A Khanna

AW Phillips

Dandan Sun

FE Boada

H Koj

Kristopher T. Kahle

RF Keep

RP Ostrowski

English

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EDITORIALDysregulation of Diverse Ion Transport Pathways ControllingCell Volume Homoestasis Contribute to Neuroglial Cell InjuryFollowing Ischemic StrokeDandan Sun & Kristopher T. KahleReceived: 5 January 2014 /Accepted: 5 January 2014 /Published online: 27 January 2014# The Author(s) 2014. This article is published with open access at Springerlink.comThis special featured issue of Translational Stroke Researchgives readers a timely update on the emerging roles of gluta-mate receptor-independent ion channels and transporters inischemic brain injury. This issue has collected contributionsfrom the leading research laboratories with expertise on themost important ion transport targets. For example, Khannaet al. [1] provide an overview on the significance of dysreg-ulated ion homeostasis in the neurogliovascular unit in thepathogenesis of ischemic cerebral edema, focusing on the roleof the sulfonylurea receptor 1-transient receptor potentialmelastatin 4 (SUR1-TRPM4) channel complex which is up-regulated in the context of hypoxia and promotes capillaryfragmentation and oncotic cell death in the vascular endothe-lium, thereby increasing vascular permeability and vasogenicedema. Song et al. write an elegant review on the distinctchanges of cell volume homeostasis in necrotic, apoptotic, andhybrid cell death that accompany ischemic stroke, along withthe N-methyl-D-aspartate-independent ion transporters andchannels that mediate apoptotic volume decrease or cytotoxiccell swelling [2]. Norenberg et al. [3] report novel mechanismsunderlying astrocyte swelling and brain edema mediated bySUR1-TRPM4 activation in acute liver failure, extendingoriginal findings by the Simard group in ischemic disease toother types of brain swelling.The second half of the issue include comprehensive dis-cussions of voltage-gated K+ channels [4] and the acid-sensing ion channel 1a ASIC1a [5, 6] in ischemic neurotox-icity, and voltage-gated H+ channel Hv1 in microglial activa-tion [7], following stroke. Uria-Avellanal et al. [8] presentcompelling clinical and experimental research data on over-stimulation of Na+/H+ exchangers and alkaline pHi in perina-tal brain injury. Pignataro et al. discuss a strategy of targetingincreased Ca2+ efflux mediated by Na+/Ca2+ exchanger instroke intervention [9]. Chen et al. review the significance ofion channels in regulation of neuronal progenitor function inischemic brains, which holds the potential for tissue regener-ation—an emerging area in the field of neuroprotection [10].In summary, these timely papers illustrate exciting newfindings in the area of glutamate receptor-independent mech-anisms of ischemic ionic injury in the nervous system, andreveal the critical role of dysregulated ion transport, mediatedby diverse ion transport proteins, in the neurogliovascularunit. These reports show that ischemia-induced ion channel/transporter dysfunction affects multiple critical cell processes,including cell volume regulation [11], intracellular ionic ho-meostasis [12], neuroinflammation [13, 14], andneuroregeneration/tissue repair [15, 16]. An increased under-standing of the role these transport proteins play in normalbiology, along with further knowledge of how these proteinsare regulated by post-translational modification and signaltransduction, might reveal novel methods by which thesetransport systems may be modulated for therapeutic benefit.Perhaps nowhere closer is the reality of clinical translationof basic findings more apparent than in the story of the SUR1-regulated TRPM4 ion channel, and its role in the pathogenesisof cerebral edema and hemorrhagic transformation followingischemic stroke (see review by Khanna et al., in this issue).Glibenclamide, an FDA-approved drug commonly used inpatients with type 2 diabetes, inhibits SUR1-TRPM4, andseveral robust preclinical studies have demonstrated theD. Sun (*)Department of Neurology, University of Pittsburgh School ofMedicine, Pittsburgh, PA 15217, USAe-mail: sund@upmc.eduK. T. KahleDepartment of Neurosurgery, Massachusetts General Hospital andHarvard Medical, Boston, MA 02115, USAK. T. KahleManton Center for Orphan Disease Research, Children’s HospitalBoston, Boston, MA 02115, USATransl. Stroke Res. (2014) 5:1–2DOI 10.1007/s12975-014-0324-3efficacy of glibenclamide in reducing edema and hemorrhagicconversion in rodent models of ischemic stroke. This has inturn prompted the study of the potential protective effects ofglibenclamide in humans in an ongoing prospective phase IIclinical trial, and preliminary data from this effort suggestsglibenclamide also significantly reduces ischemic cerebraledema and hemorrhagic conversion [17]. Many other targetslisted above are promising candidates at the cusp of humantranslational studies. We are excited to present this timelyresource to the readers of Translational Stroke Research.Conflict of Interest The authors declare no conflict of interest.Open Access This article is distributed under the terms of the CreativeCommons Attribution License which permits any use, distribution, andreproduction in any medium, provided the original author(s) and thesource are credited.References1. Brian P Walcott MD. Disruption of ion homeostasis in theneurogliovascular unit underlies the pathogenesis of ischemiccerebral edema-TRSR329R. doi:10.1007/s12975-013-0307-92. Shan Ping Yu MD PhD. Ionic regulation of cell volume changes andthe phenotype of cell death after ischemic stroke-TRSR355R1.doi:10.1007/s12975-013-0314-x3. Michael Norenberg. Sulfonylurea receptor 1 contributes to the astro-cyte swelling and brain edema in acute liver failure-TRSR346.doi:10.1007/s12975-014-0328-z4. Niyathi Hegde Shah. Voltage-gated potassium channels at the cross-roads of neuronal funct ion, ischemic tolerance, andneurodegeneration-TRSR334R1. doi:10.1007/s12975-013-0297-75. Zhi-Gang Xiong. Translational strategies for neuroprotection inischemic stroke—focusing on acid sensing ion channel1a-TRSR344R1. doi:10.1007/s12975-013-0319-56. Xiang-Ping Chu. Acid-sensing ion channels contribute toneurotoxicity-TRSR336R. doi:10.1007/s12975-013-0305-y7. Nicola J Robertson MB ChB, PhD. Na+/H + exchangers and pHi inperinatal brain injury: a review-TRSR368. doi:10.1007/s12975-013-0322-x8. Long-Jun Wu. Microglial voltage-gated proton channel Hv1 inischemic stroke-TRSR323R1. doi:10.1007/s12975-013-0289-79. Lucio Annunziato MD. Does Na+/Ca2+ exchanger, NCX, representa new druggable target in stroke intervention?-TRSR363R. doi:10.1007/s12975-013-0308-810. ShanPing Yu. Ion channels in regulation of neuronal regenerativeactivities-TRSR364R1. doi:10.1007/s12975-013-0320-z11. Keep RF et al. Brain water content. Transl Stroke Res. 2012;3:263–5.12. Boada FE, Qian Y, Nemoto E, Jovin T, Jungreis C, Jones SC, et al.SodiumMRI and the assessment of irreversible tissue damage duringhyper-acute stroke. Transl Stroke Res. 2012;3(2):236–45.13. Ostrowski RP, Schulte RW, Nie Y, Ling T, Lee T, Manaenko A, et al.Acute splenic irradiation reduces brain injury in the rat focal ischemicstroke model. Transl Stroke Res. 2012;3(4):473–81.14. Koj H. Inflammation and cerebral aneurysms. Transl Stroke Res.2013;34:2980–4.15. Phillips AW, Johnston MV, Fatermi A. The potential for cell basedtherapy in perinatal brain injury. Transl Stroke Res. 2013;4(2):137–48.16. Jieli Chen MD, Michael Chopp. Angiogenesis and arteriogenesis asstroke targets Transl. Stroke Res. (2012). pp 231–249 Chapter 11.17. Khanna A, Walcott BP, Kahle KT, Simard JM. Effect ofglibenclamide on the prevention of secondary brain injury followingischemic stroke in humans. Neurosurg Focus. 2014;36(1):E11.2 Transl. Stroke Res. (2014) 5:1–2

Translational Stroke Research

Dysregulation of Diverse Ion Transport Pathways Controlling Cell Volume Homoestasis Contribute to Neuroglial Cell Injury Following Ischemic Stroke

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Dysregulation of Diverse Ion Transport Pathways Controlling Cell Volume Homoestasis Contribute to Neuroglial Cell Injury Following Ischemic Stroke

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