Astrocytes from Na+-K+-Cl−cotransporter-null mice exhibit absence of swelling and decrease in EAA release

Su, Gui; Kintner, Douglas B.; Flagella, Michael; Shull, Gary E.; Sun, Dandan

doi:10.1152/ajpcell.00538.2001

Cited by 164 publications

(168 citation statements)

References 42 publications

(98 reference statements)

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“…Genetic ablation of NKCC1, as well as its block by bumetanide,17 causes a decrease in intracellular Cl − in hypoxic neurons145 and blocks Na + -and Cl − -mediated cell swelling in astrocytes. 101,142,143 In vivo studies have shown that intracerebral bumetanide administered via a microdialysis probe, either prior to or during ischemia/hypoxia insult caused by temporary MCA occlusion, is neuroprotective, ameliorates brain damage, and reduces brain edema in rat focal ischemia,141,172,173 reinforcing the in vitro data. Focal cerebral ischemia in rats results in elevated NKCC1 protein levels in the ipsilateral cortex and striatum.…”

Section: The Nkcc Channelmentioning

confidence: 82%

Cytotoxic edema: mechanisms of pathological cell swelling

Liang¹,

Bhatta

Gerzanich³

et al. 2007

FOC

321

237

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✓Cerebral edema is caused by a variety of pathological conditions that affect the brain. It is associated with two separate pathophysiological processes with distinct molecular and physiological antecedents: those related to cytotoxic (cellular) edema of neurons and astrocytes, and those related to transcapillary flux of Na+ and other ions, water, and serum macromolecules. In this review, the authors focus exclusively on the first of these two processes. Cytotoxic edema results from unchecked or uncompensated influx of cations, mainly Na+, through cation channels. The authors review the different cation channels that have been implicated in the formation of cytotoxic edema of astrocytes and neurons in different pathological states. A better understanding of these molecular mechanisms holds the promise of improved treatments of cerebral edema and of the secondary injury produced by this pathological process.

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Section: The Nkcc Channelmentioning

confidence: 82%

Cytotoxic edema: mechanisms of pathological cell swelling

Liang¹,

Bhatta

Gerzanich³

et al. 2007

FOC

321

237

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“…In this regards, astrocytic NKCC1 protein could function in clearing off excessive [K þ ] o . 104,105 Indeed, a short interval of anoxia/ischemia raises extracellular [K þ ] to B60 mmol/ L 106 and NKCC1 contributes to K þ influx into the cell. The activity of NKCC1 is involved not only in the control of extracellular K þ but also of extracellular Ca 2 þ ions.…”

Section: Namentioning

confidence: 99%

Ionic Transporter Activity in Astrocytes, Microglia, and Oligodendrocytes During Brain Ischemia

Annunziato

Boscia

Pignataro

2013

J Cereb Blood Flow Metab

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Glial cells constitute a large percentage of cells in the nervous system. During recent years, a large number of studies have critically attributed to glia a new role which no longer reflects the long-held view that glia constitute solely a silent and passive supportive scaffolding for brain cells. Indeed, it has been hypothesized that glia, partnering neurons, have a much more actively participating role in brain function. Alteration of intraglial ionic homeostasis in response to ischemic injury has a crucial role in inducing and maintaining glial responses in the ischemic brain. Therefore, glial transporters as potential candidates in stroke intervention are becoming promising targets to enhance an effective and additional therapy for brain ischemia. In this review, we will describe in detail the role played by ionic transporters in influencing astrocyte, microglia, and oligodendrocyte activity and the implications that these transporters have in the progression of ischemic lesion.

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“…In a rat model of cerebral ischemia, NKCC1 transcripts and protein are significantly upregulated in cortical neurons, as well as in whole brain lysates [54,55]. These changes may occur in ischemic conditions secondary to elevated extracellular potassium and glutamate levels, substances known to stimulate NKCC1 activity in neurons and neuroglia [18,56,57]. Cytokines may also be involved in ischemiainduced upregulation of NKCC1, with interleukin-6 shown to activate NKCC1 in capillaries [58].…”

Section: Nkcc1mentioning

confidence: 99%

Novel Treatment Targets for Cerebral Edema

2012

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Cerebral edema is a common finding in a variety of neurological conditions, including ischemic stroke, traumatic brain injury, ruptured cerebral aneurysm, and neoplasia. With the possible exception of neoplasia, most pathological processes leading to edema seem to share similar molecular mechanisms of edema formation. Challenges to brain-cell volume homeostasis can have dramatic consequences, given the fixed volume of the rigid skull and the effect of swelling on secondary neuronal injury. With even small changes in cellular and extracellular volume, cerebral edema can compromise regional or global cerebral blood flow and metabolism or result in compression of vital brain structures. Osmotherapy has been the mainstay of pharmacologic therapy and is typically administered as part of an escalating medical treatment algorithm that can include corticosteroids, diuretics, and pharmacological cerebral metabolic suppression. Novel treatment targets for cerebral edema include the Na(+)-K(+)-2Cl(−) co-transporter (NKCC1) and the SUR1-regulated NC Ca-ATP (SUR1/TRPM4) channel. These two ion channels have been demonstrated to be critical mediators of edema formation in brain-injured states. Their specific inhibitors, bumetanide and glibenclamide, respectively, are well-characterized Food and Drug Administration-approved drugs with excellent safety profiles. Directed inhibition of these ion transporters has the potential to reduce the development of cerebral edema and is currently being investigated in human clinical trials. Another class of treatment agents for cerebral edema is vasopressin receptor antagonists. Euvolemic hyponatremia is present in a myriad of neurological conditions resulting in cerebral edema. A specific antagonist of the vasopressin V1A-and V2-receptor, conivaptan, promotes water excretion while sparing electrolytes through a process known as aquaresis.Keywords Cerebral edema . Hyponatraemia . Osmotherapy . NKCC1 . SUR1/TRPM4 . Vaptan . Glyburide Overview of Perturbations in Brain Fluid HomeostasisCerebral edema in the neurointensive care setting can occur with a heterogenous group of neurological diseases, which typically fall under the categories of metabolic [1, 2], infectious [3], neoplastic [4], cerebrovascular [5][6][7], and traumatic [8,9] brain injury. Irrespective of the inciting process, cerebral edema results in the pathological accumulation of fluid in the brain's intracellular and extracellular spaces. This occurs secondary to alterations in the complex interplay between 4 distinct fluid compartments within the cranium; fluid is present within: 1) the blood in the cerebral blood vessels, 2) the cerebrospinal fluid in the ventricular system and subarachnoid space, 3) the interstitial fluid of the brain parenchyma, and 4) the intracellular fluid of the neurons and glia. These fluid compartments are not isolated, and specific movements of solutes and water from one compartment to another occur under normal conditions. When dysregulation of this normally tightly controlled fluid balance...

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Astrocytes from Na⁺-K⁺-Cl⁻cotransporter-null mice exhibit absence of swelling and decrease in EAA release

Cited by 164 publications

References 42 publications

Cytotoxic edema: mechanisms of pathological cell swelling

Cytotoxic edema: mechanisms of pathological cell swelling

Ionic Transporter Activity in Astrocytes, Microglia, and Oligodendrocytes During Brain Ischemia

Novel Treatment Targets for Cerebral Edema

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