ, Jin Y, Kimelberg HK. Volume-regulated anion channels are the predominant contributors to release of excitatory amino acids in the ischemic cortical penumbra. Stroke. 2004;35:1164–8.

    CAS  PubMed  Google Scholar 

  160. 160.

    Liu HT, Tashmukhamedov BA, Inoue H, Okada Y, Sabirov RZ. Roles of two types of anion channels in glutamate release from mouse astrocytes under ischemic or osmotic stress. Gia. 2006;54:343–57.

    Google Scholar 

  161. 161.

    Mongin AA, Kimelberg HK. ATP potently modulates anion channel-mediated excitatory amino acid release from cultured astrocytes. Am J Physiol Cell Physiol. 2002;283:C569–78.

    CAS  PubMed  Google Scholar 

  162. 162.

    Zhang Y, Zhang H, Feustel PJ, Kimelberg HK. DCPIB, a specific inhibitor of volume regulated anion channels (VRACs), reduces infarct size in MCAo and the release of glutamate in the ischemic cortical penumbra. Exp Neurol. 2008;210:514–20.

    CAS  PubMed  Google Scholar 

  163. 163.

    Bowens NH, Dohare P, Kuo YH, Mongin AA. DCPIB, the proposed selective blocker of volume-regulated anion channels, inhibits several glutamate transport pathways in glial cells. Mol Pharmacol. 2013;83:22–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164.

    Yang YD, Cho H, Koo JY, Tak MH, Cho Y, Shim W-S, et al. TMEM16A confers receptor-activated calcium-dependent chloride conductance. Nature. 2008;455:1210–5.

    CAS  PubMed  Google Scholar 

  165. 165.

    Caputo A, Caci E, Ferrera L, Pedemonte N, Barsanti C, Sondo E, et al. TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity. Science. 2008;322:590–4.

    CAS  PubMed  Google Scholar 

  166. 166.

    Schroeder BC, Cheng T, Jan YN, Jan LY. Expression cloning of TMEM16A as a calcium-activated chloride channel subunit. Cell. 2008;134:1019–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Pifferi S, Cenedese V, Menini A. Anoctamin 2/TMEM16B: a calcium-activated chloride channel in olfactory transduction. Exp Physiol. 2012;97:193–9.

    CAS  PubMed  Google Scholar 

  168. 168.

    Ji Q, Guo S, Wang X, Pang C, Zhan Y, Chen Y, et al. Recent advances in TMEM16A: structure, function, and disease. J Cell Physiol. 2019;234:7856–73.

    CAS  PubMed  Google Scholar 

  169. 169.

    Brunner JD, Lim NK, Schenck S, Duerst A, Dutzler R. X-ray structure of a calcium-activated TMEM16 lipid scramblase. Nature. 2014;516:207–12.

    CAS  PubMed  Google Scholar 

  170. 170.

    Paulino C, Neldner Y, Lam AK, Kalienkova V, Brunner JD, Schenck S, et al. Structural basis for anion conduction in the calcium-activated chloride channel TMEM16A. Elife. 2017;6:e26232.

    PubMed  PubMed Central  Google Scholar 

  171. 171.

    Dang S, Feng S, Tien J, Peters CJ, Bulkley D, Lolicato M, et al. Cryo-EM structures of the TMEM16A calciumactivated chloride channel. Nature. 2017;552:426–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 172.

    Xiao Q, Yu K, Perez-Cornejo P, Cui Y, Arreola J, Hartzell HC. Voltage- and calcium-dependent gating of TMEM16A/Ano1 chloride channels are physically coupled by the first intracellular loop. Proc Natl Acad Sci USA. 2011;108:8891–6.

    CAS  PubMed  Google Scholar 

  173. 173.

    Wu MM, Lou J, Song BL, Gong YF, Li YC, Yu CJ, et al. Hypoxia augments the calcium-activated chloride current carried by anoctamin-1 in cardiac vascular endothelial cells of neonatal mice. Br J Pharmacol. 2014;171:3680–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174.

    Hoffmann EK, Sørensen BH, Sauter DPR, Lambert IH. Role of volume-regulated and calcium-activated anion channels in cell volume homeostasis, cancer and drug resistance. Channels. 2015;9:380–96.

    PubMed  PubMed Central  Google Scholar 

  175. 175.

    Almaça J, Tian Y, Aldehni F, Ousingsawat J, Kongsuphol P, Rock JR, et al. TMEM16 proteins produce volume-regulated chloride currents that are reduced in mice lacking TMEM16A. J Biol Chem. 2009;284:28571–8.

    PubMed  PubMed Central  Google Scholar 

  176. 176.

    Wang H, Zou L, Ma K, Yu J, Wu H, Wei M, et al. Cell-specific mechanisms of TMEM16A Ca2+-activated chloride channel in cancer. Mol Cancer. 2017;16:152.

    PubMed  PubMed Central  Google Scholar 

  177. 177.

    Liu PY, Zhang Z, Liu Y, Tang XL, Shu S, Bao XY, et al. TMEM16A inhibition preserves blood–brain barrier integrity after ischemic stroke. Front Cell Neurosci. 2019;13:360.

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 178.

    Bill A, Hall ML, Borawski J, Hodgson C, Jenkins J, Piechon P, et al. Small molecule-facilitated degradation of ANO1 protein: a new targeting approach for anticancer therapeutics. J Biol Chem. 2014;289:11029–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  179. 179.

    Bodedtkjer DMB, Kim S, Jensen AB, Matchkov VM, Andersson KE. New selective inhibitors of calcium-activated chloride channel- T16inh-A01, CaCCinh-A01 and MONNA- what do they inhibit? Br J Pharmacol. 2015;172:4158–72.

    Google Scholar 

  180. 180.

    Ji B, Zhou F, Han L, Yang J, Fan H, Li S, et al. Sodium tanshinone IIA sulfonate enhances effectiveness Rt-PA treatment in acute ischemic stroke patients associated with ameliorating blood-brain barrier damage. Transl Stroke Res. 2017;8:334–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  181. 181.

    Liu F, Zhang Z, Csanády L, Gadsby DC, Chen J. Molecular structure of the human CFTR ion channel. Cell. 2017;169:85–92.

    CAS  PubMed  Google Scholar 

  182. 182.

    Živković SA, Jumaa M, Barišić N, McCurry K. Neurologic complications following lung transplantation. J Neurol Sci. 2009;280:90–3.

    PubMed  Google Scholar 

  183. 183.

    Goldstein AB, Goldstein LS, Perl MK, Haug MT, Arroliga AC, Stillwell PC. Cystic fibrosis patients with and without central nervous system complications following lung transplantation. Pediatr Pulmonol. 2000;30:203–6.

    CAS  PubMed  Google Scholar 

  184. 184.

    Zhang YP, Zhang Y, Xiao ZB, Zhang YB, Zhang J, Li ZQ, et al. CFTR prevents neuronal apoptosis following cerebral ischemia reperfusion via regulating mitochondrial oxidative stress. J Mol Med. 2018;96:611–20.

    CAS  PubMed  Google Scholar 

  185. 185.

    Solymosi EA, Kaestle-Gembardt SM, Vadász I, Wang L, Neye N, Chupin JCA, et al. Chloride transport-driven alveolar fluid secretion is a major contributor to cardiogenic lung edema. Proc Natl Acad Sci USA. 2013;110:E2308–16.

    CAS  PubMed  Google Scholar 

  186. 186.

    Ajonuma LC, He Q, Chan PKS, Ng EHY, Fok KL, Wong CHY, et al. Involvement of cystic fibrosis transmembrane conductance regulator in infection-induced edema. Cell Biol Int. 2008;32:801–6.

    CAS  PubMed  Google Scholar 

  187. 187.

    Lidington D, Fares JC, Uhl FE, Dinh DD, Kroetsch JT, Sauvé M, et al. CFTR therapeutics normalize cerebral perfusion deficits in mouse models of heart failure and subarachnoid hemorrhage. JACC Basic Transl Sci. 2019;4:940–58.

    PubMed  PubMed Central  Google Scholar 

  188. 188.

    Zegarra-Moran O, Galietta LJV. CFTR pharmacology. Cell Mol Life Sci. 2017;74:117–28.

    CAS  PubMed  Google Scholar 

  189. 189.

    Muanprasat C, Sonawane ND, Salinas D, Taddei A, Galietta LJV, Verkman AS. Discovery of glycine hydrazide pore-occluding CFTR inhibitors: mechanism, structure-activity analysis, and in vivo efficacy. J Gen Physiol. 2004;124:125–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  190. 190.

    Ma T, Thiagarajah JR, Yang H, Sonawane ND, Folli C, Galietta LJV, et al. Thiazolidinone CFTR inhibitor identified by high-throughput screening blocks cholera toxin-induced intestinal fluid secretion. J Clin Invest. 2002;110:1651–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  191. 191.

    Su X, Looney MR, Su HE, Lee JW, Song Y, Matthay MA. Role of CFTR expressed by neutrophils in modulating acute lung inflammation and injury in mice. Inflamm Res. 2011;60:619–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  192. 192.

    Thiagarajah JR, Broadbent T, Hsieh E, Verkman AS. Prevention of toxin-induced intestinal ion and fluid secretion by a small-molecule CFTR Inhibitor. Gastroenterology. 2004;126:511–9.

    CAS  PubMed  Google Scholar 

  193. 193.

    Snyder DS, Tradtrantip L, Yao C, Kurth MJ, Verkman AS. Potent, metabolically stable benzopyrimido-pyrrolo-oxazine-dione (BPO) CFTR inhibitors for polycystic kidney disease. J Med Chem. 2011;54:5468–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  194. 194.

    Friard J, Tauc M, Cougnon M, Compan V, Duranton C, Rubera I. Comparative effects of chloride channel inhibitors on LRRC8/VRAC-mediated chloride conductance. Front Pharmacol. 2017;8:328.

    PubMed  PubMed Central  Google Scholar 

  195. 195.

    Melis N, Tauc M, Cougnon M, Bendahhou S, Giuliano S, Rubera I, et al. Revisiting CFTR inhibition: a comparative study of CFTRinh-172 and GlyH-101 inhibitors. Br J Pharmacol. 2014;171:3716–27.

    CAS  Google Scholar 

  196. 196.

    Poroca DR, Pelis RM, Chappe VM. ClC channels and transporters: structure, physiological functions, and implications in human chloride channelopathies. Front Pharmacol. 2017;8:151.

    PubMed  PubMed Central  Google Scholar 

  197. 197.

    D’Anglemont De Tassigny A, Souktani R, Ghaleh B, Henry P, Berdeaux A. Structure and pharmacology of swelling-sensitive chloride channels, ICl,swell. Fundam Clin Pharmacol. 2003;17:539–53.

    PubMed  Google Scholar 

  198. 198.

    Roman RM, Smith RL, Feranchak AP, Clayton GH, Doctor RB, Fitz JG. ClC-2 chloride channels contribute to HTC cell volume homeostasis. Am J Physiol Gastrointest Liver Physiol. 2001;280:G334–53.

    Google Scholar 

  199. 199.

    Blanz J, Schweizer M, Auberson M, Maier H, Muenscher A, Hübner CA, et al. Leukoencephalopathy upon disruption of the chloride channel ClC-2. J Neurosci. 2007;27:6581–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  200. 200.

    Depienne C, Bugiani M, Dupuits C, Galanaud D, Touitou V, Postma N, et al. Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study. Lancet Neurol. 2013;12:659–68.

    CAS  PubMed  Google Scholar 

  201. 201.

    Duan D, Winter C, Hume JR, Horowitz B. Molecular identification of a volume-regulated chloride channel. Nature. 1997;390:417–21.

    CAS  PubMed  Google Scholar 

  202. 202.

    Zhang YP, Zhang H, Duan DD. Chloride channels in stroke. Acta Pharmacol Sin. 2013;34:17–23.

    PubMed  Google Scholar 

  203. 203.

    Wang L, Chen L, Jacob TJC. The role of ClC-3 in volume-activated chloride currents and volume regulation in bovine epithelial cells demonstrated by antisense inhibition. J Physiol. 2000;524:63–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  204. 204.

    Qian Y, Du YH, Tang YB, Lv XF, Liu J, Zhou JG, et al. ClC-3 chloride channel prevents apoptosis induced by hydrogen peroxide in basilar artery smooth muscle cells through mitochondria dependent pathway. Apoptosis. 2011;16:468–77.

    CAS  PubMed  Google Scholar 

  205. 205.

    Reyes RC, Verkhratsky A, Parpura V. Plasmalemmal Na+/Ca2+ exchanger modulates Ca2+-dependent exocytotic release of glutamate from rat cortical astrocytes. ASN Neuro. 2012;4:e00075.

    PubMed  PubMed Central  Google Scholar 

  206. 206.

    Giladi M, Tal I, Khananshvili D. Structural features of ion transport and allosteric regulation in sodium-calcium exchanger (NCX) proteins. Front Physiol. 2016;7:30.

    PubMed  PubMed Central  Google Scholar 

  207. 207.

    Hilge M, Aelen J, Vuister GW. Ca2+ regulation in the Na+/Ca2+ exchanger involves two markedly different Ca2+ sensors. Mol Cell. 2006;22:15–25.

    CAS  PubMed  Google Scholar 

  208. 208.

    Reeves JP, Hale CC. The stoichiometry of the cardiac sodium-calcium exchange system. J Biol Chem. 1984;259:7733–9.

    CAS  PubMed  Google Scholar 

  209. 209.

    Hilgemann DW, Collins A, Matsuoka S. Steady-state and dynamic properties of cardiac sodium-calcium exchange. Secondary modulation by cytoplasmic calcium and ATP. J Gen Physiol. 1992;100:933–61.

    CAS  PubMed  Google Scholar 

  210. 210.

    Kang TM, Hilgemann DW. Multiple transport modes of the cardiac Na+/Ca2+ exchanger. Nature. 2004;427:544–8.

    CAS  PubMed  Google Scholar 

  211. 211.

    Pignataro G, Tortiglione A, Scorziello A, Giaccio L, Secondo A, Severino B, et al. Evidence for a protective role played by the Na+/Ca2+ exchanger in cerebral ischemia induced by middle cerebral artery occlusion in male rats. Neuropharmacology. 2004;46:439–48.

    CAS  PubMed  Google Scholar 

  212. 212.

    Shenoda B. The role of Na+/Ca2+ exchanger subtypes in neuronal ischemic injury. Transl Stroke Res. 2015;6:181–90.

    CAS  PubMed  Google Scholar 

  213. 213.

    Floyd CL, Gorin FA, Lyeth BG. Mechanical strain injury increases intracellular sodium and reverses Na+/Ca2+ exchange in cortical astrocytes. Glia. 2005;51:35–46.

    PubMed  PubMed Central  Google Scholar 

  214. 214.

    Pignataro G, Gala R, Cuomo O, Tortiglione A, Giaccio L, Castaldo P, et al. Two sodium/calcium exchanger gene products, NCX1 and NCX3, play a major role in the development of permanent focal cerebral ischemia. Stroke. 2004;35:2566–70.

    CAS  PubMed  Google Scholar 

  215. 215.

    Jeon D, Chu K, Jung KH, Kim M, Yoon BW, Lee CJ, et al. Na+/Ca2+ exchanger 2 is neuroprotective by exporting Ca2+ during a transient focal cerebral ischemia in the mouse. Cell Calcium. 2008;43:482–91.

    CAS  PubMed  Google Scholar 

  216. 216.

    Molinaro P, Cuomo O, Pignataro G, Boscia F, Sirabella R, Pannaccione A, et al. Targeted disruption of Na+/Ca2+ exchanger 3 (NCX3) gene leads to a worsening of ischemic brain damage. J Neurosci. 2008;28:1179–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  217. 217.

    Cross JL, Meloni BP, Bakker AJ, Sokolow S, Herchuelz A, Schurmans S, et al. Neuronal injury in NCX3 knockout mice following permanent focal cerebral ischemia and in NCX3 knockout cortical neuronal cultures following oxygen-glucose deprivation and glutamate exposure. J Exp Stroke Transl Med. 2009;2:3–9.

    CAS  Google Scholar 

  218. 218.

    O’Donnell JC, Jackson JG, Robinson MB. Transient oxygen/glucose deprivation causes a delayed loss of mitochondria and increases spontaneous calcium signaling in astrocytic processes. J Neurosci. 2016;36:7109–27.

    PubMed  PubMed Central  Google Scholar 

  219. 219.

    Matsuda T, Arakawa N, Takuma K, Kishida Y, Kawasaki Y, Sakaue M, et al. SEA0400, a novel and selective inhibitor of the Na+/Ca2+ exchanger, attenuates reperfusion injury in the in vitro and in vivo cerebral ischemic models. J Pharmacol Exp Ther. 2001;298:249–56.

    CAS  PubMed  Google Scholar 

  220. 220.

    Arakawa N, Sakaue M, Yokoyama I, Hashimoto H, Koyama Y, Baba A, et al. KB-R7943 inhibits store-operated Ca2+ entry in cultured neurons and astrocytes. Biochem Biophys Res Commun. 2000;279:354–7.

    CAS  PubMed  Google Scholar 

  221. 221.

    Iwamoto T, Kita S, Uehara A, Imanaga I, Matsuda T, Baba A, et al. Molecular determinants of Na+/Ca2+ Exchange (NCX1) inhibition by SEA0400. J Biol Chem. 2004;279:7544–53.

    CAS  PubMed  Google Scholar 

  222. 222.

    Koyama Y, Matsui S, Itoh S, Osakada M, Baba A, Matsuda T. The selective Na+-Ca2+ exchange inhibitor attenuates brain edema after radiofrequency lesion in rats. Eur J Pharmacol. 2004;489:193–6.

    CAS  PubMed  Google Scholar 

  223. 223.

    Molinaro P, Sirabella R, Pignataro G, Petrozziello T, Secondo A, Boscia F, et al. Neuronal NCX1 overexpression induces stroke resistance while knockout induces vulnerability via Akt. J Cereb Blood Flow Metab. 2016;36:1790–803.

    CAS  PubMed  Google Scholar 

  224. 224.

    Molinaro P, Cantile M, Cuomo O, Secondo A, Pannaccione A, Ambrosino P, et al. Neurounina-1, a novel compound that increases Na+/Ca2+ exchanger activity, effectively protects against stroke damage. Mol Pharmacol. 2013;83:142–56.

    CAS  PubMed  Google Scholar 

  225. 225.

    Suzuki A, Stern SA, Bozdagi O, Huntley GW, Walker RH, Magistretti PJ, et al. Astrocyte-neuron lactate transport is required for long-term memory formation. Cell. 2011;144:810–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  226. 226.

    Díaz-García CM, Yellen G. Neurons rely on glucose rather than astrocytic lactate during stimulation. J Neurosci Res. 2019;97:883–9.

    PubMed  Google Scholar 

  227. 227.

    Vannucci SJ, Maher F, Simpson IA. Glucose transporter proteins in brain: delivery of glucose to neurons and glia. Glia. 1997;21:2–21.

    CAS  PubMed  Google Scholar 

  228. 228.

    Deng D, Yan N. GLUT, SGLT, and SWEET: structural and mechanistic investigations of the glucose transporters. Protein Sci. 2016;25:546–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  229. 229.

    Farrell CL, Pardridge WM. Blood-brain barrier glucose transporter is asymmetrically distributed on brain capillary endothelial lumenal and ablumenal membranes: an electron microscopic immunogold study. Proc Natl Acad Sci USA. 1991;88:5779–83.

    CAS  PubMed  Google Scholar 

  230. 230.

    Yu AS, Hirayama BA, Timbol G, Liu J, Basarah E, Kepe V, et al. Functional expression of SGLTs in rat brain. Am J Physiol Cell Physiol. 2010;299:C1277–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  231. 231.

    Vemula S, Roder KE, Yang T, Bhat GJ, Thekkumkara TJ, Abbruscato TJ. A functional role for sodium-dependent glucose transport across the blood-brain barrier during oxygen glucose deprivation. J Pharmacol Exp Ther. 2009;328:487–95.

    CAS  PubMed  Google Scholar 

  232. 232.

    Yu AS, Hirayama BA, Timbol G, Liu J, Diez-Sampedro A, Kepe V, et al. Regional distribution of SGLT activity in rat brain in vivo. Am J Physio Cell Physiol. 2013;304:C240–7.

    CAS  Google Scholar 

  233. 233.

    Sebastiani A, Greve F, Gölz C, Förster CY, Koepsell H, Thal SC. RS1 (Rsc1A1) deficiency limits cerebral SGLT1 expression and delays brain damage after experimental traumatic brain injury. J Neurochem. 2018;147:190–203.

    CAS  PubMed  Google Scholar 

  234. 234.

    Yuan H, Frank JE, Hong Y, An H, Eldeniz C, Nie J, et al. Spatiotemporal uptake characteristics of [18]F-2-fluoro-2-deoxy- d-glucose in a rat middle cerebral artery occlusion model. Stroke. 2013;44:2292–9.

    CAS  PubMed  Google Scholar 

  235. 235.

    Arnberg F, Grafström J, Lundberg J, Nikkhou-Aski S, Little P, Damberg P, et al. Imaging of a clinically relevant stroke model glucose hypermetabolism revisited. Stroke. 2015;46:835–42.

    CAS  PubMed  Google Scholar 

  236. 236.

    Thorén M, Azevedo E, Dawson J, Egido JA, Falcou A, Ford GA, et al. Predictors for cerebral edema in acute ischemic stroke treated with intravenous thrombolysis. Stroke. 2017;48:2464–71.

    PubMed  Google Scholar 

  237. 237.

    Broocks G, Kemmling A, Aberle J, Kniep H, Bechstein M, Flottmann F, et al. Elevated blood glucose is associated with aggravated brain edema in acute stroke. J Neurol. 2020;267:440–8.

    CAS  PubMed  Google Scholar 

  238. 238.

    Oerter S, Förster C, Bohnert M. Validation of sodium/glucose cotransporter proteins in human brain as a potential marker for temporal narrowing of the trauma formation. Int J Leg Med. 2019;133:1107–14.

    Google Scholar 

  239. 239.

    Sherwood TW, Lee KG, Gormley MG, Askwith CC. Heteromeric acid-sensing ion channels (ASICs) composed of ASIC2b and ASIC1a display novel channel properties and contribute to acidosis-induced neuronal death. J Neurosci. 2011;31:9723–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  240. 240.

    Sherwood TW, Frey EN, Askwith CC. Structure and activity of the acid-sensing ion channels. Am J Physiol Cell Physiol. 2012;303:C699–710.

    CAS  PubMed  PubMed Central  Google Scholar 

  241. 241.

    Deval E, Gasull X, Noël J, Salinas M, Baron A, Diochot S, et al. Acid-sensing ion channels (ASICs): pharmacology and implication in pain. Pharmacol Ther. 2010;128:549–58.

    CAS  PubMed  Google Scholar 

  242. 242.

    Yin T, Lindley TE, Albert GW, Ahmed R, Schmeiser PB, Grady MS, et al. Loss of acid sensing ion channel-1a and bicarbonate administration attenuate the severity of traumatic brain injury. PLoS ONE. 2013;8:e72379.

    CAS  PubMed  PubMed Central  Google Scholar 

  243. 243.

    Leng T, Shi Y, Xiong ZG, Sun D. Proton-sensitive cation channels and ion exchangers in ischemic brain injury: new therapeutic targets for stroke? Prog Neurobiol. 2014;115:189–209.

    CAS  PubMed  Google Scholar 

  244. 244.

    Immke DC, McCleskey EW. Lactate enhances the acid-sensing Na+ channel on ischemia-sensing neurons. Nat Neurosci. 2001;4:869–70.

    CAS  Google Scholar 

  245. 245.

    Yermolaieva O, Leonard AS, Schnizler MK, Abboud FM, Welsh MJ. Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel 1a. Proc Natl Acad Sci USA. 2004;101:6752–7.

    CAS  PubMed  Google Scholar 

  246. 246.

    Duan B, Wang YZ, Yang T, Chu XP, Yu Y, Huang Y, et al. Extracellular spermine exacerbates ischemic neuronal injury through sensitization of ASIC1a channels to extracellular acidosis. J Neurosci. 2011;31:2101–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  247. 247.

    McCarthy CA, Rash LD, Chassagnon IR, King GF, Widdop RE. PcTx1 affords neuroprotection in a conscious model of stroke in hypertensive rats via selective inhibition of ASIC1a. Neuropharmacology. 2015;99:650–7.

    CAS  PubMed  Google Scholar 

  248. 248.

    Pignataro G, Simon RP, Xiong ZG. Prolonged activation of ASIC1a and the time window for neuroprotection in cerebral ischaemia. Brain. 2007;130:151–8.

    PubMed  Google Scholar 

  249. 249.

    Zhao X, Gorin FA, Berman RF, Lyeth BG. Differential hippocampal protection when blocking intracellular sodium and calcium entry during traumatic brain injury in rats. J Neurotrauma. 2008;25:1195–205.

    PubMed  PubMed Central  Google Scholar 

  250. 250.

    Kintner DB, Su G, Lenart B, Ballard AJ, Meyer JW, Ng LL, et al. Increased tolerance to oxygen and glucose deprivation in astrocytes from Na+/H+ exchanger isoform 1 null mice. Am J Physiol Cell Physiol. 2004;287:12–21.

    Google Scholar 

  251. 251.

    Luo J, Chen H, Kintner DB, Shull GE, Sun D. Decreased neuronal death in Na+/H+ exchanger isoform 1-null mice after in vitro and in vivo ischemia. J Neurosci. 2005;25:11256–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  252. 252.

    Begum G, Song S, Wang S, Zhao H, Bhuiyan MIH, Li E, et al. Selective knockout of astrocytic Na+/H+ exchanger isoform 1 reduces astrogliosis, BBB damage, infarction, and improves neurological function after ischemic stroke. Glia. 2018;66:126–44.

    PubMed  Google Scholar 

  253. 253.

    O’Donnell ME, Chen YJ, Lam TI, Taylor KC, Walton JH, Anderson SE. Intravenous HOE-642 reduces brain edema and Na uptake in the rat permanent middle cerebral artery occlusion model of stroke: evidence for participation of the blood-brain barrier Na+/H+ exchanger. J Cereb Blood Flow Metab. 2013;33:225–34.

    PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants to ZPF from Canadian Institutes of Health Research (CIHR PJT-153155), HSS from Natural Sciences and Engineering Research Council of Canada (NSERC RGPIN-2016-04574), and BXY from National Natural Science Foundation of China grant 81620108029.

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Correspondence to Zhong-ping Feng or Hong-shuo Sun.

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Luo, Zw., Ovcjak, A., Wong, R. et al. Drug development in targeting ion channels for brain edema. Acta Pharmacol Sin 41, 1272–1288 (2020). https://doi.org/10.1038/s41401-020-00503-5

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Keywords

  • cerebral edema
  • ischemic stroke
  • traumatic brain injury
  • ion channels
  • transporters

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